Smedley, I. & Lubrzynska, E. The biochemical synthesis of the fatty acids. Biochem. J. 7, 364–374 (1913). Show
Article CAS PubMed PubMed Central Google Scholar Lai, H. T. M. et al. Serial plasma phospholipid fatty acids in the de novo lipogenesis pathway and total mortality, cause-specific mortality, and cardiovascular diseases in the cardiovascular health study. J. Am. Heart Assoc. 8, e012881 (2019). The first prospective study in adults to investigate the associations of DNL-related fatty acid biomarkers with mortality and incident CVD. Article PubMed PubMed Central Google Scholar Ference, B. A. et al. Mendelian randomization study of ACLY and cardiovascular disease. N. Engl. J. Med. 380, 1033–1042 (2019). Demonstrates that genetic variants that mimic ACLY inhibitors and statins lower plasma LDL in humans by the same mechanism of action. Article CAS PubMed Google Scholar Lawitz, E. J. et al. Acetyl-CoA carboxylase inhibitor GS-0976 for 12 weeks reduces hepatic de novo lipogenesis and steatosis in patients with nonalcoholic steatohepatitis. Clin. Gastroenterol. Hepatol. 16, 1983–1991.e3 (2018). Article CAS PubMed Google Scholar Smith, G. I. et al. Insulin resistance drives hepatic de novo lipogenesis in nonalcoholic fatty liver disease. J. Clin. Invest. 130, 1453–1460 (2020). Article CAS PubMed PubMed Central Google Scholar Imamura, F. et al. Fatty acids in the de novo lipogenesis pathway and incidence of type 2 diabetes: a pooled analysis of prospective cohort studies. PLoS Med. 17, e1003102 (2020). Article CAS PubMed PubMed Central Google Scholar Wen, J. et al. ACLY facilitates colon cancer cell metastasis by CTNNB1. J. Exp. Clin. Cancer Res. 38, 401 (2019). Article PubMed PubMed Central Google Scholar Chen, Y. et al. mTOR complex-2 stimulates acetyl-CoA and de novo lipogenesis through ATP citrate lyase in HER2/PIK3CA-hyperactive breast cancer. Oncotarget 7, 25224–25240 (2016). Article PubMed PubMed Central Google Scholar Munger, J. et al. Systems-level metabolic flux profiling identifies fatty acid synthesis as a target for antiviral therapy. Nat. Biotechnol. 26, 1179–1186 (2008). Article CAS PubMed PubMed Central Google Scholar Du, Y. et al. mRNA display with library of even-distribution reveals cellular interactors of influenza virus NS1. Nat. Commun. 11, 2449 (2020). Article CAS PubMed PubMed Central Google Scholar Yang, Z., Matteson, E. L., Goronzy, J. J. & Weyand, C. M. T-cell metabolism in autoimmune disease. Arthritis Res. Ther. 17, 29 (2015). Article PubMed PubMed Central Google Scholar Endo, Y. et al. Obesity drives Th27 cell differentiation by inducing the lipid metabolic kinase, ACC1. Cell Rep. 12, 1042–1055 (2015). Article CAS PubMed Google Scholar Carvajal-Gonzalez, S. et al. Human sebum requires de novo lipogenesis, which is increased in acne vulgaris and suppressed by acetyl-CoA carboxylase inhibition. Sci. Transl. Med. 11, eaau8465 (2019). Article PubMed Google Scholar Knobloch, M. et al. Metabolic control of adult neural stem cell activity by Fasn-dependent lipogenesis. Nature 493, 226–230 (2013). Article CAS PubMed Google Scholar Isaev, N. K., Stelmashook, E. V. & Genrikhs, E. E. Neurogenesis and brain aging. Rev. Neurosci. 30, 573–580 (2019). Article PubMed Google Scholar Markham, A. Bempedoic acid: first approval. Drugs 80, 747–753 (2020). Article PubMed Google Scholar Catlin, N. R. et al. Inhibition of ACC causes malformations in rats and rabbits: comparison of mammalian findings and alternative assays. Toxicol. Sci. 28, 183–194 (2020). Google Scholar Kelly, K. L. et al. De novo lipogenesis is essential for platelet production in humans. Nat. Metab. 2, 1163–1178 (2020). Article CAS PubMed Google Scholar Das, S. et al. ATP citrate lyase improves mitochondrial function in skeletal muscle. Cell Metab. 21, 868–876 (2015). Article CAS PubMed Google Scholar Zhao, S. et al. ATP-citrate lyase controls a glucose-to-acetate metabolic switch. Cell Rep. 17, 1037–1052 (2016). First study to describe the generation of Acly-floxed mice and ACLY-null mouse embryonic fibroblasts. Using these models of ACLY deficiency, the authors show that this leads to upregulation of ACSS2 and scavenging of acetate to maintain acetyl-CoA. Article CAS PubMed PubMed Central Google Scholar Huang, Z. et al. ACSS2 promotes systemic fat storage and utilization through selective regulation of genes involved in lipid metabolism. Proc. Natl Acad. Sci. USA 115, E9499–E9506 (2018). Article CAS PubMed PubMed Central Google Scholar Liu, X. et al. Acetate production from glucose and coupling to mitochondrial metabolism in mammals. Cell 175, 502–513.e13 (2018). Article CAS PubMed PubMed Central Google Scholar Metallo, C. M. et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481, 380–384 (2011). Article PubMed PubMed Central Google Scholar Jiang, L. et al. Quantitative metabolic flux analysis reveals an unconventional pathway of fatty acid synthesis in cancer cells deficient for the mitochondrial citrate transport protein. Metab. Eng. 43, 198–207 (2017). Article CAS PubMed Google Scholar Filipp, F. V., Scott, D. A., Ronai, Z. A., Osterman, A. L. & Smith, J. W. Reverse TCA cycle flux through isocitrate dehydrogenases 1 and 2 is required for lipogenesis in hypoxic melanoma cells. Pigment. Cell Melanoma Res. 25, 375–383 (2012). Article CAS PubMed PubMed Central Google Scholar Bideyan, L., Nagari, R. & Tontonoz, P. Hepatic transcriptional responses to fasting and feeding. Genes Dev. 35, 635–657 (2021). Article CAS PubMed PubMed Central Google Scholar Galsgaard, K. D., Pedersen, J., Knop, F. K., Holst, J. J. & Wewer Albrechtsen, N. J. Glucagon receptor signaling and lipid metabolism. Front. Physiol. 10, 413 (2019). Article PubMed PubMed Central Google Scholar Ferguson, D. & Finck, B. N. Emerging therapeutic approaches for the treatment of NAFLD and type 2 diabetes mellitus. Nat. Rev. Endocrinol. 17, 484–495 (2021). Article PubMed PubMed Central Google Scholar Viscarra, J. & Sul, H. S. Epigenetic regulation of hepatic lipogenesis: role in hepatosteatosis and diabetes. Diabetes 69, 525–531 (2020). Article CAS PubMed PubMed Central Google Scholar Solinas, G., Borén, J. & Dulloo, A. G. De novo lipogenesis in metabolic homeostasis: more friend than foe? Mol. Metab. 4, 367–377 (2015). Article CAS PubMed PubMed Central Google Scholar Yoon, H., Shaw, J. L., Haigis, M. C. & Greka, A. Lipid metabolism in sickness and in health: emerging regulators of lipotoxicity. Mol. Cell 81, 3708–3730 (2021). Article CAS PubMed Google Scholar Chakravarthy, M. V. et al. Brain fatty acid synthase activates PPARalpha to maintain energy homeostasis. J. Clin. Invest. 117, 2539–2552 (2007). Article CAS PubMed PubMed Central Google Scholar Santos, G. A. et al. Hypothalamic inhibition of acetyl-CoA carboxylase stimulates hepatic counter-regulatory response independent of AMPK activation in rats. PLoS ONE 8, e62669 (2013). Article CAS PubMed PubMed Central Google Scholar Wolfgang, M. J. & Lane, M. D. The role of hypothalamic malonyl-CoA in energy homeostasis. J. Biol. Chem. 281, 37265–37269 (2006). Article CAS PubMed Google Scholar Galic, S. et al. AMPK signaling to acetyl-CoA carboxylase is required for fasting- and cold-induced appetite but not thermogenesis. eLife 7, e32656 (2018). Article PubMed PubMed Central Google Scholar Virtanen, K. A. et al. Functional brown adipose tissue in healthy adults. N. Engl. J. Med. 360, 1518–1525 (2009). Article CAS PubMed Google Scholar Adlanmerini, M. et al. Circadian lipid synthesis in brown fat maintains murine body temperature during chronic cold. Proc. Natl Acad. Sci. USA 116, 18691–18699 (2019). Article CAS PubMed PubMed Central Google Scholar Blondin, D. P. et al. Inhibition of intracellular triglyceride lipolysis suppresses cold-induced brown adipose tissue metabolism and increases shivering in humans. Cell Metab. 25, 438–447 (2017). Article CAS PubMed Google Scholar Sanchez-Gurmaches, J. et al. Brown fat AKT2 is a cold-induced kinase that stimulates ChREBP-mediated de novo lipogenesis to optimize fuel storage and thermogenesis. Cell Metab. 27, 195–209.e6 (2018). Article CAS PubMed Google Scholar Lodhi, I. J. et al. Inhibiting adipose tissue lipogenesis reprograms thermogenesis and PPARγ activation to decrease diet-induced obesity. Cell Metab. 16, 189–201 (2012). Article CAS PubMed PubMed Central Google Scholar Yuan, F. et al. Activation of GCN2/ATF4 signals in amygdalar PKC-δ neurons promotes WAT browning under leucine deprivation. Nat. Commun. 11, 2847 (2020). Article CAS PubMed PubMed Central Google Scholar Higuchi, N. et al. Liver X receptor in cooperation with SREBP-1c is a major lipid synthesis regulator in nonalcoholic fatty liver disease. Hepatol. Res. 38, 1122–1129 (2008). Article CAS PubMed Google Scholar Tan, M. et al. Inhibition of the mitochondrial citrate carrier, Slc25a1, reverts steatosis, glucose intolerance, and inflammation in preclinical models of NAFLD/NASH. Cell Death Differ. 27, 2143–2157 (2020). First paper showing genetic inhibition of CIC (also known as SLC25A1) in the liver and that pharmacological inhibition of CIC using CTPI-2 reduces hepatic steatosis and glucose intolerance. Article CAS PubMed PubMed Central Google Scholar Wang, Q. et al. Abrogation of hepatic ATP-citrate lyase protects against fatty liver and ameliorates hyperglycemia in leptin receptor-deficient mice. Hepatology 49, 1166–1175 (2009). Article CAS PubMed Google Scholar Zhao, S. et al. Dietary fructose feeds hepatic lipogenesis via microbiota-derived acetate. Nature 579, 586–591 (2020). Article CAS PubMed PubMed Central Google Scholar Mao, J. Liver-specific deletion of acetyl-CoA carboxylase 1 reduces hepatic triglyceride accumulation without affecting glucose homeostasis. Proc. Natl Acad. Sci. USA 103, 8552–8557 (2006). Article CAS PubMed PubMed Central Google Scholar Savage, D. B. et al. Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2. J. Clin. Invest. 116, 817–824 (2006). First study showing that genetic inhibition of both ACC1 and ACC2 in the liver reduces hepatic steatosis and improves insulin sensitivity. Article CAS PubMed PubMed Central Google Scholar Kim, C. W. et al. Acetyl CoA carboxylase inhibition reduces hepatic steatosis but elevates plasma triglycerides in mice and humans: a bedside to bench investigation. Cell Metab. 26, 394–406 (2017). Demonstrates that ACC inhibitors reduce hepatic steatosis but also increase plasma triglycerides in humans. Subsequent studies in ACC hepatocyte-specific null mice show that this is an ‘on-target’ effect associated with activation of SREBP1c and increases in GPAT, which can be inhibited with fish oil. Article CAS PubMed PubMed Central Google Scholar Fullerton, M. D. et al. Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Nat. Med. 19, 1649–1654 (2013). Demonstrates additivity between ACC1 and ACC2 in the liver towards regulating liver DNL and fatty acid oxidation and that AMPK phosphorylation and inhibition of ACC1 and ACC2 reduces liver steatosis, fibrosis and insulin resistance. Article CAS PubMed PubMed Central Google Scholar Chow, J. D. et al. Genetic inhibition of hepatic acetyl-CoA carboxylase activity increases liver fat and alters global protein acetylation. Mol. Metab. 3, 419–431 (2014). Article CAS PubMed PubMed Central Google Scholar Chakravarthy, M. V. et al. “New” hepatic fat activates PPARalpha to maintain glucose, lipid, and cholesterol homeostasis. Cell Metab. 1, 309–322 (2005). Article CAS PubMed Google Scholar Roumans, K. H. M. et al. Hepatic saturated fatty acid fraction is associated with de novo lipogenesis and hepatic insulin resistance. Nat. Commun. 11, 1891 (2020). Article CAS PubMed PubMed Central Google Scholar Takagi, H. et al. ACC2 deletion enhances IMCL reduction along with acetyl-CoA metabolism and improves insulin sensitivity in male mice. Endocrinology 159, 3007–3019 (2018). Article CAS PubMed Google Scholar O’Neill, H. M. et al. AMPK phosphorylation of ACC2 is required for skeletal muscle fatty acid oxidation and insulin sensitivity in mice. Diabetologia 57, 1693–1702 (2014). Article PubMed Google Scholar Vijayakumar, A. et al. Absence of carbohydrate response element binding protein in adipocytes causes systemic insulin resistance and impairs glucose transport. Cell Rep. 21, 1021–1035 (2017). Article CAS PubMed PubMed Central Google Scholar Yore, M. M. et al. Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects. Cell 159, 318–332 (2014). Article CAS PubMed PubMed Central Google Scholar Milstein, S. W. & Hausberger, F. X. Lipogenesis and carbohydrate utilization; effects of glucose concentration and insulin in rat liver and adipose tissue. Diabetes 5, 89–92 (1956). Article CAS PubMed Google Scholar Richardson, D. K. & Czech, M. P. Primary role of decreased fatty acid synthesis in insulin resistance of large rat adipocytes. Am. J. Physiol. 234, E182–E189 (1978). CAS PubMed Google Scholar Roberts, R. et al. Markers of de novo lipogenesis in adipose tissue: associations with small adipocytes and insulin sensitivity in humans. Diabetologia 52, 882–890 (2009). Article CAS PubMed Google Scholar Virtanen, K. A. et al. Glucose uptake and perfusion in subcutaneous and visceral adipose tissue during insulin stimulation in nonobese and obese humans. J. Clin. Endocrinol. Metab. 87, 3902–3910 (2002). Article CAS PubMed Google Scholar Czech, M. P. Mechanisms of insulin resistance related to white, beige, and brown adipocytes. Mol. Metab. 34, 27–42 (2020). Article CAS PubMed PubMed Central Google Scholar Herman, M. A. et al. A novel ChREBP isoform in adipose tissue regulates systemic glucose metabolism. Nature 484, 333–338 (2012). Article CAS PubMed PubMed Central Google Scholar Fernandez, S. et al. Adipocyte ACLY facilitates dietary carbohydrate handling to maintain metabolic homeostasis in females. Cell Rep. 27, 2772–2784.e6 (2019). Article CAS PubMed PubMed Central Google Scholar Mao, J. et al. aP2-Cre-mediated inactivation of acetyl-CoA carboxylase 1 causes growth retardation and reduced lipid accumulation in adipose tissues. Proc. Natl Acad. Sci. USA 106, 17576–17581 (2009). Article CAS PubMed PubMed Central Google Scholar Brun, T. et al. Evidence for an anaplerotic/malonyl-CoA pathway in pancreatic beta-cell nutrient signaling. Diabetes 45, 190–198 (1996). Article CAS PubMed Google Scholar Cantley, J. et al. Disruption of beta cell acetyl-CoA carboxylase-1 in mice impairs insulin secretion and beta cell mass. Diabetologia 62, 99–111 (2019). Article CAS PubMed Google Scholar Roduit, R. et al. A role for the malonyl-CoA/long-chain acyl-CoA pathway of lipid signaling in the regulation of insulin secretion in response to both fuel and nonfuel stimuli. Diabetes 53, 1007–1019 (2004). Article CAS PubMed Google Scholar Kasper, P. et al. NAFLD and cardiovascular diseases: a clinical review. Clin. Res. Cardiol. 110, 921–937 (2021). Article PubMed Google Scholar Hannou, S. A., Haslam, D. E., McKeown, N. M. & Herman, M. A. Fructose metabolism and metabolic disease. J. Clin. Invest. 128, 545–555 (2018). Article PubMed PubMed Central Google Scholar Lee, Y. et al. Serial biomarkers of de novo lipogenesis fatty acids and incident heart failure in older adults: the cardiovascular health study. J. Am. Heart Assoc. 9, e014119 (2020). Article CAS PubMed PubMed Central Google Scholar Bouchard-Mercier, A., Rudkowska, I., Lemieux, S., Couture, P. & Vohl, M. C. Polymorphisms, de novo lipogenesis, and plasma triglyceride response following fish oil supplementation. J. Lipid Res. 54, 2866–2873 (2013). Article CAS PubMed PubMed Central Google Scholar Calle, R. A. et al. ACC inhibitor alone or co-administered with a DGAT2 inhibitor in patients with non-aclhoholic fatty liver disease: two parallel, placebo-controlled, randomized phase 2a trial. Nat. Med. 27, 1836–1848 (2021). First study in humans showing that ACC inhibition lowers HBA1c and that hypertriglyceridaemia can be avoided by co-administration with a DGAT2 inhibitor. Article CAS PubMed Google Scholar Morieri, M. L. PPARA polymorphism influences the cardiovascular benefit of fenofibrate in type 2 diabetes: findings from ACCORD-lipid. Diabetes 69, 771–783 (2020). Article CAS PubMed PubMed Central Google Scholar Baardman, J. et al. Macrophage ATP citrate lyase deficiency stabilizes atherosclerotic plaques. Nat. Commun. 11, 6296 (2020). Article CAS PubMed PubMed Central Google Scholar De Silva, G. S. et al. Circulating serum fatty acid synthase is elevated in patients with diabetes and carotid artery stenosis and is LDL-associated. Atherosclerosis 287, 38–45 (2019). Article PubMed PubMed Central Google Scholar Schneider, J. G. et al. Macrophage fatty-acid synthase deficiency decreases diet-induced atherosclerosis. J. Biol. Chem. 285, 23398–23409 (2010). Article CAS PubMed PubMed Central Google Scholar Sabine, J. R., Abraham, S. & Chaikoff, I. L. Control of lipid metabolism in hepatomas: insensitivity of rate of fatty acid and cholesterol synthesis by mouse hepatoma BW7756 to fasting and to feedback control. Cancer Res. 27, 793–799 (1967). CAS PubMed Google Scholar Freed-Pastor, W. A. et al. Mutant p53 disrupts mammary tissue architecture via the mevalonate pathway. Cell 148, 244–258 (2012). Article CAS PubMed PubMed Central Google Scholar Van de Sande, T., De Schrijver, E., Heyns, W., Verhoeven, G. & Swinnen, J. V. Role of the phosphatidylinositol 3’-kinase/PTEN/Akt kinase pathway in the overexpression of fatty acid synthase in LNCaP prostate cancer cells. Cancer Res. 62, 642–646 (2002). PubMed Google Scholar Swinnen, J. V. et al. Stimulation of tumor-associated fatty acid synthase expression by growth factor activation of the sterol regulatory element-binding protein pathway. Oncogene 19, 5173–5181 (2000). Article CAS PubMed Google Scholar Kumar-Sinha, C., Ignatoski, K. W., Lippman, M. E., Ethier, S. P. & Chinnaiyan, A. M. Transcriptome analysis of HER2 reveals a molecular connection to fatty acid synthesis. Cancer Res. 63, 132–139 (2003). CAS PubMed Google Scholar Chang, Y., Wang, J., Lu, X., Thewke, D. P. & Mason, R. J. KGF induces lipogenic genes through a PI3K and JNK/SREBP-1 pathway in H292 cells. J. Lipid Res. 46, 2624–2635 (2005). Article CAS PubMed Google Scholar Yang, Y. A., Han, W. F., Morin, P. J., Chrest, F. J. & Pizer, E. S. Activation of fatty acid synthesis during neoplastic transformation: role of mitogen-activated protein kinase and phosphatidylinositol 3-kinase. Exp. Cell Res. 279, 80–90 (2002). Article CAS PubMed Google Scholar Hawley, S. A. et al. Phosphorylation by Akt within the ST loop of AMPK-α1 down-regulates its activation in tumour cells. Biochem. J. 459, 275–287 (1998). Article Google Scholar Shackelford, D. B. & Shaw, R. J. The LKB1–AMPK pathway: metabolism and growth control in tumour suppression. Nat. Rev. Cancer 9, 563–575 (2009). Article CAS PubMed PubMed Central Google Scholar Hatzivassiliou, G. et al. ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell 8, 311–321 (2005). First paper showing that genetic or pharmacological inhibition of ACLY with SB-204990 reduces cancer cell proliferation in vitro and in mouse xenografts. Article CAS PubMed Google Scholar Gu, L. et al. The IKKβ-USP30-ACLY axis controls lipogenesis and tumorigenesis. Hepatology 73, 160–174 (2021). Article CAS PubMed Google Scholar Chajes, V., Cambot, M., Moreau, K., Lenoir, G. M. & Joulin, V. Acetyl-CoA carboxylase alpha is essential to breast cancer cell survival. Cancer Res. 66, 5287–5294 (2006). Article CAS PubMed Google Scholar Notarnicola, M. et al. Fatty acid synthase hyperactivation in human colorectal cancer: relationship with tumor side and sex. Oncology 71, 327–332 (2006). Article CAS PubMed Google Scholar De Piano, M. et al. Lipogenic signalling modulates prostate cancer cell adhesion and migration via modification of Rho GTPases. Oncogene 39, 3666–3679 (2020). Article PubMed PubMed Central Google Scholar Icard, P. et al. ATP citrate lyase: a central metabolic enzyme in cancer. Cancer Lett. 471, 125–134 (2020). Article CAS PubMed Google Scholar Fhu, C. W. & Ali, A. Fatty acid synthase: an emerging target in cancer. Molecules 25, 3935 (2020). Article CAS PubMed Central Google Scholar Rae, C., Haberkorn, U., Babich, J. W. & Mairs, R. J. Inhibition of fatty acid synthase sensitizes prostate cancer cells to radiotherapy. Radiat. Res. 184, 482–493 (2015). Article CAS PubMed Google Scholar Shah, S. et al. Targeting ACLY sensitizes castration-resistant prostate cancer cells to AR antagonism by impinging on an ACLY-AMPK-AR feedback mechanism. Oncotarget 7, 43713–43730 (2016). Article PubMed PubMed Central Google Scholar Zheng, Y. et al. ATP citrate lyase inhibitor triggers endoplasmic reticulum stress to induce hepatocellular carcinoma cell apoptosis via p-eIF2α/ATF4/CHOP axis. J. Cell Mol. Med. 25, 1468–1479 (2021). Article CAS PubMed PubMed Central Google Scholar Qian, X., Hu, J., Zhao, J. & Chen, H. ATP citrate lyase expression is associated with advanced stage and prognosis in gastric adenocarcinoma. Int. J. Clin. Exp. Med. 8, 7855–7860 (2015). PubMed PubMed Central Google Scholar Pearce, E. L., Poffenberger, M. C., Chang, C. H. & Jones, R. G. Fueling immunity: insights into metabolism and lymphocyte function. Science 342, 1242454 (2013). Article PubMed PubMed Central Google Scholar Berod, L. et al. De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat. Med. 20, 1327–1333 (2014). Article CAS PubMed Google Scholar Kidani, Y. et al. Sterol regulatory element-binding proteins are essential for the metabolic programming of effector T cells and adaptive immunity. Nat. Immunol. 14, 489–499 (2013). Article CAS PubMed PubMed Central Google Scholar Batista-Gonzalez, A., Vidal, R., Criollo, A. & Carreño, L. J. New insights on the role of lipid metabolism in the metabolic reprogramming of macrophages. Front. Immunol. 10, 2993 (2020). Article PubMed PubMed Central Google Scholar Lefere, S. & Tacke, F. Macrophages in obesity and non-alcoholic fatty liver disease: crosstalk with metabolism. JHEP Rep. 1, 30–43 (2019). Article PubMed PubMed Central Google Scholar Lauterbach, M. A. et al. Toll-like receptor signaling rewires macrophage metabolism and promotes histone acetylation via ATP-citrate lyase. Immunity 51, 997–1011.e7 (2019). Article CAS PubMed Google Scholar Covarrubias, A. J. et al. Akt-mTORC1 signaling regulates Acly to integrate metabolic input to control of macrophage activation. eLife 5, e11612 (2016). Article PubMed PubMed Central Google Scholar Osinalde, N. et al. Nuclear phosphoproteomic screen uncovers ACLY as mediator of IL-2-induced proliferation of CD4+T lymphocytes. Mol. Cell Proteom. 15, 2076–2092 (2016). Article CAS Google Scholar Mamareli, P. et al. Targeting cellular fatty acid synthesis limits T helper and innate lymphoid cell function during intestinal inflammation and infection. Mucosal Immunol. 14, 164–176 (2020). Article PubMed Google Scholar Lee, J. et al. Regulator of fatty acid metabolism, acetyl coenzyme a carboxylase 1, controls T cell immunity. J. Immunol. 192, 3190–3199 (2014). Article CAS PubMed Google Scholar Yuan, S. et al. SREBP-dependent lipidomic reprogramming as a broad-spectrum antiviral target. Nat. Commun. 10, 120 (2019). Article PubMed PubMed Central Google Scholar van Praag, H. et al. Functional neurogenesis in the adult hippocampus. Nature 415, 1030–1034 (2002). Article PubMed Google Scholar Dimas, P. et al. CNS myelination and remyelination depend on fatty acid synthesis by oligodendrocytes. eLife 8, e44702 (2019). Article CAS PubMed PubMed Central Google Scholar Grassi, D. et al. Identification of a highly neurotoxic α-synuclein species inducing mitochondrial damage and mitophagy in Parkinson’s disease. Proc. Natl Acad. Sci. USA 115, E2634–E2643 (2018). Article CAS PubMed PubMed Central Google Scholar Roncal, J. et al. Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer’s disease. Nat. Med. 25, 554–560 (2019). Article Google Scholar Najmabadi, H. et al. Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature 478, 57–63 (2011). Article CAS PubMed Google Scholar Bowers, M. et al. FASN-dependent lipid metabolism links neurogenic stem/progenitor cell activity to learning and memory deficits. Cell Stem Cell 27, 98–109.e11 (2020). Article CAS PubMed Google Scholar Ziegler, A. B. et al. Cell-autonomous control of neuronal dendrite expansion via the fatty acid synthesis regulator SREBP. Cell Rep. 21, 3346–3353 (2017). Article CAS PubMed Google Scholar Harayama, T. & Riezman, H. Understanding the diversity of membrane lipid composition. Nat. Rev. Mol. Cell Biol. 19, 281–296 (2018). Article CAS PubMed Google Scholar Montani, L. et al. De novo fatty acid synthesis by Schwann cells is essential for peripheral nervous system myelination. J. Cell Biol. 217, 1353–1368 (2018). Article CAS PubMed PubMed Central Google Scholar Klingenberg, M. Kinetic study of the tricarboxylate carrier in rat liver mitochondria. Eur. J. Biochem. 26, 587–594 (1972). Article CAS PubMed Google Scholar Halperin, M. L., Robinson, B. H. & Fritz, I. B. Effects of palmitoyl CoA on citrate and malate transport by rat liver mitochondria. Proc. Natl Acad. Sci. USA 69, 1003–1007 (1972). Article CAS PubMed PubMed Central Google Scholar Palmieri, E. M. et al. Acetylation of human mitochondrial citrate carrier modulates mitochondrial citrate/malate exchange activity to sustain NADPH production during macrophage activation. Biochim. Biophys. Acta 1847, 729–738 (2015). Article CAS PubMed Google Scholar Ma, C. et al. Identification of the substrate binding sites within the yeast mitochondrial citrate transport protein. J. Biol. Chem. 282, 17210–17220 (2007). Provides the first function-based identification of calcium binding sites within CIC that are crucial for the binding mechanism of CIC inhibitors. Article CAS PubMed Google Scholar Aluvila, S. et al. The yeast mitochondrial citrate transport protein: molecular determinants of its substrate specificity. J. Biol. Chem. 285, 27314–27326 (2010). Article CAS PubMed PubMed Central Google Scholar Aluvila, S., Sun, J., Harrison, D. H., Walters, D. E. & Kaplan, R. S. Inhibitors of the mitochondrial citrate transport protein: validation of the role of substrate binding residues and discovery of the first purely competitive inhibitor. Mol. Pharmacol. 77, 26–34 (2010). Article CAS PubMed PubMed Central Google Scholar Fernandez, H. R. et al. The mitochondrial citrate carrier, SLC25A1, drives stemness and therapy resistance in non-small cell lung cancer. Cell Death Differ. 25, 1239–1258 (2018). Article CAS PubMed PubMed Central Google Scholar Wei, X., Scultz, K., Bazilevsky, G. A., Vogt, A. & Marmorstein, R. Molecular basis for acetyl-CoA production by ATP-citrate lyase. Nat. Struct. Mol. Biol. 27, 33–41 (2020). Article CAS PubMed Google Scholar Martin, D. B. & Vagelos, P. R. The mechanism of tricarboxylic acid cycle regulation of fatty acid synthesis. J. Biol. Chem. 237, 1787–1792 (1962). Article CAS PubMed Google Scholar Sun, Q. et al. Regulation on citrate influx and metabolism through inhibiting SLC13A5 and ACLY: a novel mechanism mediating the therapeutic effects of curcumin on NAFLD. J. Agric. Food Chem. 69, 8714–8725 (2021). Article CAS PubMed Google Scholar Joseph, J. W. et al. The mitochondrial citrate/isocitrate carrier plays a regulatory role in glucose-stimulated insulin secretion. J. Biol. Chem. 281, 35624–35632 (2006). Article CAS PubMed Google Scholar Infantino, V., Iacobazzi, V., Menga, A., Avantaggiati, M. L. & Palmieri, F. A key role of the mitochondrial citrate carrier (SLC25A1) in TNFα- and IFNγ-triggered inflammation. Biochim. Biophys. Acta 1839, 1217–1225 (2014). Article CAS PubMed PubMed Central Google Scholar Assmann, N. et al. SREBP-controlled glucose metabolism is essential for NK cell functional responses. Nat. Immunol. 18, 1197–1206 (2017). Article CAS PubMed Google Scholar Mosaoa, R., Kasprzyk-Pawelec, A., Fernandez, H. R. & Avantaggiati, M. L. The mitochondrial citrate carrier SLC25A1/CIC and the fundamental role of citrate in cancer, inflammation and beyond. Biomolecules 11, 141 (2021). Article CAS PubMed PubMed Central Google Scholar Jiang, L. et al. Reductive carboxylation supports redox homeostasis during anchorage-independent growth. Nature 532, 255–258 (2016). Article CAS PubMed PubMed Central Google Scholar Catalina-Rodriguez, O. et al. The mitochondrial citrate transporter, CIC, is essential for mitochondrial homeostasis. Oncotarget 3, 1220–1235 (2012). Article PubMed PubMed Central Google Scholar Poolsri, W. A. et al. Combination of mitochondrial and plasma membrane citrate transporter inhibitors inhibits de novo lipogenesis pathway and triggers apoptosis in hepatocellular carcinoma cells. Biomed. Res. Int. 2018, 3683026 (2018). Article PubMed PubMed Central Google Scholar Potapova, I. A., El-Maghrabi, M. R., Doronin, S. V. & Benjamin, W. B. Phosphorylation of recombinant human ATP:citrate lyase by cAMP-dependent protein kinase abolishes homotropic allosteric regulation of the enzyme by citrate and increases the enzyme activity. Allosteric activation of ATP:citrate lyase by phosphorylated sugars. Biochemistry 39, 1169–1179 (2000). Article CAS PubMed Google Scholar Alexander, M. C., Kowaloff, E. M., Witters, L. A., Dennihy, D. T. & Avruch, J. Purification of a hepatic 123,000-dalton hormone-stimulated 32P-peptide and its identification as ATP-citrate lyase. J. Biol. Chem. 254, 8052–8056 (1979). First identification that a peptide phosphorylated by insulin and glucagon in the liver is the citrate cleavage enzyme ACLY and is the same peptide also found in white adipocytes. Article CAS PubMed Google Scholar Pierce, M. W., Palmer, J. L., Keutmann, H. T. & Avruch, J. ATP-citrate lyase. Structure of a tryptic peptide containing the phosphorylation site directed by glucagon and the cAMP-dependent protein kinase. J. Biol. Chem. 256, 8867–8870 (1981). Article CAS PubMed Google Scholar Ramakrishna, S., D’Angelo, G. & Benjamin, W. B. Sequence of sites on ATP-citrate lyase and phosphatase inhibitor 2 phosphorylated by multifunctional protein kinase (a glycogen synthase kinase 3 like kinase). Biochemistry 29, 7617–7624 (1990). Article CAS PubMed Google Scholar Pierce, M. W., Palmer, J. L., Keutmann, H. T., Hall, T. A. & Avruch, J. The insulin-directed phosphorylation site on ATP-citrate lyase is identical with the site phosphorylated by the cAMP-dependent protein kinase in vitro. J. Biol. Chem. 257, 10681–10686 (1982). Article CAS PubMed Google Scholar Berwick, D. C., Hers, I., Heesom, K. J., Moule, S. K. & Tavare, J. M. The identification of ATP-citrate lyase as a protein kinase B (Akt) substrate in primary adipocytes. J. Biol. Chem. 277, 33895–33900 (2002). Article CAS PubMed Google Scholar Martinez Calejman, C. et al. mTORC2-AKT signaling to ATP-citrate lyase drives brown adipogenesis and de novo lipogenesis. Nat. Commun. 11, 575 (2020). Article CAS PubMed PubMed Central Google Scholar White, P. J. et al. The BCKDH kinase and phosphatase integrate BCAA and lipid metabolism via regulation of ATP-citrate lyase. Cell Metab. 27, 1281–1293.e7 (2018). Article CAS PubMed PubMed Central Google Scholar Williams, S. P., Sykes, B. D. & Bridger, W. A. Phosphorus-31 nuclear magnetic resonance study of the active site phosphohistidine and regulatory phosphoserine residues of rat liver ATP-citrate lyase. Biochemistry 24, 5527–5531 (1985). Article CAS PubMed Google Scholar Fan, F. et al. On the catalytic mechanism of human ATP citrate lyase. Biochemistry 51, 5198–5211 (2012). Article CAS PubMed Google Scholar Kumari, R., Deshmukh, R. S. & Das, S. Caspase-10 inhibits ATP-citrate lyase-mediated metabolic and epigenetic reprogramming to suppress tumorigenesis. Nat. Commun. 10, 4255 (2019). Article PubMed PubMed Central Google Scholar Verschueren, K. H. G. et al. Structure of ATP citrate lyase and the origin of citrate synthase in the Krebs cycle. Nature 568, 571–575 (2019). Reports high-resolution crystal structures of human ACLY and provides insight into the conformational plasticity of ACLY that is important for regulating catalytic activity. Article CAS PubMed Google Scholar Fatland, B. L. et al. Molecular characterization of a heteromeric ATP-citrate lyase that generates cytosolic acetyl-coenzyme A in Arabidopsis. Plant Physiol. 130, 740–756 (2002). Article PubMed PubMed Central Google Scholar Watson, J. A., Fang, M. & Lowenstein, J. M. Tricarballylate and hydroxycitrate: substrate and inhibitor of ATP: citrate oxaloacetate lyase. Arch. Biochem. Biophys. 35, 209–217 (1969). Article Google Scholar Watson, J. A. & Lowenstein, J. M. Citrate and the conversion of carbohydrate into fat. J. Biol. Chem. 245, 5993–6002 (1970). Article CAS PubMed Google Scholar Triscari, J. & Sullivan, A. C. Comparative effects of (−)-hydroxycitrate and (+)-allo-hydroxycitrate on acetyl CoA carboxylase and fatty acid and cholesterol synthesis in vivo. Lipids 12, 357–363 (1977). Article CAS PubMed Google Scholar Dolle, R. E. et al. Synthesis of novel thiol-containing citric acid analogues. Kinetic evaluation of these and other potential active-site-directed and mechanism-based inhibitors of ATP citrate lyase. J. Med. Chem. 38, 537–543 (1995). Article CAS PubMed Google Scholar Chan, G. W. et al. Purpurone, an inhibitor of ATP-citrate lyase: a novel alkaloid from the marine sponge Iotrochota sp. J. Org. Chem. 58, 2544–2546 (1993). Article CAS Google Scholar Oleynek, J. J. et al. Anthrones, naturally occurring competitive inhibitors of adenosine-triphosphate-citrate lyase. Drug Dev. Res. 36, 35–42 (1995). Article CAS Google Scholar Ki, S. W. et al. Radicicol binds and inhibits mammalian ATP citrate lyase. J. Biol. Chem. 275, 39231–39236 (2000). Article CAS PubMed Google Scholar Gao, Y., Islam, M. S., Tian, J., Lui, V. W. & Xiao, D. Inactivation of ATP citrate lyase by cucurbitacin B: a bioactive compound from cucumber inhibits prostate cancer growth. Cancer Lett. 349, 15–25 (2014). Article CAS PubMed Google Scholar Koerner, S. K. Design and synthesis of emodin derivatives as novel inhibitors of ATP-citrate lyase. Eur. J. Med. Chem. 126, 920–928 (2017). Article CAS PubMed Google Scholar Kim, Y. J., Lee, S. A., Myung, S. C., Kim, W. & Lee, C. S. Radicicol, an inhibitor of Hsp90, enhances TRAIL-induced apoptosis in human epithelial ovarian carcinoma cells by promoting activation of apoptosis-related proteins. Mol. Cell Biochem. 359, 33–43 (2012). Article CAS PubMed Google Scholar Gribble, A. D. et al. ATP-citrate lyase as a target for hypolipidemic intervention. Design and synthesis of 2-substituted butanedioic acids as novel, potent inhibitors of the enzyme. J. Med. Chem. 39, 3569–3584 (1996). Article CAS PubMed Google Scholar Pearce, N. J. et al. The role of ATP citrate-lyase in the metabolic regulation of plasma lipids. Hypolipidaemic effects of SB-204990, a lactone prodrug of the potent ATP citrate-lyase inhibitor SB-201076. Biochem. J. 334, 113–119 (1998). Article CAS PubMed PubMed Central Google Scholar Jernigan, F. E., Hanai, J. I., Sukhatme, V. P. & Sun, L. Discovery of furan carboxylate derivatives as novel inhibitors of ATP-citrate lyase via virtual high-throughput screening. Bioorg. Med. Chem. Lett. 27, 929–935 (2017). Article CAS PubMed Google Scholar Li, J. J. et al. 2-Hydroxy-N-arylbenzenesulfonamides as ATP-citrate lyase inhibitors. Bioorg. Med. Chem. Lett. 17, 3208–3211 (2007). Article CAS PubMed Google Scholar Wei, J. et al. An allosteric mechanism for potent inhibition of human ATP-citrate lyase. Nature 568, 566–570 (2019). This study demonstrates that NDI-091143 binds next to the ACLY citrate binding site resulting in an extensive conformational change that prevents citrate binding and allosteric activation. Article CAS PubMed Google Scholar Bar-Tana, J., Rose-Kahn, G. & Srebnik, M. Inhibition of lipid synthesis by beta beta’-tetramethyl-substituted, C14-C22, alpha, omega-dicarboxylic acids in the rat in vivo. J. Biol. Chem. 260, 8404–8410 (1985). First study showing that the dicarboxylic acid MEDICA 16 inhibits both cholesterol and fatty acid synthesis. Article CAS PubMed Google Scholar Rose-Kahn, G. & Bar-Tana, J. Inhibition of lipid synthesis by beta beta’-tetramethyl-substituted, C14-C22, alpha, omega-dicarboxylic acids in cultured rat hepatocytes. J. Biol. Chem. 260, 8411–8415 (1985). Article CAS PubMed Google Scholar Atkinson, L. L., Kelly, S. E., Russell, J. C., Bar-Tana, J. & Lopaschuk, G. D. MEDICA 16 inhibits hepatic acetyl-CoA carboxylase and reduces plasma triacylglycerol levels in insulin-resistant JCR: LA-cp rats. Diabetes 51, 1548–1555 (2002). Article CAS PubMed Google Scholar Shurbaji, A. et al. Effect of 3-thiadicarboxylic acid on lipid metabolism in experimental nephrosis. Arterioscler. Thromb. 13, 1580–1586 (1993). Article Google Scholar Cramer, C. T. et al. Effects of a novel dual lipid synthesis inhibitor and its potential utility in treating dyslipidemia and metabolic syndrome. J. Lipid Res. 45, 1289–1301 (2004). Article CAS PubMed Google Scholar Pinkosky, S. L. et al. Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis. Nat. Commun. 7, 13457 (2016). Demonstrates that conversion of bempedoic acid into bempedoyl-CoA by a long-chain acyl-CoA synthetase (ACSVL1) expressed in the liver is necessary for suppressing ACLY activity, LDL-cholesterol and atherosclerosis in mice. Article CAS PubMed PubMed Central Google Scholar Sullivan, C. & Triscari, J. Metabolic regulation as a control for lipid disorders. I. Influence of (−)-hydroxycitrate on experimentally induced obesity in the rodent. Am. J. Clin. Nutr. 30, 767–776 (1977). Article CAS PubMed Google Scholar Asghar, M. et al. Super CitriMax (HCA-SX) attenuates increases in oxidative stress, inflammation, insulin resistance, and body weight in developing obese Zucker rats. Mol. Cell Biochem. 304, 93–99 (2007). Article CAS PubMed Google Scholar Preuss, H. G. et al. Effects of a natural extract of (−)-hydroxycitric acid (HCA-SX) and a combination of HCA-SX plus niacin-bound chromium and Gymnema sylvestre extract on weight loss. Diabetes Obes. Metab. 6, 171–180 (2004). Article CAS PubMed Google Scholar Heymsfield, S. B. et al. Garcinia cambogia (hydroxycitric acid) as a potential antiobesity agent: a randomized controlled trial. JAMA 280, 1596–1600 (1998). Article CAS PubMed Google Scholar Pinkosky, S. L. et al. AMP-activated protein kinase and ATP-citrate lyase are two distinct molecular targets for ETC-1002, a novel small molecule regulator of lipid and carbohydrate metabolism. J. Lipid Res. 54, 134–151 (2013). Article CAS PubMed PubMed Central Google Scholar Banach, M. et al. Association of bempedoic acid administration with atherogenic lipid levels in phase 3 randomized clinical trials of patients with hypercholesterolemia. JAMA Cardiol. 5, 1–12 (2020). Article PubMed Central Google Scholar Mayorek, N., Kalderon, B., Itach, E. & Bar-Tana, J. Sensitization to insulin induced by beta,beta′-methyl-substituted hexadecanedioic acid (MEDICA 16) in obese Zucker rats in vivo. Diabetes 46, 1958–1964 (1997). Article CAS PubMed Google Scholar Russell, J. C. et al. Development of insulin resistance in the JCR:LA-cp rat: role of triacylglycerols and effects of MEDICA 16. Diabetes 47, 770–778 (1998). Article CAS PubMed Google Scholar Masson, W., Lobo, M., Lavalle-Cobo, A., Masson, G. & Molinero, G. Effect of bempedoic acid on new onset or worsening diabetes: a meta-analysis. Diabetes Res. Clin. Pract. 168, 108369 (2020). Article CAS PubMed Google Scholar Russell, J. C. et al. Hypolipidemic effect of beta, beta′-tetramethyl hexadecanedioic acid (MEDICA 16) in hyperlipidemic JCR:LA-corpulent rats. Arterioscler. Thromb. 11, 602–609 (1991). Article CAS PubMed Google Scholar Russell, J. C. et al. Inhibition of atherosclerosis and myocardial lesions in the JCR:LA-cp rat by beta, beta′-tetramethylhexadecanedioic acid (MEDICA 16). Arterioscler. Thromb. Vasc. Biol. 15, 918–923 (1995). Article CAS PubMed Google Scholar Burke, A. C. et al. Bempedoic acid lowers low-density lipoprotein cholesterol and attenuates atherosclerosis in low-density lipoprotein receptor-deficient (LDLR+/− and LDLR−/−) Yucatan miniature pigs. Arterioscler. Thromb. Vasc. Biol. 38, 1178–1190 (2018). Article CAS PubMed Google Scholar Pinkosky, S. L., Groot, P. H. E., Lalwani, N. D. & Steinberg, G. R. Targeting ATP-citrate lyase in hyperlipidemia and metabolic disorders. Trends Mol. Med. 23, 1047–1063 (2017). Article CAS PubMed Google Scholar Ray, K. K. et al. Safety and efficacy of bempedoic acid to reduce LDL cholesterol. N. Engl. J. Med. 380, 1022–1032 (2019). Article CAS PubMed Google Scholar Laufs, U. et al. Efficacy and safety of bempedoic acid in patients with hypercholesterolemia and statin intolerance. J. Am. Heart Assoc. 8, e011662 (2019). Together with Ray et al. (2019), provides evidence that bempedoic acid safely lowers LDL-cholesterol in patients on maximally tolerated statin therapy or intolerant to statins. Article PubMed PubMed Central Google Scholar Abolhassani, M. et al. Screening of well-established drugs targeting cancer metabolism: reproducibility of the efficacy of a highly effective drug combination in mice. Invest. N. Drugs 30, 1331–1342 (2012). Article CAS Google Scholar Tong, L. Acetyl-coenzyme A carboxylase: crucial metabolic enzyme and attractive target for drug discovery. Cell Mol. Life Sci. 62, 1784–1803 (2005). Article CAS PubMed Google Scholar Halestrap, A. P. & Denton, R. M. Hormonal regulation of adipose-tissue acetyl-Coenzyme A carboxylase by changes in the polymeric state of the enzyme. The role of long-chain fatty acyl-coenzyme A thioesters and citrate. Biochem. J. 142, 365–377 (1974). Article CAS PubMed PubMed Central Google Scholar Carlson, C. A. & Kim, K. H. Regulation of hepatic acetyl coenzyme A carboxylase by phosphorylation and dephosphorylation. J. Biol. Chem. 248, 378–380 (1973). First study demonstrating that phosphorylation of ACC inhibits enzyme activity and could override allosteric activation by citrate. Article CAS PubMed Google Scholar Lent, B. A., Lee, K. H. & Kim, K. H. Regulation of rat liver acetyl-CoA carboxylase. Stimulation of phosphorylation and subsequent inactivation of liver acetyl-CoA carboxylase by cyclic 3′:5′-monophosphate and effect on the structure of the enzyme. J. Biol. Chem. 253, 8149–8156 (1978). Article CAS PubMed Google Scholar Munday, M. R., Campbell, D. G., Carling, D. & Hardie, D. G. Identification by amino acid sequencing of three major regulatory phosphorylation sites on rat acetyl-CoA carboxylase. Eur. J. Biochem. 175, 331–338 (1988). Article CAS PubMed Google Scholar Lally, J. S. V. et al. Inhibition of acetyl-coa carboxylase by phosphorylation or the inhibitor ND-654 suppresses lipogenesis and hepatocellular carcinoma. Cell Metab. 29, 174–182.e5 (2019). Article CAS PubMed Google Scholar Pinkosky, S. L. et al. Long-chain fatty acyl-CoA esters regulate metabolism via allosteric control of AMPK β1 isoforms. Nat. Metab. 2, 873–881 (2020). Demonstrates that fatty acyl-CoAs allosterically activate AMPK and that subsequent phosphorylation of ACC is required to increase fatty acid oxidation in mice. Article CAS PubMed PubMed Central Google Scholar Wei, J. & Tong, L. Crystal structure of the 500-kDa yeast acetyl-CoA carboxylase holoenzyme dimer. Nature 526, 723–727 (2015). Article CAS PubMed PubMed Central Google Scholar Zhang, H., Yang, Z., Shen, Y. & Tong, L. Crystal structure of the carboxyltransferase domain of acetyl-coenzyme A carboxylase. Science 299, 2064–2067 (2003). Article CAS PubMed Google Scholar Hunkele, M. et al. Structural basis for regulation of human acetyl-CoA carboxylase. Nature 558, 470–474 (2018). Reports novel insights detailing dynamic interactions that occur in human ACC upon exposure to allosteric regulators such as citrate and palmityol-CoA. Article Google Scholar Wei, J. et al. A unified molecular mechanism for the regulation of acetyl-CoA carboxylase by phosphorylation. Cell Discov. 2, 16044 (2016). Article CAS PubMed PubMed Central Google Scholar Vahlensieck, H. F., Pridzun, L., Reichenbach, H. & Hinnen, A. Identification of the yeast ACC1 gene product (acetyl-CoA carboxylase) as the target of the polyketide fungicide soraphen A. Curr. Genet. 25, 95–100 (1994). Article CAS PubMed Google Scholar Shen, Y., Volrath, S. L., Weatherly, S. C., Elich, T. D. & Tong, L. A mechanism for the potent inhibition of eukaryotic acetyl-coenzyme A carboxylase by soraphen A, a macrocyclic polyketide natural product. Mol. Cell 16, 881–891 (2004). Article CAS PubMed Google Scholar Bianchi, A., Evans, J. L., Nordlund, A. C., Watts, T. D. & Witters, L. A. Acetyl-CoA carboxylase in Reuber hepatoma cells: variation in enzyme activity, insulin regulation, and cellular lipid content. J. Cell Biochem. 48, 86–97 (1992). Article CAS PubMed Google Scholar Harwood, H. J. Jr et al. Isozyme-nonselective N-substituted bipiperidylcarboxamide acetyl-CoA carboxylase inhibitors reduce tissue malonyl-CoA concentrations, inhibit fatty acid synthesis, and increase fatty acid oxidation in cultured cells and in experimental animals. J. Biol. Chem. 278, 37099–37111 (2003). First study describing the discovery of a synthetic isozyme-nonselective ACC inhibitor, CP-610431, and its analogue CP-640186, by high-throughput inhibition screening and that this compound reduced fatty acid synthesis and increased fatty acid oxidation. Article CAS PubMed Google Scholar Zhang, H., Tweel, B., Li, J. & Tong, L. Crystal structure of the carboxyltransferase domain of acetyl-coenzyme A carboxylase in complex with CP-640186. Structure 12, 1683–1691 (2004). Article CAS PubMed Google Scholar Chonan, T. et al. (4-Piperidinyl)-piperazine: a new platform for acetyl-CoA carboxylase inhibitors. Bioorg. Med. Chem. Lett. 19, 6645–6648 (2009). Article CAS PubMed Google Scholar Yamashita, T. et al. Design, synthesis, and structure-activity relationships of spirolactones bearing 2-ureidobenzothiophene as acetyl-CoA carboxylases inhibitors. Bioorg. Med. Chem. Lett. 21, 6314–6318 (2011). Article CAS PubMed Google Scholar Kamata, M. et al. Design, synthesis, and structure-activity relationships of novel spiro-piperidines as acetyl-CoA carboxylase inhibitors. Bioorg. Med. Chem. Lett. 22, 3643–3647 (2012). Article CAS PubMed Google Scholar Kamata, M. et al. Symmetrical approach of spiro-pyrazolidinediones as acetyl-CoA carboxylase inhibitors. Bioorg. Med. Chem. Lett. 22, 4769–4772 (2012). Article CAS PubMed Google Scholar Gao, Y. S. et al. WZ66, a novel acetyl-CoA carboxylase inhibitor, alleviates nonalcoholic steatohepatitis (NASH) in mice. Acta Pharmacol. Sin. 41, 336–347 (2020). Article CAS PubMed Google Scholar Bergman, A. et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of a liver-targeting acetyl-CoA carboxylase inhibitor (PF-05221304): a three-part randomized phase 1 study. Clin. Pharmacol. Drug Dev. 9, 514–526 (2020). Article CAS PubMed PubMed Central Google Scholar Harriman, G. et al. Acetyl-CoA carboxylase inhibition by ND-630 reduces hepatic steatosis, improves insulin sensitivity, and modulates dyslipidemia in rats. Proc. Natl Acad. Sci. USA 113, E1796–E1805 (2016). Describes the development of a new ACC inhibitor (GS-0976 (Firsocostat)) that inhibits dimerization by binding to and mimicking the AMPK phosphorylation site. This compound inhibited DNL, increased fatty acid oxidation and improved insulin sensitivity in rodents. In subsequent studies, related molecules were shown to reduce non-small-cell lung cancer (Svensson et al. (2006)) and hepatocellular carcinoma (Lally et al. (2019)). Article CAS PubMed PubMed Central Google Scholar Svensson, R. U. et al. Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models. Nat. Med. 22, 1108–1119 (2016). Article CAS PubMed PubMed Central Google Scholar Mizojiri, R. et al. Discovery of novel selective acetyl-CoA carboxylase (ACC) 1 inhibitors. J. Med. Chem. 61, 1098–1117 (2018). Article CAS PubMed Google Scholar Mizojiri, R. et al. Design and synthesis of a novel 1H-pyrrolo[3,2-b]pyridine-3-carboxamide derivative as an orally available ACC1 inhibitor. Bioorg. Med. Chem. 27, 2521–2530 (2019). Article CAS PubMed Google Scholar Gu, Y. G. et al. Synthesis and structure-activity relationships of N-{3-[2-(4-alkoxyphenoxy)thiazol-5-yl]-1- methylprop-2-ynyl}carboxy derivatives as selective acetyl-CoA carboxylase 2 inhibitors. J. Med. Chem. 49, 3770–3773 (2006). Article CAS PubMed Google Scholar Gu, Y. G. et al. N-{3-[2-(4-alkoxyphenoxy)thiazol-5-yl]-1-methylprop-2-ynyl}carboxy derivatives as acetyl-coA carboxylase inhibitors–improvement of cardiovascular and neurological liabilities via structural modifications. J. Med. Chem. 50, 1078–1082 (2007). Article CAS PubMed Google Scholar Glund, S. et al. Inhibition of acetyl-CoA carboxylase 2 enhances skeletal muscle fatty acid oxidation and improves whole-body glucose homeostasis in db/db mice. Diabetologia 55, 2044–2053 (2012). Article CAS PubMed Google Scholar Nishiura, Y. et al. Discovery of a novel olefin derivative as a highly potent and selective acetyl-CoA carboxylase 2 inhibitor with in vivo efficacy. Bioorg. Med. Chem. Lett. 28, 2498–2503 (2018). Article CAS PubMed Google Scholar Schreurs, M. et al. Soraphen, an inhibitor of the acetyl-CoA carboxylase system, improves peripheral insulin sensitivity in mice fed a high-fat diet. Diabetes Obes. Metab. 11, 987–991 (2009). Article CAS PubMed Google Scholar Ronnebaum, S. M. et al. Chronic suppression of acetyl-CoA carboxylase 1 in beta-cells impairs insulin secretion via inhibition of glucose rather than lipid metabolism. J. Biol. Chem. 283, 14248–14256 (2008). Article CAS PubMed PubMed Central Google Scholar Liu, T., Gou, L., Yan, S. & Huang, T. Inhibition of acetyl-CoA carboxylase by PP-7a exerts beneficial effects on metabolic dysregulation in a mouse model of diet-induced obesity. Exp. Ther. Med. 20, 521–529 (2020). Article PubMed PubMed Central Google Scholar Griffith, D. A. et al. Decreasing the rate of metabolic ketone reduction in the discovery of a clinical acetyl-CoA carboxylase inhibitor for the treatment of diabetes. J. Med. Chem. 57, 10512–10526 (2014). Article CAS PubMed PubMed Central Google Scholar Ross, T. T. et al. Acetyl-CoA carboxylase inhibition improves multiple dimensions of NASH pathogenesis in model systems. Cell Mol. Gastroenterol. Hepatol. 10, 829–851 (2020). Article PubMed PubMed Central Google Scholar Huard, K. et al. Optimizing the benefit/risk of acetyl-CoA carboxylase inhibitors through liver targeting. J. Med. Chem. 63, 10879–10896 (2020). Article CAS PubMed Google Scholar Zhang, J. et al. Molecular profiling reveals a common metabolic signature of tissue fibrosis. Cell Rep. Med. 1, 100056 (2020). Article PubMed PubMed Central Google Scholar Matsumoto, M. et al. Acetyl-CoA carboxylase 1 and 2 inhibition ameliorates steatosis and hepatic fibrosis in a MC4R knockout murine model of nonalcoholic steatohepatitis. PLoS ONE 15, e0228212 (2020). Article CAS PubMed PubMed Central Google Scholar Bates, J. et al. Acetyl-CoA carboxylase inhibition disrupts metabolic reprogramming during hepatic stellate cell activation. J. Hepatol. 73, 896–905 (2020). Article CAS PubMed Google Scholar Stiede, K. et al. Acetyl-coenzyme A carboxylase inhibition reduces de novo lipogenesis in overweight male subjects: a randomized, double-blind, crossover study. Hepatology 66, 324–334 (2017). First study in humans showing that ACC inhibition (with ND-630/GS-0976) reduces liver DNL. Article CAS PubMed Google Scholar Loomba, R. et al. GS-0976 reduces hepatic steatosis and fibrosis markers in patients with nonalcoholic fatty liver disease. Gastroenterology 155, 1463–1473.e6 (2018). First study in humans showing that ACC inhibition reduces liver fat and markers of fibrosis. Article CAS PubMed Google Scholar Loomba, R. et al. Combination therapies including cilofexor and firsocostat for bridging fibrosis and cirrhosis attributable to NASH. Hepatology 73, 625–643 (2021). Phase II clinical trial demonstrating that a combination of ND-630 and a FXR agonist cilofexor reduces liver fibrosis in people with NASH. Article CAS PubMed Google Scholar Waring, J. F. et al. Gene expression analysis in rats treated with experimental acetyl-coenzyme A carboxylase inhibitors suggests interactions with the peroxisome proliferator-activated receptor alpha pathway. J. Pharmacol. Exp. Ther. 324, 507–516 (2008). Article CAS PubMed Google Scholar Goedeke, L. et al. Acetyl-CoA carboxylase inhibition reverses NAFLD and hepatic insulin resistance but promotes hypertriglyceridemia in rodents. Hepatology 68, 2197–2211 (2018). Article CAS PubMed Google Scholar Corominas-Faja, B. et al. Chemical inhibition of acetyl-CoA carboxylase suppresses self-renewal growth of cancer stem cells. Oncotarget 5, 8306–8316 (2014). Article PubMed PubMed Central Google Scholar Li, S. et al. TOFA suppresses ovarian cancer cell growth in vitro and in vivo. Mol. Med. Rep. 8, 373–378 (2013). Article PubMed Google Scholar Hess, D., Chisholm, J. W. & Igal, R. A. Inhibition of stearoylCoA desaturase activity blocks cell cycle progression and induces programmed cell death in lung cancer cells. PLoS ONE 5, e11394 (2010). Article PubMed PubMed Central Google Scholar Martínez-Montañés, F. et al. Phosphoproteomic analysis across the yeast life cycle reveals control of fatty acyl chain length by phosphorylation of the fatty acid synthase complex. Cell Rep. 32, 108024 (2020). Article PubMed Google Scholar Jin, Q. et al. Fatty acid synthase phosphorylation: a novel therapeutic target in HER2-overexpressing breast cancer cells. Breast Cancer Res. 12, R96 (2010). Article CAS PubMed PubMed Central Google Scholar Sun, T., Liu, Z. & Yang, Q. The role of ubiquitination and deubiquitination in cancer metabolism. Mol. Cancer 19, 146 (2020). Article PubMed PubMed Central Google Scholar Smith, S., Witkowski, A. & Joshi, A. K. Structural and functional organization of the animal fatty acid synthase. Prog. Lipid Res. 42, 289–317 (2003). Article CAS PubMed Google Scholar Hiltunen, J. K. et al. Mitochondrial fatty acid synthesis type II: more than just fatty acids. J. Biol. Chem. 284, 9011–9015 (2009). Article CAS PubMed PubMed Central Google Scholar White, S. W., Zheng, J., Zhang, Y. M. & Rock The structural biology of type II fatty acid biosynthesis. Annu. Rev. Biochem. 74, 791–831 (2005). Article CAS PubMed Google Scholar Maier, T., Leibundgut, M. & Ban, N. The crystal structure of a mammalian fatty acid synthase. Science 321, 1315–1322 (2008). Report of the crystal structure of full mammalian FAS and molecular details of active sites. Article CAS PubMed Google Scholar Omura, S. The antibiotic cerulenin, a novel tool for biochemistry as an inhibitor of fatty acid synthesis. Bacteriol. Rev. 40, 681–697 (1976). Article CAS PubMed PubMed Central Google Scholar Kuhajda, F. P. et al. Synthesis and antitumor activity of an inhibitor of fatty acid synthase. Proc. Natl Acad. Sci. USA 97, 3450–3454 (2000). First paper describing the generation of the FAS inhibitor C75 and that inhibiting DNL in cancer cells using this compound reduces cell proliferation. Article CAS PubMed PubMed Central Google Scholar Cheng, F., Wang, Q., Chen, M., Quiocho, F. A. & Ma, J. Molecular docking study of the interactions between the thioesterase domain of human fatty acid synthase and its ligands. Proteins 70, 1228–1234 (2008). Article CAS PubMed Google Scholar Kridel, S. J., Axelrod, F., Rozenkrantz, N. & Smith, J. W. Orlistat is a novel inhibitor of fatty acid synthase with antitumor activity. Cancer Res. 64, 2070–2075 (2004). Article CAS PubMed Google Scholar Hill, T. K. et al. Development of a self-assembled nanoparticle formulation of orlistat, Nano-ORL, with increased cytotoxicity against human tumor cell lines. Mol. Pharm. 13, 720–728 (2016). Article CAS PubMed PubMed Central Google Scholar Bhargava-Shah, A., Foygel, K., Devulapally, R. & Paulmurugan, R. Orlistat and antisense-miRNA-loaded PLGA-PEG nanoparticles for enhanced triple negative breast cancer therapy. Nanomedicine 11, 235–247 (2016). Article CAS PubMed PubMed Central Google Scholar Paulmurugan, R. et al. Folate receptor-targeted polymeric micellar nanocarriers for delivery of orlistat as a repurposed drug against triple-negative breast cancer. Mol. Cancer Ther. 15, 221–231 (2016). Article CAS PubMed Google Scholar Alwarawrah, Y. et al. Fasnall, a selective FASN inhibitor, shows potent anti-tumor activity in the MMTV-Neu model of HER2(+) breast cancer. Cell Chem. Biol. 23, 678–688 (2016). Article CAS PubMed PubMed Central Google Scholar Singha, P. K. et al. Evaluation of FASN inhibitors by a versatile toolkit reveals differences in pharmacology between human and rodent FASN preparations and in antiproliferative efficacy in vitro vs. in situ in human cancer cells. Eur. J. Pharm. Sci. 149, 105321 2020). Article CAS PubMed Google Scholar Zadra, G. et al. Inhibition of de novo lipogenesis targets androgen receptor signaling in castration-resistant prostate cancer. Proc. Natl Acad. Sci. USA 116, 631–640 (2019). Article CAS PubMed Google Scholar Hardwicke, M. A. et al. A human fatty acid synthase inhibitor binds β-ketoacyl reductase in the keto-substrate site. Nat. Chem. Biol. 10, 774–779 (2014). Article CAS PubMed Google Scholar Kley, J. T., Mack, J., Hamilton, B., Scheuerer, S. & Redemann, N. Discovery of BI 99179, a potent and selective inhibitor of type I fatty acid synthase with central exposure. Bioorg. Med. Chem. Lett. 21, 5924–5927 (2011). CAS PubMed Google Scholar Ventura, R. et al. Inhibition of de novo palmitate synthesis by fatty acid synthase induces apoptosis in tumor cells by remodeling cell membranes, inhibiting signaling pathways, and reprogramming gene expression. EBioMedicine 2, 808–824 (2015). Article PubMed PubMed Central Google Scholar Beysen, C. et al. Inhibition of fatty acid synthase with FT-4101 safely reduces hepatic de novo lipogenesis and steatosis in obese subjects with non-alcoholic fatty liver disease: results from two early-phase randomized trials. Diabetes Obes. Metab. 23, 700–710 (2021). First clinical findings that the FAS inhibitor FT-4101 reduces steatosis in people with NAFLD. Article CAS PubMed Google Scholar Loftus, T. M. et al. Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors. Science 288, 2379–2381 (2000). First paper indicating that regulating malony-CoA in the hypothalamus is important for regulating energy intake. Article CAS PubMed Google Scholar Makimura, H. et al. Cerulenin mimics effects of leptin on metabolic rate, food intake, and body weight independent of the melanocortin system, but unlike leptin, cerulenin fails to block neuroendocrine effects of fasting. Diabetes 50, 733–739 (2001). Article CAS PubMed Google Scholar Gao, S. & Lane, M. D. Effect of the anorectic fatty acid synthase inhibitor C75 on neuronal activity in the hypothalamus and brainstem. Proc. Natl Acad. Sci. USA 100, 5628–5633 (2003). Article CAS PubMed PubMed Central Google Scholar Thupari, J. N., Landree, L. E., Ronnett, G. V. & Kuhajda, F. P. C75 increases peripheral energy utilization and fatty acid oxidation in diet-induced obesity. Proc. Natl Acad. Sci. USA 99, 9498–9502 (2002). Article CAS PubMed PubMed Central Google Scholar Thupari, J. N., Kim, E. K., Moran, T. H., Ronnett, G. V. & Kuhajda, F. P. Chronic C75 treatment of diet-induced obese mice increases fat oxidation and reduces food intake to reduce adipose mass. Am. J. Physiol. Endocrinol. Metab. 287, E97–E104 (2004). Article CAS PubMed Google Scholar Shimokawa, T., Kumar, M. V. & Lane, M. D. Effect of a fatty acid synthase inhibitor on food intake and expression of hypothalamic neuropeptides. Proc. Natl Acad. Sci. USA 99, 66–71 (2002). Article CAS PubMed Google Scholar Syed-Abdul, M. M. et al. Fatty acid synthase inhibitor TVB-2640 reduces hepatic de novo lipogenesis in males with metabolic abnormalities. Hepatology 72, 103–118 (2020). First clinical findings indicating that inhibiting FAS in individuals with obesity using TVB-2640 suppresses liver DNL with minimal adverse events. Article CAS PubMed Google Scholar Pandey, P. R., Liu, W., Xing, F., Fukuda, K. & Watabe, K. Anti-cancer drugs targeting fatty acid synthase (FAS). Recent Pat. Anticancer Drug Discov. 7, 185–197 (2012). Article CAS PubMed Google Scholar Pizer, E. S. et al. Inhibition of fatty acid synthesis delays disease progression in a xenograft model of ovarian cancer. Cancer Res. 56, 1189–1193 (1996). CAS PubMed Google Scholar Ho, T. S. et al. Fatty acid synthase inhibitors cerulenin and C75 retard growth and induce caspase-dependent apoptosis in human melanoma A-375 cells. Biomed. Pharmacother. 61, 578–587 (2007). Article CAS PubMed Google Scholar Elix, C. C. et al. Peroxisome proliferator-activated receptor gamma controls prostate cancer cell growth through AR-dependent and independent mechanisms. Prostate 80, 162–172 (2020). Article CAS PubMed Google Scholar Ferraro, G. B. et al. Fatty acid synthesis is required for breast cancer brain metastasis. Nat. Cancer 2, 414–428 (2021). Article CAS PubMed PubMed Central Google Scholar Falchook, G. et al. First-in-human study of the safety, pharmacokinetics, and pharmacodynamics of first-in-class fatty acid synthase inhibitor TVB-2640 alone and with a taxane in advanced tumors. EClinicalMedicine 34, 100797 (2021). Article PubMed PubMed Central Google Scholar Beigneux, A. P. et al. ATP-citrate lyase deficiency in the mouse. J. Biol. Chem. 279, 9557–9564 (2004). Article CAS PubMed Google Scholar Abu-Elheiga, L. et al. Mutant mice lacking acetyl-CoA carboxylase 1 are embryonically lethal. Proc. Natl Acad. Sci. USA 102, 12011–12016 (2005). Article CAS PubMed PubMed Central Google Scholar Chirala, S. S. et al. Fatty acid synthesis is essential in embryonic development: fatty acid synthase null mutants and most of the heterozygotes die in utero. Proc. Natl Acad. Sci. USA 100, 6358–6363 (2003). Article CAS PubMed PubMed Central Google Scholar Palmieri, F., Scarcia, P. & Monné, M. Diseases caused by mutations in mitochondrial carrier genes SLC25: a review. Biomolecules 10, 655 (2020). Together with Beigneux et al. (2004), Abu-Elheiga et al. (2005) and Chirala et al. (2003), provides evidence demonstrating a crucial role for DNL in normal embryonic development. Article CAS PubMed Central Google Scholar Esquejo, R. M. et al. Activation of Liver AMPK with PF-06409577 corrects NAFLD and lowers cholesterol in rodent and primate preclinical models. EBioMedicine 31, 122–132 (2018). Article PubMed PubMed Central Google Scholar Gluais-Dagorn, P. et al. Direct AMPK activation corrects NASH in rodents through metabolic effects and direct action on inflammation and fibrogenesis. Hepatol. Commun. 6, 101–119 (2021). Article PubMed PubMed Central Google Scholar Bruning, U. et al. Impairment of angiogenesis by fatty acid synthase Inhibition Involves mTOR malonylation. Cell Metab. 28, 866–880.e15 (2018). Article CAS PubMed PubMed Central Google Scholar Colak, G. et al. Proteomic and biochemical studies of lysine malonylation suggest its malonic aciduria-associated regulatory role in mitochondrial function and fatty acid oxidation. Mol. Cell Proteom. 14, 3056–3071 (2015). Article CAS Google Scholar Ishiguro, T. et al. Malonylation of histone H2A at lysine 119 inhibits Bub1-dependent H2A phosphorylation and chromosomal localization of shugoshin proteins. Sci. Rep. 8, 7671 (2018). Article PubMed PubMed Central Google Scholar Covarrubias, S. et al. Malonylation of GAPDH is an inflammatory signal in macrophages. Nat. Commun. 10, 338 (2019). Article PubMed PubMed Central Google Scholar Wellen, K. E. et al. ATP-citrate lyase links cellular metabolism to histone acetylation. Science 324, 1076–1080 (2009). The first paper linking nutrient availability with histone acetylation through regulation of ACLY activity. Article CAS PubMed PubMed Central Google Scholar Kamphorst, J. J. et al. Hypoxic and Ras-transformed cells support growth by scavenging unsaturated fatty acids from lysophospholipids. Proc. Natl Acad. Sci. USA 110, 8882–8887 (2013). Article CAS PubMed PubMed Central Google Scholar Watt, M. J. et al. Suppressing fatty acid uptake has therapeutic effects in preclinical models of prostate cancer. Sci. Transl Med. 11, eaau5758 (2019). Article CAS PubMed Google Scholar Zaidi, N., Royaux, I., Swinnen, J. V. & Smans, K. ATP citrate lyase knockdown induces growth arrest and apoptosis through different cell- and environment-dependent mechanisms. Mol. Cancer Ther. 11, 1925–1935 (2012). Article CAS PubMed Google Scholar Nazy, I., Arnold, D. M. & Steinberg, G. R. The mega-importance of de novo lipogenesis in platelet production. Nat. Metab. 2, 999–1000 (2020). Article CAS PubMed Google Scholar Eissing, L. et al. De novo lipogenesis in human fat and liver is linked to ChREBP-β and metabolic health. Nat. Commun. 4, 1528 (2013). Article PubMed Google Scholar Abdul-Wahed, A., Guilmeau, S. & Postic, C. Sweet sixteenth for ChREBP: established roles and future goals. Cell Metab. 26, 324–341 (2017). Article CAS PubMed Google Scholar Ye, J. & DeBose-Boyd, R. A. Regulation of cholesterol and fatty acid synthesis. Cold Spring Harb. Perspect. Biol. 3, a004754 (2011). Article PubMed PubMed Central Google Scholar Chen, G., Liang, G., Ou, J., Goldstein, J. L. & Brown, M. S. Central role for liver X receptor in insulin-mediated activation of Srebp-1c transcription and stimulation of fatty acid synthesis in liver. Proc. Natl Acad. Sci. USA 101, 11245–11250 (2004). Article CAS PubMed PubMed Central Google Scholar Cha, J. Y. & Repa, J. J. The liver X receptor (LXR) and hepatic lipogenesis. The carbohydrate-response element-binding protein is a target gene of LXR. J. Biol. Chem. 282, 743–751 (2007). Article CAS PubMed Google Scholar Denechaud, P. D. et al. ChREBP, but not LXRs, is required for the induction of glucose-regulated genes in mouse liver. J. Clin. Invest. 118, 956–964 (2008). CAS PubMed PubMed Central Google Scholar Koutsoudakis, G. et al. Soraphen A: a broad-spectrum antiviral natural product with potent anti-hepatitis C virus activity. J. Hepatol. 63, 813–821 (2015). Article CAS PubMed Google Scholar Fleta-Soriano, E. et al. The myxobacterial metabolite soraphen a inhibits HIV-1 by reducing virus production and altering virion composition. Antimicrob. Agents Chemother. 61, e00739-17 (2017). Article PubMed PubMed Central Google Scholar Merino-Ramos, T. et al. Modification of the host cell lipid metabolism induced by hypolipidemic drugs targeting the acetyl coenzyme a carboxylase impairs west nile virus replication. Antimicrob. Agents Chemother. 60, 307–315 (2015). Article PubMed PubMed Central Google Scholar Gaunt, E. R., Cheung, W., Richards, J. E., Lever, A. & Desselberger, U. Inhibition of rotavirus replication by downregulation of fatty acid synthesis. J. Gen. Virol. 94, 1310–1317 (2013). Article CAS PubMed Google Scholar Li, Y., Webster-Cyriaque, J., Tomlinson, C. C., Yohe, M. & Kenney, S. Fatty acid synthase expression is induced by the Epstein–Barr virus immediate-early protein BRLF1 and is required for lytic viral gene expression. J. Virol. 78, 4197–4206 (2004). Article CAS PubMed PubMed Central Google Scholar Hitakarun, A. et al. Evaluation of the antiviral activity of orlistat (tetrahydrolipstatin) against dengue virus, Japanese encephalitis virus, zika virus and chikungunya virus. Sci. Rep. 10, 1499 (2020). Article CAS PubMed PubMed Central Google Scholar Tanner, J. E. & Alfieri, C. The fatty acid lipid metabolism nexus in COVID-19. Viruses 13, 90 (2021). Article CAS PubMed PubMed Central Google Scholar Chu, J. et al. Pharmacological inhibition of fatty acid synthesis blocks SARS-CoV-2 replication. Nat. Metab. 3, 1466–1475 (2021). Indicates that FAS inhibition may be beneficial against COVID-19. Article CAS PubMed PubMed Central Google Scholar Hunt, D. W. et al. Inhibition of sebum production with the acetyl coenzyme a carboxylase inhibitor olumacostat glasaretil. J. Invest. Dermatol. 137, 1415–1423 (2017). Article CAS PubMed Google Scholar Raha, S. et al. Disruption of de novo fatty acid synthesis via acetyl-CoA carboxylase 1 inhibition prevents acute graft-versus-host disease. Eur. J. Immunol. 46, 2233–2238 (2016). Article CAS PubMed Google Scholar Wang, X. et al. ACC1 (Acetyl Coenzyme A Carboxylase 1) is a potential immune modulatory target of cerebral ischemic. Stroke Stroke 50, 1869–1878 (2019). Article CAS PubMed Google Scholar Gross, A. S. et al. Acetyl-CoA carboxylase 1-dependent lipogenesis promotes autophagy downstream of AMPK. J. Biol. Chem. 294, 12020–12039 (2019). Article CAS PubMed PubMed Central Google Scholar Glatzel, D. K. et al. Acetyl-CoA carboxylase 1 regulates endothelial cell migration by shifting the phospholipid composition. J. Lipid Res. 59, 298–311 (2018). Article CAS PubMed Google Scholar Ibitokou, S. A. et al. Early inhibition of fatty acid synthesis reduces generation of memory precursor effector T cells in chronic infection. J. Immunol. 200, 643–656 (2018). Article CAS PubMed Google Scholar Rymut, S. M. et al. Acetyl-CoA carboxylase inhibition regulates microtubule dynamics and intracellular transport in cystic fibrosis epithelial cells. Am. J. Physiol. Lung Cell Mol. Physiol. 316, L1081–L1093 (2019). Article CAS PubMed PubMed Central Google Scholar Which of the following statements provides evidence to support the claim that no ATP will be?Which of the following statements provides evidence to support the claim that no ATP will be synthesized in the absence of a proton gradient across the thylakoid membrane? No ATP is synthesized when channel proteins that allow the free passage of protons are inserted into the thylakoid membrane.
Which of the following best explains why triploid bananas do not produce seeds?Triploids seldom produce eggs or sperm that have a balanced set of chromosomes and so successful seed set is very rare. Bananas, too, are parthenocarpic and produce fruit in the absence of successful fertilization. These bananas are asexually propagated.
Which of the following statements correctly explains the observed effect of the acetylcholine concentration on the rate of the enzyme catalyzed reaction?Which of the following statements correctly explains the observed effect of the acetylcholine concentration on the rate of the enzyme-catalyzed reaction? The active site of AChE is specific for acetylcholine, and only one substrate molecule can occupy the active site at a time.
Which of the following most likely explains how the amino acid substitution has resulted in increased catalytic activity by the mutated enzyme?Which of the following most likely explains how the amino acid substitution has resulted in decreased catalytic activity by the mutated enzyme? The substitution decreased the mass of the enzyme so that the mutated enzyme binds more weakly to the substrate than the normal enzyme does.
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