Inhibition of ATP-citrate lyase improves NASH, liver fibrosis, and dyslipidemia
Journal article
Morrow, Marisa R., Batchuluun, Battsetseg, Wu, Jianhan, Ahmadi, Elham, Leroux, Julie M., Mohammadi-Shemirani, Pedrum, Desjardins, Eric M., Wang, Zhichao, Tsakiridis, Evangelia E., Lavoie, Declan C. T., Reihani, Amir, Smith, Brennan K., Kwiecien, Jacek M., Lally, James S. V., Nero, Tracy L., Parker, Michael W., Ask, Kjetil, Scott, John W., Jiang, Lei, ... Steinberg, Gregory R.. (2022). Inhibition of ATP-citrate lyase improves NASH, liver fibrosis, and dyslipidemia. Cell Metabolism. 34(6), pp. 919-936. https://doi.org/10.1016/j.cmet.2022.05.004
Authors | Morrow, Marisa R., Batchuluun, Battsetseg, Wu, Jianhan, Ahmadi, Elham, Leroux, Julie M., Mohammadi-Shemirani, Pedrum, Desjardins, Eric M., Wang, Zhichao, Tsakiridis, Evangelia E., Lavoie, Declan C. T., Reihani, Amir, Smith, Brennan K., Kwiecien, Jacek M., Lally, James S. V., Nero, Tracy L., Parker, Michael W., Ask, Kjetil, Scott, John W., Jiang, Lei, Paré, Guillaume, Pinkosky, Stephen L. and Steinberg, Gregory R. |
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Abstract | Elevated liver de novo lipogenesis contributes to non-alcoholic steatohepatitis (NASH) and can be inhibited by targeting acetyl-CoA carboxylase (ACC). However, hypertriglyceridemia limits the use of pharmacological ACC inhibitors as a monotherapy. ATP-citrate lyase (ACLY) generates acetyl-CoA and oxaloacetate from citrate, but whether inhibition is effective for treating NASH is unknown. Here, we characterize a new mouse model that replicates many of the pathological and molecular drivers of NASH and find that genetically inhibiting ACLY in hepatocytes reduces liver malonyl-CoA, oxaloacetate, steatosis, and ballooning as well as blood glucose, triglycerides, and cholesterol. Pharmacological inhibition of ACLY mirrors genetic inhibition but has additional positive effects on hepatic stellate cells, liver inflammation, and fibrosis. Mendelian randomization of human variants that mimic reductions in ACLY also associate with lower circulating triglycerides and biomarkers of NASH. These data indicate that inhibiting liver ACLY may be an effective approach for treatment of NASH and dyslipidemia. |
Keywords | lipogenesis; fatty acid oxidation; hypertriglyceridemia; non-alcoholic steatohepatitis; NASH; diabetes; insulin resistance; gluconeogenesis; steatosis; cardiovascular disease |
Year | 2022 |
Journal | Cell Metabolism |
Journal citation | 34 (6), pp. 919-936 |
Publisher | Elsevier Inc. |
ISSN | 1550-4131 |
Digital Object Identifier (DOI) | https://doi.org/10.1016/j.cmet.2022.05.004 |
Scopus EID | 2-s2.0-85131372261 |
Page range | 919-936 |
Funder | Esperion Therapeutics |
Espervita Therapeutics | |
Poxel Pharmaceuticals | |
Nestlé | |
Novo Nordisk Foundation | |
AstraZeneca | |
Eli Lilly and Company | |
Merck Pty Ltd | |
Publisher's version | License All rights reserved File Access Level Controlled |
Output status | Published |
Publication dates | |
Online | 07 Jun 2022 |
Publication process dates | |
Accepted | 16 May 2022 |
Deposited | 01 Mar 2023 |
https://acuresearchbank.acu.edu.au/item/8yw2q/inhibition-of-atp-citrate-lyase-improves-nash-liver-fibrosis-and-dyslipidemia
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