Inhibition of ATP-citrate lyase improves NASH, liver fibrosis, and dyslipidemia

Marisa R Morrow; Battsetseg Batchuluun; Jianhan Wu; Elham Ahmadi; Julie M Leroux; Pedrum Mohammadi-Shemirani; Eric M Desjardins; Zhichao Wang; Evangelia E Tsakiridis; Declan C T Lavoie; Amir Reihani; Brennan K Smith; Jacek M Kwiecien; James S V Lally; Tracy L Nero; Michael W Parker; Kjetil Ask; John W Scott; Lei Jiang; Guillaume Paré; Stephen L Pinkosky; Gregory R Steinberg

doi:10.1016/j.cmet.2022.05.004

Inhibition of ATP-citrate lyase improves NASH, liver fibrosis, and dyslipidemia

Cell Metab. 2022 Jun 7;34(6):919-936.e8. doi: 10.1016/j.cmet.2022.05.004.

Authors

Marisa R Morrow¹, Battsetseg Batchuluun¹, Jianhan Wu¹, Elham Ahmadi¹, Julie M Leroux¹, Pedrum Mohammadi-Shemirani², Eric M Desjardins¹, Zhichao Wang³, Evangelia E Tsakiridis¹, Declan C T Lavoie¹, Amir Reihani⁴, Brennan K Smith¹, Jacek M Kwiecien⁵, James S V Lally¹, Tracy L Nero⁶, Michael W Parker⁷, Kjetil Ask⁴, John W Scott⁸, Lei Jiang⁹, Guillaume Paré¹⁰, Stephen L Pinkosky¹¹, Gregory R Steinberg¹²

Affiliations

¹ Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON L8S 4L8, Canada; Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada.
² Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON L8L 2X2, Canada; Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton Health Sciences, Hamilton, ON L8L 2X2, Canada.
³ Department of Molecular & Cellular Endocrinology, Diabetes and Metabolism Research Institute, City of Hope Medical Center, Duarte, CA 91010, USA.
⁴ Department of Medicine, Division of Respirology, McMaster University and St. Joseph's Healthcare Hamilton, Hamilton, ON, Canada.
⁵ Department of Pathology, McMaster University, Hamilton, ON L8S 4L8, Canada.
⁶ Structural Biology and Computational Design Laboratory, Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC 3065, Australia.
⁷ Structural Biology and Computational Design Laboratory, Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC 3065, Australia; ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, VIC 3065, Australia.
⁸ Protein Chemistry & Metabolism, St. Vincent's Institute of Medical Research and School of Medicine, University of Melbourne, Fitzroy, VIC 3065, Australia; The Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3052, Australia; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC 3052, Australia.
⁹ Department of Molecular & Cellular Endocrinology, Diabetes and Metabolism Research Institute, City of Hope Medical Center, Duarte, CA 91010, USA; Comprehensive Cancer Center, Beckman Research Institute, City of Hope Medical Center, Duarte, CA 91010, USA.
¹⁰ Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON L8L 2X2, Canada; Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton Health Sciences, Hamilton, ON L8L 2X2, Canada; Department of Medicine, Division of Respirology, McMaster University and St. Joseph's Healthcare Hamilton, Hamilton, ON, Canada; Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON L8S 4L8, Canada.
¹¹ Esperion Therapeutics, Inc., Ann Arbor, MI, USA.
¹² Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON L8S 4L8, Canada; Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4L8, Canada. Electronic address: gsteinberg@mcmaster.ca.

PMID: 35675800
DOI: 10.1016/j.cmet.2022.05.004

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: NASH; cardiovascular disease; diabetes; fatty acid oxidation; gluconeogenesis; hypertriglyceridemia; insulin resistance; lipogenesis; non-alcoholic steatohepatitis; steatosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATP Citrate (pro-S)-Lyase* / antagonists & inhibitors
Acetyl-CoA Carboxylase
Animals
Dyslipidemias* / drug therapy
Dyslipidemias* / pathology
Liver
Liver Cirrhosis / drug therapy
Liver Cirrhosis / pathology
Mice
Non-alcoholic Fatty Liver Disease* / drug therapy
Non-alcoholic Fatty Liver Disease* / pathology
Oxaloacetates / metabolism
Triglycerides

Substances

Oxaloacetates
Triglycerides
ATP Citrate (pro-S)-Lyase
Acetyl-CoA Carboxylase

Grants and funding

201709FDN-CEBA-116200/CIHR/Canada