Journal
CELL METABOLISM
Volume 34, Issue 6, Pages 919-+Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2022.05.004
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Funding
- Canadian Institutes of Health Research [201709FDN-CEBA-116200]
- Diabetes Canada [DI-5-17-5302]
- Esperion Therapeutics
- Tier 1 Canada Research Chairs
- J. Bruce Duncan Endowed Chair in Metabolic Diseases
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This study demonstrates that inhibiting liver ACLY can effectively reduce the pathological and molecular drivers of NASH and improve blood glucose, triglycerides, and cholesterol levels. Pharmacological inhibition of ACLY also positively affects hepatic stellate cells, liver inflammation, and fibrosis. Furthermore, human ACLY variants are associated with lower circulating triglycerides and NASH biomarkers.
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.
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