2. Academic Validation
  3. Bempedoic acid suppresses diet-induced hepatic steatosis independently of ATP-citrate lyase

Bempedoic acid suppresses diet-induced hepatic steatosis independently of ATP-citrate lyase

  • Cell Metab. 2025 Jan 7;37(1):239-254.e7. doi: 10.1016/j.cmet.2024.10.014.
Joyce Y Liu 1,  Ramya S Kuna 2,  Laura V Pinheiro 1,  Phuong T T Nguyen 3,  Jaclyn E Welles 4,  Jack M Drummond 5,  Nivitha Murali 5,  Prateek V Sharma 6,  Julianna G Supplee 1,  Mia Shiue 5,  Steven Zhao 6,  Aimee T Farria 5,  Avi Kumar 2,  Mauren L Ruchhoeft 2,  Christina Demetriadou 7,  Daniel S Kantner 8,  Adam Chatoff 8,  Emily Megill 8,  Paul M Titchenell 4,  Nathaniel W Snyder 8,  Christian M Metallo 9,  Kathryn E Wellen 10
Affiliations

Affiliations

  • 1 Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA; Biochemistry and Molecular Biophysics Graduate Group, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 2 Department of Molecular and Cell Biology, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
  • 3 Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA; Neuroscience Graduate Group, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 4 Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 5 Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 6 Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA; Cell and Molecular Biology Graduate Group, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 7 Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Aging + Cardiovascular Discovery Center, Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
  • 8 Aging + Cardiovascular Discovery Center, Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
  • 9 Department of Molecular and Cell Biology, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: metallo@salk.edu.
  • 10 Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: wellenk@upenn.edu.
PMID: 39471816 DOI: 10.1016/j.cmet.2024.10.014
Abstract

ATP Citrate Lyase (ACLY) synthesizes acetyl-CoA for de novo lipogenesis (DNL), which is elevated in metabolic dysfunction-associated steatotic liver disease. Hepatic ACLY is inhibited by the LDL-cholesterol-lowering drug bempedoic acid (BPA), which also improves steatosis in mice. While BPA potently suppresses hepatic DNL and increases fat catabolism, it is unclear if ACLY is its primary molecular target in reducing liver triglyceride. We show that on a Western diet, loss of hepatic ACLY alone or together with the acetyl-CoA synthetase ACSS2 unexpectedly exacerbates steatosis, linked to reduced PPARα target gene expression and fatty acid oxidation. Importantly, BPA treatment ameliorates Western diet-mediated triacylglyceride accumulation in both WT and liver ACLY knockout mice, indicating that its primary effects on hepatic steatosis are ACLY independent. Together, these data indicate that hepatic ACLY plays an unexpected role in restraining diet-dependent lipid accumulation and that BPA exerts substantial effects on hepatic lipid metabolism independently of ACLY.

Keywords

ACLY; ACSS2; PPARα; bempedoic acid; lipid metabolism; metabolic dysfunction-associated steatotic liver disease.

Figures
Products