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

Autor:	Liu JY; 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., Kuna RS; 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., Pinheiro LV; 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., Nguyen PTT; 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., Welles JE; 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., Drummond JM; Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA., Murali N; Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA., Sharma PV; 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., Supplee JG; 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., Shiue M; Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA., Zhao S; 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., Farria AT; Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA., Kumar A; 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., Ruchhoeft ML; 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., Demetriadou C; 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., Kantner DS; Aging + Cardiovascular Discovery Center, Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA., Chatoff A; Aging + Cardiovascular Discovery Center, Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA., Megill E; Aging + Cardiovascular Discovery Center, Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA., Titchenell PM; 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., Snyder NW; Aging + Cardiovascular Discovery Center, Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA., Metallo CM; 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., Wellen KE; 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.
Jazyk:	angličtina
Zdroj:	Cell metabolism [Cell Metab] 2024 Oct 28. Date of Electronic Publication: 2024 Oct 28.
DOI:	10.1016/j.cmet.2024.10.014
Abstrakt:	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. Competing Interests: Declaration of interests C.M.M. is an advisor to Faeth Therapeutics. C.M.M. is a founder and shareholder of Amprenta Therapeutics. K.E.W. is an Advisory Board member of Cell Metabolism. K.E.W. is a Scientific Advisory Board member of Crescenta Biosciences. (Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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