Acetyl-CoA Carboxylase Inhibition Improves Multiple Dimensions of NASH Pathogenesis in Model Systems.

Cellular and Molecular Gastroenterology and Hepatology
Trenton T RossWilliam P Esler

Abstract

Disordered metabolism, steatosis, hepatic inflammation, and fibrosis contribute to the pathogenesis of nonalcoholic steatohepatitis (NASH). Acetyl-CoA carboxylase (ACC) catalyzes the first committed step in de novo lipogenesis (DNL) and modulates mitochondrial fatty acid oxidation. Increased hepatic DNL flux and reduced fatty acid oxidation are hypothesized to contribute to steatosis. Some proinflammatory cells also show increased dependency on DNL, suggesting that ACC may regulate aspects of the inflammatory response in NASH. PF-05221304 is an orally bioavailable, liver-directed ACC1/2 inhibitor. The present studies sought to evaluate the effects of PF-05221304 on NASH pathogenic factors in experimental model systems. The effects of PF-05221304 on lipid metabolism, steatosis, inflammation, and fibrogenesis were investigated in both primary human-derived in vitro systems and in vivo rodent models. PF-05221304 inhibited DNL, stimulated fatty acid oxidation, and reduced triglyceride accumulation in primary human hepatocytes, and reduced DNL and steatosis in Western diet-fed rats in vivo, showing the potential to reduce hepatic lipid accumulation and potentially lipotoxicity. PF-05221304 blocked polarization of human T cells to pr...Continue Reading

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Citations

Nov 29, 2020·Toxicological Sciences : an Official Journal of the Society of Toxicology·Natasha R CatlinGregg D Cappon
Dec 22, 2020·Molecular Metabolism·Kendra K Bence, Morris J Birnbaum
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Jan 14, 2022·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Pierluigi RamadoriMathias Heikenwalder

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Methods Mentioned

BETA
flow cytometry

Software Mentioned

VISIOPHARM
MACSquantify
NLMixed
SAS
Definiens Tissue Studio Image Analysis
Excel
Aperio eslide Manager

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