Acetyl-CoA Carboxylase Inhibition as a Therapeutic Tool in the Battle Against NASH: Hitting More Than Just One Mechanism?
| Autor: | Frank Tacke, Joeri Lambrecht |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Male
Battle HSC primary hepatic stellate cell IC50 median inhibitory concentration ACC acetyl-CoA carboxylase AST aspartate aminotransferase DMSO dimethyl sulfoxide Rats Sprague-Dawley TGFβ1 transforming growth factor β1 Non-alcoholic Fatty Liver Disease Medicine Enzyme Inhibitors media_common Original Research TG triglyceride TH17 cells inflammatory interleukin 17 secreting T cells of the T helper 17 lineage Gastroenterology NASH αSMA α-smooth muscle actin Editorial hACC human ACC PSR Picro Sirius red Liver Biochemistry NASH nonalcoholic steatohepatitis IHC immunohistochemistry ATP adenosine triphosphate media_common.quotation_subject EC50 median effective concentration DNL de novo lipogenesis Fatty Liver Disease ALT alanine aminotransferase Treg cells anti-inflammatory Foxp3(+) regulatory T cells Animals Humans lcsh:RC799-869 CDAHFD choline-deficient and high-fat diet Hepatology DAB 3 3′-diaminobenzidine business.industry Mechanism (biology) Lipogenesis Acetyl-CoA carboxylase VLDL very-low-density lipoprotein Fibrosis IL interleukin CD3 cluster of differentiation 3 SWE shear wave elastography lcsh:Diseases of the digestive system. Gastroenterology NAFLD nonalcoholic fatty liver disease business Acetyl-CoA Carboxylase DEN diethylnitrosamine |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology Cellular and Molecular Gastroenterology and Hepatology, Vol 10, Iss 4, Pp 859-861 (2020) |
| ISSN: | 2352-345X |
| Popis: | Background & Aims 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. Methods 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. Results 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 proinflammatory but not anti-inflammatory T cells, and suppressed activation of primary human stellate cells to myofibroblasts in vitro, showing direct effects on inflammation and fibrogenesis. Consistent with these observations, PF-05221304 also reduced markers of inflammation and fibrosis in the diethylnitrosamine chemical–induced liver injury model and the choline-deficient, high-fat–fed rat model. Conclusions The liver-directed dual ACC1/ACC2 inhibitor directly improved multiple nonalcoholic fatty liver disease/NASH pathogenic factors including steatosis, inflammation, and fibrosis in both human-derived in vitro systems and rat models. Graphical abstract |
| Databáze: | OpenAIRE |
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