Cholesterol-binding translocator protein TSPO regulates steatosis and bile acid synthesis in nonalcoholic fatty liver disease.

Autor:	Li Y; Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA., Chen L; Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA., Li L; Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA., Sottas C; Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA., Petrillo SK; Research Institute of the McGill University Health Center, Montreal, QC H4A 3J1, Canada.; Department of Surgery, McGill University, Montreal, QC H3G 1A4, Canada., Lazaris A; Research Institute of the McGill University Health Center, Montreal, QC H4A 3J1, Canada.; Department of Surgery, McGill University, Montreal, QC H3G 1A4, Canada., Metrakos P; Research Institute of the McGill University Health Center, Montreal, QC H4A 3J1, Canada.; Department of Surgery, McGill University, Montreal, QC H3G 1A4, Canada., Wu H; Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA., Ishida Y; Department of Medicine, Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.; Research & Development Department, PhoenixBio, Co., Ltd, Higashi-Hiroshima, Hiroshima, Japan., Saito T; Department of Medicine, Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.; University of Southern California Research Center for Liver Diseases, Los Angeles, CA 90089, USA., Golden-Mason L; Department of Medicine, Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.; University of Southern California Research Center for Liver Diseases, Los Angeles, CA 90089, USA., Rosen HR; Department of Medicine, Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.; University of Southern California Research Center for Liver Diseases, Los Angeles, CA 90089, USA., Wolff JJ; Bruker Daltonics, 40 Manning Road Billerica, MA 01821, USA., Silvescu CI; Bruker Daltonics, 40 Manning Road Billerica, MA 01821, USA., Garza S; Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA., Cheung G; Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA., Huang T; Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA., Fan J; Research Institute of the McGill University Health Center, Montreal, QC H4A 3J1, Canada.; Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada., Culty M; Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA., Stiles B; Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA., Asahina K; University of Southern California Research Center for Liver Diseases, Los Angeles, CA 90089, USA.; Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.; Southern California Research Center for ALPD and Cirrhosis, Los Angeles, CA 90089, USA., Papadopoulos V; Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA.; Research Institute of the McGill University Health Center, Montreal, QC H4A 3J1, Canada.; Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada.
Jazyk:	angličtina
Zdroj:	IScience [iScience] 2021 May 01; Vol. 24 (5), pp. 102457. Date of Electronic Publication: 2021 May 01 (Print Publication: 2021).
DOI:	10.1016/j.isci.2021.102457
Abstrakt:	Translocator protein (TSPO, 18 kDa) levels increase in parallel with the evolution of simple steatosis (SS) to nonalcoholic steatohepatitis (NASH) in nonalcoholic fatty liver disease (NAFLD). However, TSPO function in SS and NASH is unknown. Loss of TSPO in hepatocytes in vitro downregulated acetyl-CoA acetyltransferase 2 and increased free cholesterol (FC). FC accumulation induced endoplasmic reticulum stress via IRE1A and protein kinase RNA-like ER kinase/ATF4/CCAAT-enhancer-binding protein homologous protein pathways and autophagy. TSPO deficiency activated cellular adaptive antioxidant protection; this adaptation was lost upon excessive FC accumulation. A TSPO ligand 19-Atriol blocked cholesterol binding and recapitulated many of the alterations seen in TSPO-deficient cells. These data suggest that TSPO deficiency accelerated the progression of SS. In NASH, however, loss of TSPO ameliorated liver fibrosis through downregulation of bile acid synthesis by reducing CYP7A1 and CYP27A1 levels and increasing farnesoid X receptor expression. These studies indicate a dynamic and complex role for TSPO in the evolution of NAFLD. Competing Interests: Dr. Yuji Ichida is an employee of PhoenixBio, Co., Ltd, Higashi-Hiroshima, Hiroshima, Japan; Dr. Cristina I. Silvescu is an employee of Bruker Daltonics, Billerica, MA 01821, USA; Dr. Jeremy J. Wolff was an employee of Bruker Daltonics, Billerica, MA 01821, USA, when this work was done. (© 2021 The Author(s).)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu