iScience (May 2021)
Cholesterol-binding translocator protein TSPO regulates steatosis and bile acid synthesis in nonalcoholic fatty liver disease
- Yuchang Li,
- Liting Chen,
- Lu Li,
- Chantal Sottas,
- Stephanie K. Petrillo,
- Anthoula Lazaris,
- Peter Metrakos,
- Hangyu Wu,
- Yuji Ishida,
- Takeshi Saito,
- Lucy Golden-Mason,
- Hugo R. Rosen,
- Jeremy J. Wolff,
- Cristina I. Silvescu,
- Samuel Garza,
- Garett Cheung,
- Tiffany Huang,
- Jinjiang Fan,
- Martine Culty,
- Bangyan Stiles,
- Kinji Asahina,
- Vassilios Papadopoulos
Affiliations
- Yuchang Li
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA
- Liting Chen
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA
- Lu Li
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA
- Chantal Sottas
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA
- Stephanie K. Petrillo
- Research Institute of the McGill University Health Center, Montreal, QC H4A 3J1, Canada; Department of Surgery, McGill University, Montreal, QC H3G 1A4, Canada
- Anthoula Lazaris
- Research Institute of the McGill University Health Center, Montreal, QC H4A 3J1, Canada; Department of Surgery, McGill University, Montreal, QC H3G 1A4, Canada
- Peter Metrakos
- Research Institute of the McGill University Health Center, Montreal, QC H4A 3J1, Canada; Department of Surgery, McGill University, Montreal, QC H3G 1A4, Canada
- Hangyu Wu
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA
- Yuji Ishida
- 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
- Takeshi Saito
- 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
- Lucy Golden-Mason
- 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
- Hugo R. Rosen
- 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
- Jeremy J. Wolff
- Bruker Daltonics, 40 Manning Road Billerica, MA 01821, USA
- Cristina I. Silvescu
- Bruker Daltonics, 40 Manning Road Billerica, MA 01821, USA
- Samuel Garza
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA
- Garett Cheung
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA
- Tiffany Huang
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA
- Jinjiang Fan
- Research Institute of the McGill University Health Center, Montreal, QC H4A 3J1, Canada; Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada
- Martine Culty
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA
- Bangyan Stiles
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA
- Kinji Asahina
- 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
- Vassilios Papadopoulos
- 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; Corresponding author
- Journal volume & issue
-
Vol. 24,
no. 5
p. 102457
Abstract
Summary: 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.
