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

doi:10.1016/j.isci.2021.102457

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

iScience. 2021 May 1;24(5):102457. doi: 10.1016/j.isci.2021.102457. eCollection 2021 May 21.

Authors

Yuchang Li¹, Liting Chen¹, Lu Li¹, Chantal Sottas¹, Stephanie K Petrillo^{2

3}, Anthoula Lazaris^{2

3}, Peter Metrakos^{2

3}, Hangyu Wu¹, Yuji Ishida^{4

5}, Takeshi Saito^{4

6}, Lucy Golden-Mason^{4

6}, Hugo R Rosen^{4

6}, Jeremy J Wolff⁷, Cristina I Silvescu⁷, Samuel Garza¹, Garett Cheung¹, Tiffany Huang¹, Jinjiang Fan^{2

8}, Martine Culty¹, Bangyan Stiles¹, Kinji Asahina^{6

9

10}, Vassilios Papadopoulos^{1

2

8}

Affiliations

¹ Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA.
² Research Institute of the McGill University Health Center, Montreal, QC H4A 3J1, Canada.
³ Department of Surgery, McGill University, Montreal, QC H3G 1A4, Canada.
⁴ Department of Medicine, Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
⁵ Research & Development Department, PhoenixBio, Co., Ltd, Higashi-Hiroshima, Hiroshima, Japan.
⁶ University of Southern California Research Center for Liver Diseases, Los Angeles, CA 90089, USA.
⁷ Bruker Daltonics, 40 Manning Road Billerica, MA 01821, USA.
⁸ Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada.
⁹ Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
¹⁰ Southern California Research Center for ALPD and Cirrhosis, Los Angeles, CA 90089, USA.

Abstract

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.

Keywords: Cell biology; Metabolomics; Molecular biology.

Abstract

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