Cholesterol-binding translocator protein TSPO regulates steatosis and bile acid synthesis in nonalcoholic fatty liver disease
Yuchang Li, Liting Chen, Lu Li, Chantal M. Sottas, Stephanie 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 L. Stiles, Kinji Asahina, Vassilios Papadopoulos
Abstract
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.