The TSPO ligand 3,17,19‐androsten‐5‐triol attenuates NASH by increasing FXR expression and autophagy

Abstract

Translocator protein (TSPO; 18 kDa) is a ubiquitous high‐affinity cholesterol‐ and drug‐binding protein located in the outer mitochondrial membrane. 3,17,19‐androsten‐5‐triol (19‐Atriol) is a ligand binding at the cholesterol recognition amino acid consensus domain of TSPO. Our previous study suggested that TSPO deficiency ameliorated methionine‐choline‐deficient induced non‐alcoholic steatohepatitis (NASH) through downregulation of bile acid synthesis (Li et al., iScience 24: 102457, 2021). We examined the role of cholesterol binding to TSPO in NASH using the 19‐Atriol on high‐fat‐fructose‐cholesterol diet (HFFC)‐induced NASH in rats. After HFFC‐feeding for 13weeks, the rats were subcutaneously administered daily 19‐Atriol (20mg/kg) for 2 weeks (weeks 13‐15). The ratio of liver/body weight and serum triacylglycerol content were significantly reduced in 19‐Atriol‐ compared to vehicle‐treated rats. Immunoblot analyses indicated that liver inflammation (TNFα) and fibrosis markers (COL1A1, ACTA2) were reduced following 19‐Atriol treatment. Farnesoid X receptor (FXR), a bile acid receptor, was upregulated in response to 19‐Atriol treatment in HFFC‐fed rats. In search of the mechanism mediating the effects of 19‐Atriol we observed an increase in autophagy flux and the levels of phosphorylated transcription factor EB (TFEB), a major regulator of autophagy and lysosomal biogenesis. Taken together these results suggest that blocking cholesterol binding to TSPO by 19‐Atriol leads to the attenuation of NASH by increasing FXR expression levels and activating of autophagic degradation as was the case in TSPO‐deficient rats.