Stard1 promotes cholestatic liver injury and disease progression by sensitizing to bile acid hepatotoxicity

Background and Aims: Cholestatic liver diseases are often accompanied by hepatocellular injury, fibrosis, and cirrhosis due to the intracellular accumulation of solutes that cannot be excreted into bile, including bile acids (BAs). These are synthesized in hepatocytes from cholesterol mainly via the classic pathway and in a lower proportion through the mitochondrial acidic pathway. The latter requires STARD1-dependent cholesterol transport to the mitochondrial inner membrane for metabolism, whose contribution to BA-induced hepatotoxicity and cholestatic liver disease is unknown. Approach and Results: Here we show that patients with primary biliary cholangitis exhibit increased expression of STARD1 compared to control subjects. Mice with hepatocyte-specific Stard1 deletion ( Stard1 Δhep ) were more resistant to experimental models of complete (bile duct ligation) and chemical obstructive cholestasis-induced liver injury, inflammation, and fibrosis than Stard1 f/f mice. Stard1 Δhep mice exhibited reduced hepatic BAs and mitochondrial cholesterol accumulation but increased mitochondrial glutathione levels following bile duct ligation compared to Stard1 f/f mice. Pharmacological mGSH depletion sensitized primary mouse hepatocytes to a mix of BAs mimicking the profile seen in Stard1 f/f mice after bile duct ligation leading to increased inflammatory response and cytotoxicity. Conclusions: These findings highlight a role for STARD1 in cholestatic liver injury and suggest that its targeting may be of relevance for cholestatic liver disease.