Liver plays a key role in cholesterol metabolism. Impaired hepatic cholesterol homeostasis causes intracellular free cholesterol accumulation and hepatocyte injury. Sortilin 1 (Sort1) is an intracellular lysosomal trafficking receptor that was recently identified by GWAS as a novel regulator of cholesterol metabolism in humans. Here we report that Sort1 deficiency protected against cholesterol accumulation-induced liver injury and inflammation in mice. Using LC-MS/MS based proteomics approach, we identified liver carboxyesterase 1 (CES1) as a novel Sort1 interacting protein. Mechanistic studies further showed that Sort1 may regulate CES1 lysosomal targeting and degradation, and Sort1-deficiency resulted in higher liver CES1 protein abundance. Previous studies have established an important role of hepatic CES1 in promoting intracellular cholesterol mobilization, cholesterol efflux and bile acid synthesis. Consistently, high cholesterol atherogenic diet-challenged sort1 knockout mice showed less hepatic free cholesterol accumulation, increased bile acid synthesis, decreased biliary cholesterol secretion and absence of gallstone formation. Sort1 deficiency did not alter hepatic ceramide and fatty acid metabolism in high cholesterol atherogenic diet-fed mice. Finally, knockdown of liver CES1 in mice markedly increased the susceptibility to high cholesterol diet-induced liver injury, and abolished the protective effect against cholesterol lipotoxicity in sort1 knockout mice. In summary, this study identified a novel Sort1-CES1 axis that regulates cholesterol-induced liver injury, which provides novel insights to improve our current understanding of the molecular links between Sort1 and cholesterol metabolism. This study further suggests that therapeutic inhibition of Sort1 may be beneficial in improving hepatic cholesterol homeostasis in metabolic and inflammatory liver diseases.

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