Targeting the Enterohepatic Bile Acid Signaling to Modulate Hepatic Autophagic Activity in Non-alcoholic steatohepatitis

Non-alcoholic steatohepatitis is associated with hepatic free cholesterol accumulation and defective autophagy activity, which sensitize hepatocytes to injury and inflammation. Bile acid synthesis is the only quantitatively significant mechanism for hepatic cholesterol catabolism. Stimulating bile acid synthesis prevented hypercholesterolemia and hepatic steatosis in mice. Autophagy delivers intracellularly stored cholesterol to the lysosome where cholesterol ester is hydrolyzed for subsequent cellular distribution, efflux and bile acid synthesis. The objective of this study is to investigate the molecular link between cholesterol and bile acid metabolism and autophagic activity in hepatocytes and in mouse models of fatty liver disease. Confocal microscopy, immunoblot and cathespin B activity assay showed that excessive intracellular free cholesterol accumulation caused by free cholesterol loading and inhibition of cholesterol esterification in the endoplasmic reticulum (ER) with an ACAT inhibitor blocked...