Hepatic NPC1L1 promotes hyperlipidemia in LDL receptor deficient mice

Abstract

Background and aimsNiemann-Pick C1-like1 (NPC1L1), a crucial cholesterol absorption receptor expressed in human intestine and liver. But in mouse it is only expressed in intestine. Previous studies elucidated that expression of human NPC1L1 in mouse liver led to increase of plasma cholesterol due to activation of absorption from bile. However, hepatic NPC1L1 function was not elucidated in LDL receptor deficient mouse (LDLR−/−) in which LDL was a main lipoprotein as in human. Methods and resultsL1-Tg/LDLR−/− mouse was created by crossing liver-specific NPC1L1 transgenic mouse (L1-Tg) with LDLR−/−. L1-Tg/LDLR−/− mice developed hyperlipidemia when fed with atherogenic diet (AD) containing 0.2% cholesterol for 21days. Compared with control mice, biliary cholesterol level in L1-Tg/LDLR−/− mice was significantly lower, plasma cholesterol level was significantly higher in L1-Tg/LDLR−/− mice under both chow diet and AD feeding. New finding in this study is augmentations of plasma TAG L1-Tg/LDLR−/− mice fed with AD. Results were shown that very low density lipoprotein (VLDL) secretion was elevated in L1-Tg/LDLR−/− mice after AD fed. The increase of VLDL secretion was further confirmed by higher expression of hepatic triacylglycerol hydrolase (TGH) and microsomal triglyceride transfer protein (MTP). ConclusionL1-Tg/LDLR−/− mouse is a humanized model to study cholesterol absorption and transportation. The results obtained from L1-Tg/LDLR−/− mouse indicated no feedback mechanism to inhibit NPC1L1 function in liver and hepatic expression of NPC1L1 correlated with VLDL secretion in hypercholesterolemia state.