Role of NPC1L1 (Niemann‐Pick C1‐Like 1) in preventing hepatic steatosis

Abstract

NPC1L1 (Niemann‐Pick C1‐like 1) protein is known as a multipass membrane protein for cholesterol transport, found in liver and intestine, which involved in intracellular cholesterol synthesis and absorption. NPC1L1 inhibitor, ezetimibe has been used as a cholesterol‐lowering drug for diabetes and cardiovascular disease. Recently clinical studies also showed beneficial effects of ezetimibe on hepatic steatosis. The purpose of this study is to investigate molecular mechanism(s) by which NPC1L1 has an influence on hepatic steatosis. Ezetimibe (10 mg kg(−1)day(−1)) was administrated by stomach gavage in an animal model of type II diabetes with obesity, OLETF rat. Without changing body weight and food intake, 20 wks ezetimibe decreased significantly liver weight, liver cholesterol and TG amounts and concomitantly improved glycemic control. The cholesterol absorption inhibitor, ezetimibe altered liver gene expression; an increase of cholesterol influx, up‐regulation of cholesterol efflux and synthesis and no change in inflammation and insulin signaling. Furthermore, ezetimibe treatment significantly increased mRNA expression related to autophagy. In conclusion, ezetimibe might prevent and reverse fat accumulation in the liver as well as its complications such as systemic insulin resistance.