Novel Role of NPC1L1 in the Regulation of Hepatic Metabolism: Potential Contribution of Ezetimibe in NAFLD/NASH Treatment

Masayuki      Yoshida

doi:10.2174/157016111793744715

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries and also in other parts of the world. NAFLD encompasses a histological spectrum ranging from simple steatosis to steatohepatitis, advanced fibrosis and inflammatory changes. It frequently occurs with features of the metabolic syndrome including obesity, type 2 diabetes mellitus, dyslipidemia and hypertension. In fact, the metabolic syndrome is a strong predictor of NAFLD. Recently, Niemann-Pick C1-like 1 (NPC1L1) has been shown to play a pivotal role in cholesterol absorption. Unlike mouse NPC1L1 protein, predominantly expressed in the intestines, human and rat NPC1L1 is also abundantly expressed in the liver. Though the exact functions of hepatic NPC1L1 remain unknown, NPC1L1 may facilitate the hepatic accumulation of cholesterol. This raises a potential possibility that ezetimibe may improve fatty liver formation. In this review, potential role of lipid metabolism in NAFLD and its possible modulation through NPC1L1 blockade is discussed.

Keywords: NAFLD, NPC1L1, metabolic syndrome, insulin resistance, steatosis, steatohepa-titis, fibrosis, type 2 diabetes mellitus, dyslipidemia, hypertension, Niemann-Pick C1-like 1, adipogenic/lipogenic, alcoholic steatohepatitis (NASH), transcription factor PPAR, lipogenic factor SREBP, C/EBP, Ezetimibe, hepatocytes, tu-mor necrosis factor (TNF), lipopolysaccaride (LPS)-mediated steatosis, unfolded pro-tein response (UPR), splanchnic lipolysis, ZOF rats, Akt phosphorylation, gluconeogenic en-zymes (PEPCK and G6Pase), SREBP1c, ChREBP, FoxO1, CHOP, p38, methionine choline-deficient, TNF-alpha, SREBP2, HNF1