Purpose of review: The discovery of Niemann–Pick C1-like 1 (NPC1L1) and ezetimibe, a drug that lowers intestinal cholesterol absorption, has contributed to the recognition of the intestine as an important organ in whole-body cholesterol homeostasis. Unfortunately, the majority of the studies on NPC1L1 have been conducted in rodent models, which, in contrast to humans, do not express this protein in the liver. Thus the function of NPC1L1 in the liver is still not defined in detail. In this review, we discuss some of the recent progress in the understanding of the role of hepatic NPC1L1 in cholesterol metabolism.
Recent findings: Mice expressing human NPC1L1 in the liver have decreased biliary cholesterol concentration, suggesting the involvement of this protein in the hepatic reabsorption of biliary cholesterol. Studies in gallstone patients have shown that only women have decreased hepatic NPC1L1 expression, suggesting a possible role for the sex-related differences in cholesterol gallstone disease. Also, several transcription factors (e.g., sterol regulatory element-binding protein 2, hepatocyte nuclear factor 1α) appear to modulate the expression of NPC1L1.
Summary: Evidence suggests the involvement of NPC1L1 in biliary cholesterol uptake, HDL metabolism and cholesterol gallstone disease. Although difficult, studies in humans are required to further elucidate the function of this protein in the liver.