Investigating the behavior of NPC1L1 expressed in the mouse liver
The cholesterol transporter Niemann–Pick C1-like protein, or NPC1L1, efficiently absorbs cholesterol in the small intestine. The popular drug ezetimibe, marketed under the trade name Zetia, blocks function of this transporter, effectively lowering cholesterol levels, especially that of low-density lipoprotein. While NPC1L1 is found in abundance in the human liver, its relationship with liver-related cholesterol has not been clear. Another problem is that NPC1L1 is not present in the liver of mice, the primary animal model for NPC1L1 studies.
In a commentary appearing in the November issue of the Journal of Lipid Research, Philip N. Howles and editorial board member David Y. Hui of the University of Cincinnati College of Medicine discuss the findings presented in “Modulation of lipid metabolism with the overexpression of NPC1L1” by Makoto Kurano and colleagues at the University of Tokyo. Utilizing adenovirus-mediated, gene-transfer technology, human NPC1L1 was overexpressed in mouse liver, and the effects of this overexpression were examined in mice fed normal diets with or without ezetimibe.
As should be expected, the expression of NPC1L1 in the liver led to increased intrahepatic cholesterol as the efficiency of cholesterol absorption increased there. But there were two results that weren’t expected. Apolipoprotein E-rich lipoprotein was found in plasma, indicating there was increased uptake of cholesterol from bile, as overexpressed NPC1L1 was discovered to be located near channels of bile ducts. And VLDL triglyceride content decreased, explained by the authors as possibly being affected either by stress on the endoplasmic reticulum of liver cells or by the suppression of expression of the forkhead box protein O1 gene, known as FoxO1, directly by the overexpression of NPC1L1. Treatment with ezetimibe made minimal difference to these effects.
While there are significant differences between a mouse and a human — including the mouse’s lack of cholesteryl ester transfer protein, which plays a major role in lipoprotein metabolism in most mammals — this study and others point to NPC1L1 in the liver as having important functions not yet discovered.
Mary L. Chang (email@example.com) is managing editor of the Journal of Lipid Research and coordinating journal manager of the journal Molecular & Cellular Proteomics.