Abstract 11292: Modulation of Lipoprotein and Glucose Metabolism with the Over-expression of Niemann-pick C1 Like 1 Protein (NPC1L1) In Mice Liver
Background: Niemann-Pick C1 like 1 Protein (NPC1L1), a target protein of ezetimibe, is expressed not only in the small intestine but also in the liver of humans, while its expression in the liver of mice has been shown to be little. To elucidate the role of hepatic NPC1L1 expression on lipoprotein and glucose metabolism, we over-expressed NPC1L1 in mice liver utilizing adenoviral gene transfer.
Methods & Results: C57BL/6 mice, fed on normal chow with or without ezetimibe for 4 weeks, were injected with NPC1L1 adenovirus (L1-mice) or control virus (C-mice). Four and 5 days after injection, we analyzed glucose metabolism and plasma lipid profiles, respectively. The plasma cholesterol levels increased in L1-mice (C-mice 96 mg/dl vs L1-mice 155 mg/dl); the FPLC profile of pooled plasma revealed increased cholesterol contents in the LDL-sized and large HDL-sized lipoprotein fractions. The large HDL fractions, which showed α-mobility on agarose electrophoresis, were rich in apoE and free cholesterol (55.3% of total cholesterol). The expression of ABCA1 protein, which is important for the maturation of apoA-I containing HDL, was not altered in L1-mice. These lipoprotein changes in L1-mice were partially reversed by ezetimibe treatment. Plasma TG levels and TG contents of VLDL fractions were decreased in L1-mice (plasma TG: C-mice 146 mg/dl vs L1-mice 87 mg/dl). Expression of hepatic MTP, which is important for the hepatic VLDL-TG secretion and known to be negatively regulated by SREBP-2 and insulin pathway, was markedly decreased in L1-mice (26% of the control). While the nuclear SREBP-1 and -2 were not increased in the liver of L1-mice, insulin tolerance test revealed an increased insulin sensitivity in L1-mice, which was partially reversed with ezetimibe treatment. These results suggested that hepatic NPC1L1 not only reduced cholesterol secretion in the bile which was reported previously, but also affected hepatic lipid, lipoprotein and glucose metabolism.
Conclusions: Hepatic NPC1L1 expression not only induced the secretion of apoE-rich large HDL particles, but also reduced VLDL-TG secretion by down-regulating MTP which was possibly due to the increase in hepatic insulin sensitivity.
- © 2010 by American Heart Association, Inc.