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      Modulation of lipid metabolism with the overexpression of NPC1L1 in mouse liver.

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          Abstract

          Niemann-Pick C1-like 1 protein (NPC1L1), a transporter crucial in intestinal cholesterol absorption, is expressed in human liver but not in murine liver. To elucidate the role of hepatic NPC1L1 on lipid metabolism, we overexpressed NPC1L1 in murine liver utilizing adenovirus-mediated gene transfer. C57BL/6 mice, fed on normal chow with or without ezetimibe, were injected with NPC1L1 adenovirus (L1-mice) or control virus (Null-mice), and lipid analyses were performed five days after the injection. The plasma cholesterol levels increased in L1-mice, and FPLC analyses revealed increased cholesterol contents in large HDL lipoprotein fractions. These fractions, which showed α-mobility on agarose electrophoresis, were rich in apoE and free cholesterol. These lipoprotein changes were partially inhibited by ezetimibe treatment and were not observed in apoE-deficient mice. In addition, plasma and VLDL triglyceride (TG) levels decreased in L1-mice. The expression of microsomal triglyceride transfer protein (MTP) was markedly decreased in L1-mice, accompanied by the reduced protein levels of forkhead box protein O1 (FoxO1). These changes were not observed in mice with increased hepatic de novo cholesterol synthesis. These data demonstrate that cholesterol absorbed through NPC1L1 plays a distinct role in cellular and plasma lipid metabolism, such as the appearance of apoE-rich lipoproteins and the diminished VLDL-TG secretion.

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          Author and article information

          Journal
          J. Lipid Res.
          Journal of lipid research
          American Society for Biochemistry & Molecular Biology (ASBMB)
          1539-7262
          0022-2275
          Nov 2012
          : 53
          : 11
          Affiliations
          [1 ] Departments of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Japan.
          Article
          jlr.M026575
          10.1194/jlr.M026575
          3465997
          22891292
          ea05cbb4-4a76-42f0-824f-615a1b8fc599
          History

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