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

Makoto Kurano, Masumi Hara, Koichi Tsuneyama, Koji Okamoto, Naoyuki Iso-O, Teruhiko Matsushima, Kazuhiko Koike, Kazuhisa Tsukamoto

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)

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 fi ve 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-defi cient 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.

Original languageEnglish
Pages (from-to)2275-2285
Number of pages11
JournalJournal of lipid research
Volume53
Issue number11
DOIs
Publication statusPublished - 2012 Nov
Externally publishedYes

Keywords

  • ApoE-rich lipoprotein
  • Biliary cholesterol
  • Ezetimibe
  • Niemann-Pick C1-like 1 protein

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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