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Hepatocyte-specific IKK-β activation enhances VLDL-triglyceride production in APOE*3-Leiden mice.

Authors
  • van Diepen, Janna A
  • Wong, Man C
  • Guigas, Bruno
  • Bos, Jasper
  • Stienstra, Rinke
  • Hodson, Leanne
  • Shoelson, Steven E
  • Berbée, Jimmy F P
  • Rensen, Patrick C N
  • Romijn, Johannes A
  • Havekes, Louis M
  • Voshol, Peter J
Type
Published Article
Journal
Journal of lipid research
Publication Date
May 01, 2011
Volume
52
Issue
5
Pages
942–950
Identifiers
DOI: 10.1194/jlr.M010405
PMID: 21357939
Source
Medline
License
Unknown

Abstract

Low-grade inflammation in different tissues, including activation of the nuclear factor κB pathway in liver, is involved in metabolic disorders such as type 2 diabetes and cardiovascular diseases (CVDs). In this study, we investigated the relation between chronic hepatocyte-specific overexpression of IkB kinase (IKK)-β and hypertriglyceridemia, an important risk factor for CVD, by evaluating whether activation of IKK-β only in the hepatocyte affects VLDL-triglyceride (TG) metabolism directly. Transgenic overexpression of constitutively active human IKK-β specifically in hepatocytes of hyperlipidemic APOE*3-Leiden mice clearly induced hypertriglyceridemia. Mechanistic in vivo studies revealed that the hypertriglyceridemia was caused by increased hepatic VLDL-TG production rather than a change in plasma VLDL-TG clearance. Studies in primary hepatocytes showed that IKK-β overexpression also enhances TG secretion in vitro, indicating a direct relation between IKK-β activation and TG production within the hepatocyte. Hepatic lipid analysis and hepatic gene expression analysis of pathways involved in lipid metabolism suggested that hepatocyte-specific IKK-β overexpression increases VLDL production not by increased steatosis or decreased FA oxidation, but most likely by carbohydrate-responsive element binding protein-mediated upregulation of Fas expression. These findings implicate that specific activation of inflammatory pathways exclusively within hepatocytes induces hypertriglyceridemia. Furthermore, we identify the hepatocytic IKK-β pathway as a possible target to treat hypertriglyceridemia.

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