title: Hepatocyte-specific IKK-β activation enhances VLDL-triglyceride production in APOE*3-Leiden mice.
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.
authors.affiliation: Department of General Internal Medicine, Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands. J.A.van_Diepen@lumc.nl
authors.forename: Janna A
authors.initials: JA
authors.lastname: van Diepen
authors.forename: Man C
authors.initials: MC
authors.lastname: Wong
authors.forename: Bruno
authors.initials: B
authors.lastname: Guigas
authors.forename: Jasper
authors.initials: J
authors.lastname: Bos
authors.forename: Rinke
authors.initials: R
authors.lastname: Stienstra
authors.forename: Leanne
authors.initials: L
authors.lastname: Hodson
authors.forename: Steven E
authors.initials: SE
authors.lastname: Shoelson
authors.forename: Jimmy F P
authors.initials: JF
authors.lastname: Berbée
authors.forename: Patrick C N
authors.initials: PC
authors.lastname: Rensen
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Romijn
authors.forename: Louis M
authors.initials: LM
authors.lastname: Havekes
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Voshol
mesh_terms: D000818:Animals; D053318:Apolipoprotein E3 / Q000378:metabolism*; D001057:Apolipoproteins E / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D015228:Hypertriglyceridemia / Q000235:genetics / Q000378:metabolism; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D008079:Lipoproteins, VLDL / Q000096:biosynthesis*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D014280:Triglycerides / Q000096:biosynthesis*
chemical_list: D053318:Apolipoprotein E3; D001057:Apolipoproteins E; D008079:Lipoproteins, VLDL; D014280:Triglycerides; C030106:very low density lipoprotein triglyceride; D051550:I-kappa B Kinase