Title
Hepatocyte-specifi c IKK- beta activation enhances VLDL-triglyceride production in APOE*3-Leiden mice
Author
TNO Kwaliteit van Leven
Diepen, J.A.V.
Wong, M.C.
Guigas, B.
Bos, J.
Stienstra, R.
Hodson, L.
Shoelson, S.E.
Jimmy F. P. Berbée,
Rensen, P.C.N.
Romijn, J.A.
Havekes, L.M.
Voshol, P.J.
Publication year
2011
Abstract
Low-grade inflammation in different tissues, including activation of the nuclear factor k B 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-specifi c overexpression of IkB kinase (IKK)- beta and hypertriglyceridemia, an important risk factor for CVD, by evaluating whether activation of IKK- beta only in the hepatocyte affects VLDL-triglyceride (TG) metabolism directly. Transgenic overexpression of constitutively active human IKK- beta specifi cally 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- beta overexpression also enhances TG secretion in vitro, indicating a direct relation between IKK- beta activation and TG production within the hepatocyte. Hepatic lipid analysis and hepatic gene expression analysis of pathways involved in lipid metabolism suggested that hepatocyte- specifi c IKK- beta 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 fi ndings implicate that specifi c activation of infl ammatory pathways exclusively within hepatocytes induces hypertriglyceridemia. Furthermore, we identify the hepatocytic IKK- beta pathway as a possible target to treat hypertriglyceridemia. Copyright © 2011 by the American Society for Biochemistry and Molecular Biology, Inc.
Subject
EELS - Earth, Environmental and Life Sciences
Life
I k B kinase beta
Lipid metabolism
Liver
Nuclear factor kappa B
Very low density lipoprotein
MHR - Metabolic Health Research
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http://resolver.tudelft.nl/uuid:cf99fd7c-2166-4f03-9d00-78ad61299b2c
DOI
https://doi.org/10.1194/jlr.m010405
TNO identifier
429284
ISSN
0022-2275
Source
Journal of Lipid Research, 52 (52), 942-950
Document type
article