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


ABSTRACT: Low-grade inflammation in different tissues, including activation of the nuclear factor ?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-specific overexpression of IkB kinase (IKK)-? and hypertriglyceridemia, an important risk factor for CVD, by evaluating whether activation of IKK-? only in the hepatocyte affects VLDL-triglyceride (TG) metabolism directly. Transgenic overexpression of constitutively active human IKK-? 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-? overexpression also enhances TG secretion in vitro, indicating a direct relation between IKK-? 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-? 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-? pathway as a possible target to treat hypertriglyceridemia.

SUBMITTER: van Diepen JA 

PROVIDER: S-EPMC3073472 | biostudies-other | 2011 May

REPOSITORIES: biostudies-other

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

van Diepen Janna A JA   Wong Man C MC   Guigas Bruno B   Bos Jasper J   Stienstra Rinke R   Hodson Leanne L   Shoelson Steven E SE   Berbée Jimmy F P JF   Rensen Patrick C N PC   Romijn Johannes A JA   Havekes Louis M LM   Voshol Peter J PJ  

Journal of lipid research 20110228 5


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. Tr  ...[more]

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