| Autor: |
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. |
| Přispěvatelé: |
TNO Kwaliteit van Leven |
| Jazyk: |
angličtina |
| Rok vydání: |
2011 |
| Předmět: |
|
| Zdroj: |
Journal of Lipid Research, 5, 52, 942-950 |
| Popis: |
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)- 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 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- 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- specifi c 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 fi ndings implicate that specifi c activation of infl ammatory pathways exclusively within hepatocytes induces hypertriglyceridemia. Furthermore, we identify the hepatocytic IKK- β pathway as a possible target to treat hypertriglyceridemia. Copyright © 2011 by the American Society for Biochemistry and Molecular Biology, Inc. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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