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

Low-grade inflammation in different tissues, including activation of the nuclear factor kappa 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)-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 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-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- specific 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.jlr These findings implicate that specific activation of inflammatory pathways exclusively within hepatocytes induces hypertriglyceridemia. Furthermore, we identify the hepatocytic IKK-beta pathway as a possible target to treat hypertriglyceridemia. van Diepen, J. A., M. C. Wong, B. Guigas, J. Bos, R. Stienstra, L. Hodson, S. E. Shoelson, J. F. P. Berbee, P. C. N. Rensen, J. A. Romijn, L. M. Havekes, and P. J. Voshol. Hepatocyte-specific IKK-beta activation enhances VLDL-triglyceride production in APOE*3-Leiden mice. J. Lipid Res. 2011. 52: 942-950.