| First Author | van Diepen JA | Year | 2011 |
| Journal | J Lipid Res | Volume | 52 |
| Issue | 5 | Pages | 942-50 |
| PubMed ID | 21357939 | Mgi Jnum | J:171454 |
| Mgi Id | MGI:4949976 | Doi | 10.1194/jlr.M010405 |
| Citation | van Diepen JA, et al. (2011) Hepatocyte-specific IKK-{beta} activation enhances VLDL-triglyceride production in APOE*3-Leiden mice. J Lipid Res 52(5):942-50 |
| abstractText | Low-grade inflammation in different tissues, including activation of the nuclear factor kappaB 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. 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. |
