Hepatocyte-specific IKKβ expression aggravates atherosclerosis development in APOE3-Leiden mice

• Published in: Atherosclerosis 2012-02, Vol.220 (2), p.362-368
• Main Authors: Wong, Man C, van Diepen, Janna A, Hu, Lihui, Guigas, Bruno, de Boer, Hetty C, van Puijvelde, Gijs H, Kuiper, Johan, van Zonneveld, Anton J, Shoelson, Steven E, Voshol, Peter J, Romijn, Johannes A, Havekes, Louis M, Tamsma, Jouke T, Rensen, Patrick C.N, Hiemstra, Pieter S, Berbée, Jimmy F.P
• Format: Article
• Language: English
• Subjects: Animals; Aortic Diseases - enzymology; Aortic Diseases - genetics; Aortic Diseases - immunology; Aortic Diseases - pathology; Apolipoprotein E3 - genetics; Apolipoprotein E3 - metabolism; atherogenesis; Atherosclerosis; Atherosclerosis (general aspects, experimental research); Atherosclerosis - enzymology; Atherosclerosis - genetics; Atherosclerosis - immunology; Atherosclerosis - pathology; Biological and medical sciences; Biomarkers - blood; Blood and lymphatic vessels; Cardiology. Vascular system; Cardiovascular; cholesterol; Cholesterol, VLDL - blood; cytokines; Cytokines - blood; diet; Diet, High-Fat; Disease Models, Animal; Female; Hepatocyte; hepatocytes; Hepatocytes - enzymology; Humans; I-kappa B Kinase - genetics; I-kappa B Kinase - metabolism; Inflammation; Inflammation - enzymology; Inflammation - genetics; Inflammation - immunology; Inflammation - pathology; Inflammation Mediators - blood; Lipid metabolism; lipopolysaccharides; Liver; low density lipoprotein; Medical sciences; Mice; Mice, Transgenic; Mouse models; NF-kappa B - metabolism; NF-κB; Orthopedic surgery; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Time Factors; transcription factor NF-kappa B; Up-Regulation
• ISSN: 0021-9150; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2011.06.055

Abstract Objective The liver is the key organ involved in systemic inflammation, but the relation between hepatic inflammation and atherogenesis is poorly understood. Since nuclear factor-κB (NF-κB) is a central regulator of inflammatory processes, we hypothesized that chronically enhanced hepatic NF-κB activation, through hepatocyte-specific expression of IκB kinase-β (IKKβ) ( LIKK ), will aggravate atherosclerosis development in APOE*3-Leiden ( E3L ) mice. Methods and results E3L.LIKK and E3L control littermates were fed a Western-type diet for 24 weeks. E3L.LIKK mice showed a 2.3-fold increased atherosclerotic lesion area and more advanced atherosclerosis in the aortic root with less segments without atherosclerotic lesions (11% vs. 42%), and more segments with mild (63% vs. 44%) and severe (26% vs. 14%) lesions. Expression of LIKK did not affect basal levels of inflammatory parameters, but plasma cytokine levels tended to be higher in E3L.LIKK mice after lipopolysaccharide (LPS) administration. E3L.LIKK mice showed transiently increased plasma cholesterol levels, confined to (V)LDL. This transient character resulted in a mild (+17%) increased cumulative plasma cholesterol exposure. Conclusion We conclude that selective activation of NF-κB in hepatocytes considerably promotes atherosclerosis development which is (at least partly) explained by an increased sensitivity to proinflammatory triggers and transiently increased plasma cholesterol levels.