title: Reduced expression of adipose triglyceride lipase enhances tumor necrosis factor alpha-induced intercellular adhesion molecule-1 expression in human aortic endothelial cells via protein kinase C-dependent activation of nuclear factor-kappaB.
abstract: We examined the effects of adipose triglyceride lipase (ATGL) on the initiation of atherosclerosis. ATGL was recently identified as a rate-limiting triglyceride (TG) lipase. Mutations in the human ATGL gene are associated with neutral lipid storage disease with myopathy, a rare genetic disease characterized by excessive accumulation of TG in multiple tissues. The cardiac phenotype, known as triglyceride deposit cardiomyovasculopathy, shows massive TG accumulation in both coronary atherosclerotic lesions and the myocardium. Recent reports show that myocardial triglyceride content is significantly higher in patients with prediabetes or diabetes and that ATGL expression is decreased in the obese insulin-resistant state. Therefore, we investigated the effect of decreased ATGL activity on the development of atherosclerosis using human aortic endothelial cells. We found that ATGL knockdown enhanced monocyte adhesion via increased expression of TNFα-induced intercellular adhesion molecule-1 (ICAM-1). Next, we determined the pathways (MAPK, PKC, or NFκB) involved in ICAM-1 up-regulation induced by ATGL knockdown. Both phosphorylation of PKC and degradation of IκBα were increased in ATGL knockdown human aortic endothelial cells. In addition, intracellular diacylglycerol levels and free fatty acid uptake via CD36 were significantly increased in these cells. Inhibition of the PKC pathway using calphostin C and GF109203X suppressed TNFα-induced ICAM-1 expression. In conclusion, we showed that ATGL knockdown increased monocyte adhesion to the endothelium through enhanced TNFα-induced ICAM-1 expression via activation of NFκB and PKC. These results suggest that reduced ATGL expression may influence the atherogenic process in neutral lipid storage diseases and in the insulin-resistant state.
authors.affiliation: Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Inoue
authors.forename: Kunihisa
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Toyoshi
authors.initials: T
authors.lastname: Inoguchi
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Sonoda
authors.forename: Masakazu
authors.initials: M
authors.lastname: Fujii
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Maeda
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Fujimura
authors.forename: Daisuke
authors.initials: D
authors.lastname: Miura
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Hirano
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Takayanagi
mesh_terms: D001011:Aorta; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology; D007333:Insulin Resistance / Q000235:genetics; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis* / Q000235:genetics; D008049:Lipase / Q000235:genetics / Q000378:metabolism*; D008301:Maleimides / Q000494:pharmacology; D009000:Monocytes / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D020298:U937 Cells; D015854:Up-Regulation; D000217:Acyltransferases
chemical_list: D018955:CD36 Antigens; D004791:Enzyme Inhibitors; D020672:I-kappa B Proteins; D007211:Indoles; D018799:Intercellular Adhesion Molecule-1; D008049:Lipase; D008301:Maleimides; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D009281:Naphthalenes; D011493:Protein Kinase C; D014409:Tumor Necrosis Factor-alpha; C000606204:NFKBIA protein, human; C494794:PNPLA2 protein, human; D000217:Acyltransferases; C058819:calphostin C; C070515:bisindolylmaleimide I