Al-Rasheed Nawal M, Chana Ravinder S, Baines Richard J, Willars Gary B, Brunskill Nigel J
Department of Cell Physiology and Pharmacology, University of Leicester, Leicester LE1 9HN, United Kingdom.
J Biol Chem. 2004 Nov 26;279(48):49747-54. doi: 10.1074/jbc.M408268200. Epub 2004 Sep 16.
Peroxisome proliferator-activated receptor gamma (PPARgamma) has key roles in the regulation of adipogenesis, inflammation, and lipid and glucose metabolism. C-peptide is believed to be inert and without appreciable biological functions. Recent studies suggest that C-peptide possesses multiple functions. The present study investigated the effects of insulin and C-peptide on PPARgamma transcriptional activity in opossum kidney proximal tubular cells. Both insulin and C-peptide induced a concentration-dependent stimulation of PPARgamma transcriptional activity. Both agents substantially augmented thiazolidinedione-stimulated PPARgamma transcriptional activity. Neither insulin nor C-peptide had any effect on the expression levels of PPARgamma. GW9662, a PPARgamma antagonist, blocked PPARgamma activation by thiazolidinediones but had no effect on either insulin- or C-peptide-stimulated PPARgamma transcriptional activity. Co-transfection of opossum kidney cells with dominant negative mitogen-activated protein kinase kinase significantly depressed basal PPARgamma transcriptional activity but had no effect on that induced by either insulin or C-peptide. Both insulin- and C-peptide-stimulated PPARgamma transcriptional activity were attenuated by wortmannin and by expression of a dominant negative phosphatidylinositol (PI) 3-kinase p85 regulatory subunit. In addition PI 3-kinase-dependent phosphorylation of PPARgamma was observed after stimulation by C-peptide or insulin. C-peptide effects but not insulin on PPARgamma transcriptional activity were abolished by pertussis toxin pretreatment. Finally both C-peptide and insulin positively control the expression of the PPARgamma-regulated CD36 scavenger receptor in human THP-1 monocytes. We concluded that insulin and C-peptide can stimulate PPARgamma activity in a ligand-independent fashion and that this effect is mediated by PI 3-kinase. These results support a new and potentially important physiological role for C-peptide in regulation of PPARgamma-related cell functions.
过氧化物酶体增殖物激活受体γ（PPARγ）在脂肪生成、炎症以及脂质和葡萄糖代谢的调节中起关键作用。C肽被认为是无活性的，没有明显的生物学功能。最近的研究表明C肽具有多种功能。本研究调查了胰岛素和C肽对负鼠肾近端小管细胞中PPARγ转录活性的影响。胰岛素和C肽均诱导了PPARγ转录活性的浓度依赖性刺激。两种药物均显著增强了噻唑烷二酮刺激的PPARγ转录活性。胰岛素和C肽对PPARγ的表达水平均无任何影响。GW9662，一种PPARγ拮抗剂，可阻断噻唑烷二酮对PPARγ的激活，但对胰岛素或C肽刺激的PPARγ转录活性均无影响。将负鼠肾细胞与显性负性丝裂原活化蛋白激酶激酶共转染可显著降低基础PPARγ转录活性，但对胰岛素或C肽诱导的活性无影响。渥曼青霉素和显性负性磷脂酰肌醇（PI）3激酶p85调节亚基的表达均减弱了胰岛素和C肽刺激的PPARγ转录活性。此外，在C肽或胰岛素刺激后观察到PPARγ的PI 3激酶依赖性磷酸化。百日咳毒素预处理消除了C肽对PPARγ转录活性的影响，但未消除胰岛素的影响。最后，C肽和胰岛素均正向调控人THP-1单核细胞中PPARγ调节的CD36清道夫受体的表达。我们得出结论，胰岛素和C肽可以以不依赖配体的方式刺激PPARγ活性，并且这种作用是由PI 3激酶介导的。这些结果支持了C肽在调节PPARγ相关细胞功能方面具有新的且潜在重要的生理作用。
