Regulation of microsomal triglyceride transfer protein gene by insulin in HepG2 cells: roles of MAPKerk and MAPKp38.
Microsomal triglyceride transfer protein (MTP) is rate limiting for the assembly and secretion of apolipoprotein B-containing lipoproteins. Elevated hepatic MTP mRNA level, presumably as a result of impaired insulin signaling, has been implicated in the pathophysiology of dyslipidemia associated with insulin resistance/type 2 diabetes. In this study, we showed that insulin decreases MTP mRNA level mainly through transcriptional regulation in HepG2 cells. We further characterized the corresponding signal transduction pathway, using chemical inhibitors and constitutively active and dominant negative forms of regulatory enzymes. We demonstrated that insulin inhibits MTP gene transcription through MAPK(erk) cascade but not through the PI 3-kinase pathway. Activation of ras through farnesylation is not a prerequisite for the inhibition. In addition, cellular MAPK(erk) and MAPK(p38) activities play a counterbalancing role in regulating the MTP gene transcription. These complex regulations may represent a means to fine-tuning MTP gene transcription in response to a diverse set of environmental stimuli and may have important implications for the onset and development of diabetes-associated dyslipidemia.
Au
Wo-Shing
WS
Institute of Molecular Biology, Open Laboratory of Chemical Biology of the Institute of Molecular Technology for Drug Discovery and Synthesis, the University of Hong Kong, Pokfulam, Hong Kong, China.
Kung
Hsiang-fu
HF
Lin
Marie C
MC
D006528:Carcinoma, Hepatocellular; D002352:Carrier Proteins / Q000187:drug effects / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D007700:Kinetics; D008113:Liver Neoplasms; D008861:Microsomes / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases
D002352:Carrier Proteins; D007328:Insulin; D012333:RNA, Messenger; C106092:microsomal triglyceride transfer protein; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases