Regulation of Microsomal Triglyceride Transfer Protein Gene by Insulin in HepG2 Cells

doi:10.2337/diabetes.52.5.1073

Regulation of Microsomal Triglyceride Transfer Protein Gene by Insulin in HepG2 Cells

Roles of MAPK^erk and MAPK^p38

From the 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, Hong Kong, China

Abstract

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.

Footnotes

Address correspondence and reprint requests to Marie C. Lin, Institute of molecular biology, the University of Hong Kong, Pokfulam, Hong Kong. E-mail: mcllin{at}hkusua.hku.hk.

Received for publication 13 September 2002 and accepted in revised form 27 January 2003.

apoB, apolipoprotein B; ER, endoplasmic reticulum; FBS, fetal bovine serum; LDL-R, LDL receptor; MAPK, mitogen-activated protein kinase; MTP, microsomal triglyceride transfer protein; PI 3-K, phosphatidylinositol 3-kinase; SREBP, sterol responsive element binding proteins.
DIABETES