Insulin regulation of sterol regulatory element-binding protein-1 expression in L-6 muscle cells and 3T3 L1 adipocytes.
Sterol regulatory element-binding proteins (SREBPs) are transcription factors that regulate enzymes required for cholesterol and fatty acid synthesis. Expression of SREBP-1 is enhanced by insulin; however, the actual insulin-signaling cascades employed are yet unclear. We determined the roles of the phosphatidylinositol (PI) 3-kinase and mitogen-activated protein (MAP) kinase-dependent pathways in the effect of mediating insulin on SREBP-1 in L-6 skeletal muscle cells and 3T3 L1 adipocytes, using wortmannin or LY294002 to inhibit the PI 3-kinase pathway, and PD98059 to inhibit the MAP kinase-dependent pathway. In myocytes, insulin increased SREBP-1 protein in a dose-dependent manner. 1 and 10 nm insulin significantly increased expression of total cellular SREBP-1 protein at 24 and 48 h, nuclear SREBP-1 protein at 24 h, and SREBP-1a mRNA at 24 h. Although wortmannin and LY294002 had no effect on this aspect of insulin action, PD98059 completely blocked each of these responses. Transfection of a dominant negative mutant of Ras similarly blocked the insulin effect on SREBP-1. In contrast, in adipocytes, the insulin effect on SREBP-1 was mediated via the PI 3-kinase and not the MAP kinase pathway. In conclusion, although insulin increases skeletal muscle SREBP-1 expression in a dose-dependent fashion via the MAP kinase-dependent signaling pathway, insulin action on adipocyte SREBP-1 is mediated via the PI 3-kinase signaling pathway. In the state of insulin resistance, characterized by selective inhibition of the PI 3-kinase pathway, the usual stimulation of lipogenesis by insulin in adipocytes may be inhibited, whereas intramyocellular lipogenesis via the MAP kinase pathway of insulin may continue unabated.
Nadeau
Kristen J
KJ
Division of Pediatric Endocrinology, Department of Pediatrics, University of Colorado Health Sciences Center, 1056 East 19th Avenue, Denver, CO 80218, USA. kristen.nadeau@UCHSC.edu
Leitner
J Wayne
JW
Gurerich
Inga
I
Draznin
Boris
B
D041721:3T3-L1 Cells / Q000378:metabolism*; D017667:Adipocytes / Q000378:metabolism*; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D022762:CCAAT-Enhancer-Binding Proteins / Q000096:biosynthesis*; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D020935:MAP Kinase Signaling System; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism; D009132:Muscles / Q000166:cytology*; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D015398:Signal Transduction; D051780:Sterol Regulatory Element Binding Protein 1; D013997:Time Factors; D014157:Transcription Factors; D000077191:Wortmannin
D000730:Androstadienes; D022762:CCAAT-Enhancer-Binding Proteins; D002867:Chromones; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007328:Insulin; D009025:Morpholines; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D012313:RNA; D019869:Phosphatidylinositol 3-Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D000077191:Wortmannin