Insulin regulation of sterol regulatory element-binding protein-1 expression in L-6 muscle cells and 3T3 L1 adipocytes.

Abstract

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.

• Authors: Kristen J Nadeau, J Wayne Leitner, Inga Gurerich, Boris Draznin
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 279 Issue 33 Pg. 34380-7 (Aug 13 2004) ISSN: 0021-9258 [Print] United States
• PMID: 15187085 (Publication Type: Journal Article)

Chemical References

• Androstadienes
• CCAAT-Enhancer-Binding Proteins
• Chromones
• DNA-Binding Proteins
• Enzyme Inhibitors
• Flavonoids
• Insulin
• Morpholines
• Srebf1 protein, mouse
• Sterol Regulatory Element Binding Protein 1
• Transcription Factors
• 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
• RNA
• Phosphatidylinositol 3-Kinases
• 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
• Wortmannin

Topics

• 3T3-L1 Cells (metabolism)
• Adipocytes (metabolism)
• Androstadienes (pharmacology)
• Animals
• Blotting, Western
• CCAAT-Enhancer-Binding Proteins (biosynthesis)
• Cell Line
• Chromones (pharmacology)
• DNA-Binding Proteins (biosynthesis)
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (pharmacology)
• Flavonoids (pharmacology)
• Insulin (metabolism)
• Insulin Resistance
• MAP Kinase Signaling System
• Mice
• Morpholines (pharmacology)
• Muscle, Skeletal (cytology, metabolism)
• Muscles (cytology)
• Mutation
• Phosphatidylinositol 3-Kinases (metabolism)
• RNA (metabolism)
• Signal Transduction
• Sterol Regulatory Element Binding Protein 1
• Time Factors
• Transcription Factors
• Wortmannin