title: Insulin stimulation of SREBP-1c processing in transgenic rat hepatocytes requires p70 S6-kinase.
abstract: Insulin activates sterol regulatory element-binding protein-1c (SREBP-1c) in liver, thereby increasing fatty acid and triglyceride synthesis. We created a line of transgenic rats that produce epitope-tagged human SREBP-1c in liver under control of the constitutive apolipoprotein E promoter/enhancer. This system allows us to dissect the pathway by which insulin stimulates SREBP-1c processing without interference by the insulin-mediated increase in SREBP-1c mRNA. Rats are used because freshly isolated rat hepatocytes respond much more robustly to insulin than do mouse hepatocytes. The data reveal that insulin-mediated stimulation of SREBP-1c processing requires the mechanistic target of rapamycin complex 1 (mTORC1), which also is required for insulin-mediated SREBP-1c mRNA induction. However, in contrast to mRNA induction, insulin stimulation of SREBP-1c processing is blocked by an inhibitor of p70 S6-kinase. The data indicate that the pathways for insulin enhancement of SREBP-1c mRNA and proteolytic processing diverge after mTORC1. Stimulation of processing requires the mTORC1 target p70 S6-kinase, whereas induction of mRNA bypasses this enzyme. Insulin stimulation of both processes is blocked by glucagon. The transgenic rat system will be useful in further defining the molecular mechanism for insulin stimulation of lipid synthesis in liver in normal and diabetic states.
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Owen
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Soo-Han
authors.initials: SH
authors.lastname: Bae
authors.forename: Midhat S
authors.initials: MS
authors.lastname: Farooqi
authors.forename: Guosheng
authors.initials: G
authors.lastname: Liang
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hammer
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Goldstein
authors.forename: Michael S
authors.initials: MS
authors.lastname: Brown
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D018014:Gene Transfer Techniques; D005934:Glucagon; D006801:Humans; D015151:Immunoblotting; D007328:Insulin / Q000494:pharmacology*; D050155:Lipogenesis / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D011506:Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D060888:Real-Time Polymerase Chain Reaction; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases
chemical_list: D001057:Apolipoproteins E; D017931:DNA Primers; D007328:Insulin; D046912:Multiprotein Complexes; D011506:Proteins; D051780:Sterol Regulatory Element Binding Protein 1; D005934:Glucagon; D000076222:Mechanistic Target of Rapamycin Complex 1; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases