Distinct roles of insulin and liver X receptor in the induction and cleavage of sterol regulatory element-binding protein-1c.
Sterol regulatory element-binding proteins (SREBPs) are transcription factors central to the regulation of lipid metabolism. The SREBPs are synthesized as precursor proteins that require proteolytic processing to become transcriptionally active. Whereas the regulation of SREBP-1a and -2 cleavage by cellular sterol content is well defined, much less is known about the regulation of SREBP-1c, the predominant SREBP isoform in the liver. Both insulin and liver X receptor alpha (LXRalpha) induce SREBP-1c transcription; however, the respective roles of these factors and the mechanism responsible for proteolytic cleavage of this SREBP isoform are not known. In this study, we compare the effects of insulin and LXR agonist TO-901317 on SREBP-1c expression and transcriptional activity in isolated rat hepatocytes. We report that full induction of the mature and transcriptionally active form of SREBP-1c protein requires insulin. Although activation of LXR leads to the induction of SREBP-1c gene expression and precursor protein, it has a very poor effect in inducing the mature nuclear form of the transcription factor. This may be due to the induction of insulin-induced gene-2a mRNA and protein by LXR activation. The LXR-induced SREBP-1c precursor, however, is rapidly cleaved on acute exposure to insulin via a phosphatidylinositol 3-kinase-dependent mechanism. Finally, we show through experiments in suckling mice that this acute action of insulin to stimulate the proteolytic processing of SREBP-1c is functional in vivo.
Hegarty
Bronwyn D
BD
Institut National de la Santé et de la Recherche Médicale Unit 465, Université Paris 6, 15, Rue de l'Ecole de Médecine, 75006 Paris, France.
Bobard
Alexandre
A
Hainault
Isabelle
I
Ferré
Pascal
P
Bossard
Pascale
P
Foufelle
Fabienne
F
D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000737:chemistry / Q000378:metabolism; D006868:Hydrolysis; D007328:Insulin / Q000502:physiology*; D008099:Liver / Q000737:chemistry / Q000166:cytology; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D020033:Protein Isoforms / Q000235:genetics; D011499:Protein Processing, Post-Translational; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism / Q000502:physiology*; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D007328:Insulin; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; C000605215:Nr1h3 protein, rat; D057093:Orphan Nuclear Receptors; D020033:Protein Isoforms; D018160:Receptors, Cytoplasmic and Nuclear; C497389:Srebf1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D019869:Phosphatidylinositol 3-Kinases