Coordinated regulation of hepatic FoxO1, PGC-1α and SREBP-1c facilitates insulin action and resistance |
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| Institution: | 1. Medical and Research Services, James A. Haley Veterans Administration Hospital, Department of Internal Medicine, University of South Florida College of Medicine, Tampa, FL 33704, USA;2. Institut National de la Sante et de la Recherche Medicale (INSERM) UMRS 1138, Sorbonne Universites, UMPC Universite Paris 06, Sorbonne Paris Cite, Universite Paris Descartes, Universite Paris Diderot, Centre de Recherche Biomedicales des Cordeliers, Paris, France;1. Department of Fundamental and Applied Neurobiology, Serbsky Federal Medical Research Center of Psychiatry and Narcology, 119991 Moscow, Russia;2. Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, Moscow 125315, Russia;3. Department of Biophysics, Biological Faculty, Moscow State University, Moscow 119991, Russia;4. Institute for Atherosclerosis Research, Skolkovo Innovative Center, Moscow 121609, Russia;5. School of Medicine, University of Western Sydney, Campbelltown, NSW 2560, Australia |
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| Abstract: | Type 2 diabetes is characterized by insulin resistance, hyperinsulinemia and hepatic overproduction of glucose and lipids. Insulin increases lipogenic enzyme expression by activating Akt and aPKC which activate SREBP-1c; this pathway is hyperactivated in insulin-resistant states. Insulin suppresses gluconeogenic enzyme expression by Akt-dependent phosphorylation/inactivation of FoxO1 and PGC-1α; this pathway is impaired in insulin-resistant states by aPKC excess, which displaces Akt from scaffolding-protein WD40/ProF, where Akt phosphorylates/inhibits FoxO1. But how PGC-1α and FoxO1 are coordinated in insulin action and resistance is uncertain. Here, in normal mice, we found, along with Akt and aPKC, insulin increased PGC-1α association with WD40/ProF by an aPKC-dependent mechanism. However, in insulin-resistant high-fat-fed mice, like FoxO1, PGC-1α phosphorylation was impaired by aPKC-mediated displacement of Akt from WD40/ProF, as aPKC inhibition diminished its association with WD40/ProF, and simultaneously restored Akt association with WD40/ProF and phosphorylation/inhibition of both PGC-1α and FoxO1. Moreover, in high-fat-fed mice, in addition to activity, PGC-1α expression was increased, not only by FoxO1 activation, but also, as found in human hepatocytes, by a mechanism requiring aPKC and SREBP-1c, which also increased expression and activity of PKC-ι. In high-fat-fed mice, inhibition of hepatic aPKC, not only restored Akt association with WD40/ProF and FoxO1/PGC-1α phosphorylation, but also diminished expression of SREBP-1c, PGC-1α, PKC-ι and gluconeogenic and lipogenic enzymes, and corrected glucose intolerance and hyperlipidemia. Conclusion: Insulin suppression of gluconeogenic enzyme expression is facilitated by coordinated inactivation of FoxO1 and PGC-1α by WD40/ProF-associated Akt; but this coordination also increases vulnerability to aPKC hyperactivity, which is abetted by SREBP-1c-induced increases in PGC-1α and PKC-ι. |
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