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    Mitochondrial fatty acid oxidation and metabolic diseases

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    Principal Investigator : Carina Prip-Buus

    Contact: - Phone: +33 1 53 73 27 04

     

     

    Objective

     

    Reduced mitochondrial fatty acid oxidation (mFAO) and ectopic lipid accumulation in the liver and skeletal muscle have been proposed as a link to explain insulin resistance, a hallmark feature of obesity and type 2 diabetes. Indeed, increased lipid supply to tissues, exceeding their oxidative capacities, leads to the accumulation of intermediate lipotoxic metabolites that interfere with insulin signaling and induce insulin resistance. The malonyl-CoA/CPT1 partnership is considered as a « fuel sensor » regulating the rate of mFAO according to the relative disposal of LCFA and glucose. However, direct evidence for such a role remains poorly investigated in different pathophysiological situations. Therefore, our objective is to investigate in the liver and skeletal muscle, two target tissues of insulin action, the pathophysiological importance of the control of CPT1 activity by malonyl-CoA in relation to mitochondrial function.

    The group

    Corinne Vons (MD, PU-PH AP-HP researcher), Nada Helmy (MD, on going PhD), Eliska Vavrova (on going PhD), and Véronique Lenoir (Engineer IE).

     

    Research interests

     

    Skeletal muscle: we showed that the expression of a constitutively active CPT1 (CPT1mt, i.e. insensitive to malonyl-CoA inhibition) in cultured myotubes increased mFAO and protect cells from palmitate-induced apoptosis and insulin resistance (Hénique 2010). When expressed in the mouse Tibialis anterior using the in vivo electrotransfer technology, CPT1mt expression induced muscle remodelling towards an oxidative phenotype that mimicked physical exercise and reversed aging-associated muscle alterations (Hénique 2015). Our goal is now to determine, using the transgenic approach (LoxP-Cre system), whether muscle-specific CPT1mt expression has beneficial or harmful effects on insulin sensitivity in different animal models of obesity and T2D.

     

     

    Liver, we showed that adenoviral-mediated CPT1mt expression in the liver of obese animals decreased glucose intolerance and insulin resistance but not hepatic steatosis. These beneficial effects were associated with decreased hepatic lipotoxicity and improved insulin signaling in the liver (Monsénégo 2012). Our present project addresses Non-alcoholic fatty liver disease (NAFLD), which is the hepatic manifestation of metabolic syndrome and ranges from isolated steatosis (reversible) to non-alcoholic steatohepatitis (NASH). In collaboration with physicians at Jean Verdier Hospital (Bondy), we currently investigate a prospective cohort of obese patients referred for bariatric surgery to evaluate whether alterations in hepatic lipid metabolism and/or mitochondrial function could participate to NAFLD progression (Helmy 2014).

     

     

    Main publications

    Ramachandran D, Clara R, Fedele S, Michel L, Burkard J, Kaufman S, Diaz AA, Weissfeld N, De Bock K, Prip-Buus C, Langhans W, Mansouri A. Enhancing enterocyte fatty acid oxidation in mice affects glycemic control depending on dietary fat. Sci Rep. 2018 Jul 17;8(1):10818

    Bricambert J, Alves-Guerra MC, Esteves P, Prip-Buus C, Bertrand-Michel J, Guillou H, Chang CJ, Vander Wal MN, Canonne-Hergaux F, Mathurin P, Raverdy V, Pattou F, Girard J, Postic C, Dentin R. The histone demethylase Phf2 acts as a molecular checkpoint to prevent NAFLD progression during obesity. Nat Commun. 2018 May 29;9(1):2092.

    Bellini L, Campana M, Rouch C, Chacinska M, Bugliani M, Meneyrol K, Hainault I, Lenoir V, Denom J, Véret J, Kassis N, Thorens B, Ibberson M, Marchetti P, Blachnio-Zabielska A, Cruciani-Guglielmacci C, Prip-Buus C, Magnan C, Le Stunff H. Protective role of the ELOVL2/docosahexaenoic acid axis in glucolipotoxicity-induced apoptosis in rodent beta cells and human islets. Diabetologia. 2018 May 12. sous presse

    Baraibar MA, Hyzewicz J, Rogowska-Wrzesinska A, Bulteau AL, Prip-Buus C, Butler-Browne G, Friguet B. Impaired energy metabolism of senescent muscle satellite cells is associated with oxidative modifications of glycolytic enzymes. Aging (Albany NY). 2016 Dec 4;8(12):3375-3389.

    Capel F, Cheraiti N, Acquaviva C, Hénique C, Bertrand-Michel J, Vianey-Saban C, Prip-Buus C, Morio B. Oleate dose-dependently regulates palmitate metabolism and insulin signaling in C2C12 myotubes. Oleate dose-dependently regulates palmitate metabolism and insulin signaling in C2C12 myotubes. Biochim Biophys Acta. 2016 Dec;1861(12 Pt A):2000-2010

    Vavrova E, Lenoir V, Alves-Guerra MC, Denis RG, Castel J, Esnous C, Dyck JR, Luquet S, Metzger D, Bouillaud F, Prip-Buus C. Muscle expression of a malonyl-CoA-insensitive carnitine palmitoyltransferase-1 protects mice against high-fat/high-sucrose diet-induced insulin resistance. Am J Physiol Endocrinol Metab. 2016 Sep 1;311(3):E649-60.

    Popineau L, Morzyglod L, Carré N, Caüzac M, Bossard P, Prip-Buus C, Lenoir V, Ragazzon B, Fauveau V, Robert L, Guilmeau S, Postic C, Komatsu M, Canonne-Hergaux F, Guillou H, Burnol AF. Novel Grb14-Mediated Cross Talk between Insulin and p62/Nrf2 Pathways Regulates Liver Lipogenesis and Selective Insulin Resistance. Mol Cell Biol. 2016 Jul 29;36(16):2168-81.    

    Pinel A, Rigaudière JP, Laillet B, Pouyet C, Malpuech-Brugère C, Prip-Buus C, Morio B, Capel F. N-3PUFA differentially modulate palmitate-induced lipotoxicity through alterations of its metabolism in C2C12 muscle cells. Biochim Biophys Acta. 2016 Jan;1861(1):12-20.

    Loyer X, Paradis V, Hénique C, Vion AC, Colnot N, Guerin CL, Devue C, On S, Scetbun J, Romain M, Paul JL, Rothenberg ME, Marcellin P, Durand F, Bedossa P, Prip-Buus C, Baugé E, Staels B, Boulanger CM, Tedgui A, Rautou PE. Liver microRNA-21 is overexpressed in non-alcoholic steatohepatitis and contributes to the disease in experimental models by inhibiting PPARα expression. Gut. 2016 Nov;65(11):1882-1894    

    Hénique C, Mansouri A, Vavrova E, Lenoir V, Ferry A, Esnous C, Ramond E, Girard J, Bouillaud F, Prip-Buus C, Cohen I. Increasing mitochondrial muscle fatty acid oxidation induces skeletal muscle remodeling toward an oxidative phenotype. FASEB J. 2015 29(6):2473-83

    Mansouri A, Pacheco-López G, Ramachandran D, Arnold M, Leitner C, Prip-Buus C, Langhans W, Morral N. Enhancing hepatic mitochondrial fatty acid oxidation stimulates eating in food-deprived mice. Am J Physiol Regul Integr Comp Physiol. 2015 Jan 15;308(2):R131-7.

    Helmy N, Prip-Buus C, Vons C, Lenoir V, Abou-Hamdan A, Guedouari-Bounihi H, Lombès A, Bouillaud F. Oxidation of hydrogen sulfide by human liver mitochondria. Nitric Oxide. 2014 Sep 15;41:105-12.

    Dahmani R, Just PA, Delay A, Canal F, Finzi L, Prip-Buus C, Lambert M, Sujobert P, Buchet-Poyau K, Miller E, Cavard C, Marmier S, Terris B, Billaud M, Perret C. A novel LKB1 isoform enhances AMPK metabolic activity and displays oncogenic properties. Oncogene. 2014 Jul 7.

    Collin de l'Hortet A, Zerrad-Saadi A, Prip-Buus C, Fauveau V, Helmy N, Ziol M, Vons C, Billot K, Baud V, Gilgenkrantz H, Guidotti JE. GH administration rescues fatty liver regeneration impairment by restoring GH/EGFR pathway deficiency. Endocrinology. 2014 Jul;155(7):2545-54.

    Monsénégo J, Mansouri A, Akkaoui M, Lenoir V, Esnous C, Fauveau V, Tavernier V, Girard J, Prip-Buus C. Enhancing liver mitochondrial fatty acid oxidation capacity in obese mice improves insulin sensitivity independently of hepatic steatosis. J Hepatol. 2012 Mar;56(3):632-9.

    Cherbuy C, Guesnet P, Morel MT, Kohl C, Thomas M, Duée PH, Prip-Buus C. Oleate metabolism in pig enterocytes is characterized by an increased oxidation rate in the presence of a high esterification rate within two days after birth. J Nutr. 2012 Feb;142(2):221-6.

    Henique C, Mansouri A, Fumey G, Lenoir V, Girard J, Bouillaud F, Prip-Buus C, Cohen I. Increased mitochondrial fatty acid oxidation is sufficient to protect skeletal muscle cells from palmitate-induced apoptosis. J Biol Chem. 2010 Nov 19;285(47):36818-27.

     

    Past members

     

    Carole Hénique - PhD (2007-2010)

    Isabelle Cohen - CR (2004-2010)

    Abdelak Mansouri - Post-Doc (2008-2011)

    Julia Monsénégo - PhD (2009-2012)

    Catherine Esnous - Assistant ingénieur (2001-2015)

     

    Financial supports

     

    Ces programmes de recherche sont soutenus par l'AFEF (Association Française pour l'Etude du Foie), la SFD (Société Francophone du Diabète), et CORDDIM-Ile de France.