Iershov A, Nemazanyy I, Alkhoury C, Girard M, Barth E, Cagnard N, Montagner A, Chretien D, Rugarli E, Guillou H, Pende M, Panasyuk G The class 3 PI3K coordinates autophagy and mitochondrial lipid catabolism by controlling nuclear receptor PPARa. Nat Commun. 2019 Apr 5; 10(1):1566.
Lysosomal degradation by autophagy and mitochondrial catabolism are induced during fasting to maintan energy levels. These essential metabolic processes are transcriptionally controlled by nutrient sensing nuclear receptors. However, how they are coordinated and whether class 3 PI3K contributes to this regulation was unknown. In this work, we discovered that class 3 PI3K controls selective autophagy of transcriptional repressors NCoR1 and HDAC3 to activate nuclear receptor PPARα, a master transcription factor for lipid uptake and catabolism. We have also demonstrated that PPARa in fasting acivates at transcriptional level mitochondria biogenesis. Thus, we discovered that the class 3 PI3K acts as an ultimate sensor to match autophagic activity with transcriptional activation of PPARa to promote lipid catabolism and in synchrony to activate mitochondrial biogenesis during fasting.
Wang H, Lekbaby B, Fares N, Augustin J, Attout T, Schnuriger A, Cassard AM, Panasyuk G, Perlemuter G, Bieche I, Vacher S, Selves J, Péron JM, Bancel B, Merle P, Kremsdorf D, Hall J, Chemin I, Soussan P. Alteration of splicing factors' expression during liver disease progression: impact on hepatocellular carcinoma outcome. Hepatol Int. 2019 May 28. doi: 10.1007/s12072-019-09950-7.
Girard M, Panasyuk G. Genetics in biliary atresia. Curr Opin Gastroenterol. 2019 Mar;35(2):73-81.
Niemir N, Rouvière L, Besse A, Vanier M, Dmytrus J, Marais T, Astord S, Puech J-P, Panasyuk G, Cooper J, Barkats M and Caillaud C. Intravenous administration of scAAV9-Hexb normalizes lifespan and prevents pathology in Sandhoff disease mice. Hum Mol Genet., 2018 Jan 8.
Patitucci C, Couchy G, Bagattin A, Cañeque T, de Reyniès A, Scoazec JY, Rodriguez R, Pontoglio M, Zucman-Rossi J, Pende M, Panasyuk G. Hepatocyte nuclear factor 1α suppresses steatosis-associated liver cancer by inhibiting PPARγ transcription. J Clin Invest. 2017 May 1;127(5):1873-1888.
Activation of aerobic glycolysis and lipid synthesis is a key mechanism of metabolic adaptation in cancer, yet how they are activated in coordination is still not fully uderstood. We discovered that these two metabolic hallmarks are induced by one transcription factor, a nuclear receptor PPARg. Our work integrated analyses of the human Liver Cancer Atlas collection, in vivo studies in pre-clinical animal models, and mechanistic studies showing that chronic activation of Ser/Thr protein kinase Akt2, but not other effector kinases in insulin signaling pathway, results in inhibition of tumor suppressor master regulator of hepatocyte fate transcription factor, HNF1a. We discovered that inactivation of HNF1a de-represses PPARg which, in a context of activated insulin signaling, drives liver cancer. This work has provided the first evidence that pharmacologic inhibition of PPARg is therapeutic in a pre-clinical model of liver cancer, opening new treatment opportunities in humans.
Rujano MA, Cannata Serio M, Panasyuk G, Péanne R, Reunert J, Rymen D, Hauser V, Park JH, Freisinger P, Souche E, Guida MC, Maier EM, Wada Y, Jäger S, Krogan NJ, Kretz O, Nobre S, Garcia P, Quelhas D, Bird TD, Raskind WH, Schwake M, Duvet S, Foulquier F, Matthijs G, Marquardt T, Simons M. Mutations in the X-linked ATP6AP2 cause a glycosylation disorder with autophagic defects. J Exp Med. 2017 Dec 4;214(12):3707-3729.
Nemazanyy I, Montagnac G, Russell R, Guan KL, Pende M, Panasyuk G. Class III PI3K controls hepatic insulin receptor function on whole body glucose homeostasis by a retrograde signalling mechanism. Nature Comm. 2015 Sep; 6:8283.
In this work we resolved a long-standing question of how autophagy and vesicular trafficking, two processes activated by class 3 PI3K, are oppositely controlled by anabolic insulin signaling. We discovered a novel retro-control loop in which insulin activates lipid kinase activity of class 3 PI3K selectively for endocytic trafficking to assure insulin receptor degradation and shut-down of its downstream Akt protein kinase signalling. Reciprocally, we found that inhibition of class 3 PI3K by depleting its essential regulatory subunit, Vps15 protein, in hepatocytes results in persistent insulin signaling and improved glucose metabolism acompaned by defects in gluconeogenesis. We have also demonstrated that acute hepatic downregulation of class 3 PI3K alleviates the manifestations of metabolic syndrome in models of insulin resistance and diabetes suggesting that class 3 PI3K inhibition might be a therapeutic target in those conditions.
Gentric G, Maillet V, Paradis V, Couton D, L’Hermitte A, Panasyuk G, Fromenty B, Celton-Morizur S and Desdouets C. Oxidative Stress Promotes Pathological Liver Polyploidization in NAFLD. J Clin Invest. 2015 Jan 26.
Liang N, Zhang C, Dill P, Panasyuk G, Pion D, Koka V, Gallazzini M, Olson EN, Lam H, Henske EP, Dong Z, Apte U, Pallet N, Johnson RL, Terzi F,
Kwiatkowski DJ, Scoazec JY, Martignoni G, Pende M. Regulation of YAP by mTOR and autophagy reveals a therapeutic target of tuberous sclerosis complex. J Exp Med. 2014 Oct 20;211(11):2249-63.
Nemazanyy I, Espeillac C, Pende M, Panasyuk G. Role of PI3K, mTOR and Akt2 signalling in hepatic tumorigenesis via the control of PKM2 expression. Biochem Soc Trans. 2013 Aug;41(4):917-22.
Nemazanyy I, Blaauw B, Paolini C, Caillaud C, Protasi F, Mueller A, Proikas-Cezanne T, Russell RC, Guan KL, Nishino I, Sandri M, Pende M, Panasyuk G. Defects of Vps15 in skeletal muscles lead to autophagic vacuolar myopathy and lysosomal disease. EMBO Mol Med. 2013 Jun;5(6):870-90.
Panasyuk G, Patitucci C, Espeillac C, Pende M. The role of the mTOR pathway during liver regeneration and tumorigenesis. Ann Endocrinol (Paris). 2013 May;74(2):121-2.
Panasyuk G, Espeillac C, Chauvin C, Pradelli L, Horie Y, Suzuki A, Annicotte JS, Fajas L, Foretz M, Verdeguer F, Pontoglio M, Ferré P, Scoazec JY, Birnbaum M, Ricci JE, Pende M. PPARγ contributes to PKM2 and HK2 expression in fatty liver. Nat. Commun. 2012 3:672.