Solenne Marmier1,2,3, Renaud Dentin1,2,3, Martine Daujat-Chavanieu4,5,6, Hervé Guillou7, Justine Bertrand-Michel8, Sabine Gerbal-Chaloin4,5,6, Jean Girard1,2,3, Sophie Lotersztajn9,10, Catherine Postic1,2,3. 1. Inserm U1016 Institut Cochin, Paris, France. 2. CNRS UMR 8104, Paris, France. 3. Université Paris Descartes, Sorbonne Paris Cité, Paris, France. 4. INSERM, U1040, Institut de Recherche en Biothérapie, Montpellier, France. 5. Université Montpellier 1, UMR 1040, Montpellier, France. 6. CHU Montpellier, Institut de Recherche en Biothérapie, Montpellier, France. 7. INRA-ToxAlim, Toxicologie Intégrative et Métabolisme, Toulouse, France. 8. Plateau de lipidomique IFR-BMT, INSERM, Plateforme MetaToul, Toulouse, France. 9. Inserm UMR 1149-Center for Research on Inflammation, Paris, France. 10. Université Paris Diderot, Sorbonne Paris Cité, Faculté de Médecine Xavier Bichat, Paris, France.
Abstract
UNLABELLED: Carbohydrate responsive element binding protein (ChREBP) is central for de novo fatty acid synthesis under physiological conditions and in the context of nonalcoholic fatty liver disease. We explored its contribution to alcohol-induced steatosis in a mouse model of binge drinking as acute ethanol (EtOH) intoxication has become an alarming health problem. Within 6 hours, ChREBP acetylation and its recruitment onto target gene promoters were increased in liver of EtOH-fed mice. Acetylation of ChREBP was dependent on alcohol metabolism because inhibition of alcohol dehydrogenase (ADH) activity blunted ChREBP EtOH-induced acetylation in mouse hepatocytes. Transfection of an acetylation-defective mutant of ChREBP (ChREBP(K672A) ) in HepG2 cells impaired the stimulatory effect of EtOH on ChREBP activity. Importantly, ChREBP silencing in the liver of EtOH-fed mice prevented alcohol-induced triglyceride accumulation through an inhibition of the lipogenic pathway but also led, unexpectedly, to hypothermia, increased blood acetaldehyde concentrations, and enhanced lethality. This phenotype was associated with impaired hepatic EtOH metabolism as a consequence of reduced ADH activity. While the expression and activity of the NAD(+) dependent deacetylase sirtuin 1, a ChREBP-negative target, were down-regulated in the liver of alcohol-fed mice, they were restored to control levels upon ChREBP silencing. In turn, ADH acetylation was reduced, suggesting that ChREBP regulates EtOH metabolism and ADH activity through its direct control of sirtuin 1 expression. Indeed, when sirtuin 1 activity was rescued by resveratrol pretreatment in EtOH-treated hepatocytes, a significant decrease in ADH protein content and/or acetylation was observed. CONCLUSION: our study describes a novel role for ChREBP in EtOH metabolism and unravels its protective effect against severe intoxication in response to binge drinking.
UNLABELLED: Carbohydrate responsive element binding protein (ChREBP) is central for de novo fatty acid synthesis under physiological conditions and in the context of nonalcoholic fatty liver disease. We explored its contribution to alcohol-induced steatosis in a mouse model of binge drinking as acute ethanol (EtOH) intoxication has become an alarming health problem. Within 6 hours, ChREBP acetylation and its recruitment onto target gene promoters were increased in liver of EtOH-fed mice. Acetylation of ChREBP was dependent on alcohol metabolism because inhibition of alcohol dehydrogenase (ADH) activity blunted ChREBPEtOH-induced acetylation in mouse hepatocytes. Transfection of an acetylation-defective mutant of ChREBP (ChREBP(K672A)) in HepG2 cells impaired the stimulatory effect of EtOH on ChREBP activity. Importantly, ChREBP silencing in the liver of EtOH-fed mice prevented alcohol-induced triglyceride accumulation through an inhibition of the lipogenic pathway but also led, unexpectedly, to hypothermia, increased blood acetaldehyde concentrations, and enhanced lethality. This phenotype was associated with impaired hepatic EtOH metabolism as a consequence of reduced ADH activity. While the expression and activity of the NAD(+) dependent deacetylase sirtuin 1, a ChREBP-negative target, were down-regulated in the liver of alcohol-fed mice, they were restored to control levels upon ChREBP silencing. In turn, ADH acetylation was reduced, suggesting that ChREBP regulates EtOH metabolism and ADH activity through its direct control of sirtuin 1 expression. Indeed, when sirtuin 1 activity was rescued by resveratrol pretreatment in EtOH-treated hepatocytes, a significant decrease in ADH protein content and/or acetylation was observed. CONCLUSION: our study describes a novel role for ChREBP in EtOH metabolism and unravels its protective effect against severe intoxication in response to binge drinking.
Authors: Samir Softic; Kimber L Stanhope; Jeremie Boucher; Senad Divanovic; Miguel A Lanaspa; Richard J Johnson; C Ronald Kahn Journal: Crit Rev Clin Lab Sci Date: 2020-01-14 Impact factor: 6.250
Authors: Jonathan Gaucher; Kenichiro Kinouchi; Nicholas Ceglia; Emilie Montellier; Shahaf Peleg; Carolina Magdalen Greco; Andreas Schmidt; Ignasi Forne; Selma Masri; Pierre Baldi; Axel Imhof; Paolo Sassone-Corsi Journal: Proc Natl Acad Sci U S A Date: 2019-11-22 Impact factor: 11.205