title: Prohibitin-1 deficiency promotes inflammation and increases sensitivity to liver injury.
abstract: Liver diseases are the fifth cause of mortality in Western countries, and as opposed to other major causes of mortality, their incidence is increasing. Understanding the molecular background contributing to the progression of liver ailments will surely open new perspectives for the better management of patients. The aim of this study is to elucidate mechanisms underlying the progression of liver injury associated with deficient prohibitin 1, an essential protein to maintain mitochondrial homeostasis and gene expression. PHB1+/- mice developed a more severe steatohepatitis than WT littermates when exposed to a choline and methionine deficient diet. The increased sensitivity was mediated by mitochondrial dysfunction and metabolic impairment in PHB1+/- livers, including inactivation of AMP kinase, measured under a non-restricted diet. Moreover, pro-inflammatory challenges induced higher mortality and liver injury in PHB+/- mice. The increased proliferative capacity of PHB+/- splenocytes, resulting from constitutive defects in central molecular pathways as stated by deregulation of GSK3β, Erk, Akt or SHP-1, and the concomitant overproduction of pro-inflammatory mediators in Phb1 deficient mice, might account for these effects. In light of these results it might be concluded that Phb1 deficiency is a potential driver of chronic liver diseases by inducing hepatocyte damage and inflammation.
authors.affiliation: Center for Applied Medical Research (CIMA), University of Navarra. Pamplona, Spain.
authors.forename: Virginia
authors.initials: V
authors.lastname: Sánchez-Quiles
authors.forename: Víctor
authors.initials: V
authors.lastname: Segura
authors.forename: Emilie
authors.initials: E
authors.lastname: Bigaud
authors.forename: Bin
authors.initials: B
authors.lastname: He
authors.forename: Bert W
authors.initials: BW
authors.lastname: O'Malley
authors.forename: Enrique
authors.initials: E
authors.lastname: Santamaría
authors.forename: Jesús
authors.initials: J
authors.lastname: Prieto
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Corrales
mesh_terms: D000818:Animals; D002796:Choline Deficiency / Q000150:complications; D005234:Fatty Liver / Q000209:etiology*; D007249:Inflammation / Q000150:complications*; D008297:Male; D008715:Methionine / Q000172:deficiency; D051379:Mice; D000091402:Prohibitins; D012097:Repressor Proteins / Q000172:deficiency*; D059467:Transcriptome
chemical_list: D000091402:Prohibitins; D012097:Repressor Proteins; D008715:Methionine