title: Increased hepatic receptor interacting protein kinase 3 expression due to impaired proteasomal functions contributes to alcohol-induced steatosis and liver injury.
abstract: Chronic alcohol exposure increased hepatic receptor-interacting protein kinase (RIP) 3 expression and necroptosis in the liver but its mechanisms are unclear. In the present study, we demonstrated that chronic alcohol feeding plus binge (Gao-binge) increased RIP3 but not RIP1 protein levels in mouse livers. RIP3 knockout mice had decreased serum alanine amino transferase activity and hepatic steatosis but had no effect on hepatic neutrophil infiltration compared with wild type mice after Gao-binge alcohol treatment. The hepatic mRNA levels of RIP3 did not change between Gao-binge and control mice, suggesting that alcohol-induced hepatic RIP3 proteins are regulated at the posttranslational level. We found that Gao-binge treatment decreased the levels of proteasome subunit alpha type-2 (PSMA2) and proteasome 26S subunit, ATPase 1 (PSMC1) and impaired hepatic proteasome function. Pharmacological or genetic inhibition of proteasome resulted in the accumulation of RIP3 in mouse livers. More importantly, human alcoholics had decreased expression of PSMA2 and PSMC1 but increased protein levels of RIP3 compared with healthy human livers. Moreover, pharmacological inhibition of RIP1 decreased Gao-binge-induced hepatic inflammation, neutrophil infiltration and NF-κB subunit (p65) nuclear translocation but failed to protect against steatosis and liver injury induced by Gao-binge alcohol. In conclusion, results from this study suggest that impaired hepatic proteasome function by alcohol exposure may contribute to hepatic accumulation of RIP3 resulting in necroptosis and steatosis while RIP1 kinase activity is important for alcohol-induced inflammation.
authors.affiliation: Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.|Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Shaogui
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Hong-Min
authors.initials: HM
authors.lastname: Ni
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Dorko
authors.affiliation: Department of General Surgery, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Sean C
authors.initials: SC
authors.lastname: Kumer
authors.affiliation: Department of General Surgery, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Schmitt
authors.affiliation: Department of General Surgery, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Atta
authors.initials: A
authors.lastname: Nawabi
authors.affiliation: Department of Biochemistry, School of Medicine Niigata University, Chuo-ku, Niigata 951-8510, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Komatsu
authors.affiliation: Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Heqing
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Wen-Xing
authors.initials: WX
authors.lastname: Ding
mesh_terms: D000818:Animals; D063425:Binge Drinking / Q000201:enzymology / Q000473:pathology; D000431:Ethanol / Q000008:administration & dosage; D005234:Fatty Liver / Q000201:enzymology*; D020690:GTPase-Activating Proteins / Q000096:biosynthesis / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D028861:Nuclear Pore Complex Proteins / Q000096:biosynthesis / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000378:metabolism
chemical_list: C119724:AGFG1 protein, human; D020690:GTPase-Activating Proteins; D028861:Nuclear Pore Complex Proteins; D016601:RNA-Binding Proteins; C490620:Ralbp1 protein, mouse; D000431:Ethanol; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse; D046988:Proteasome Endopeptidase Complex
keywords: RIP3; alcohol; liver injury; necroptosis; steatosis