title: Interleukin-6 is associated with liver lipid homeostasis but not with cell death in experimental hepatic steatosis.
abstract: Hepatic steatosis is a risk factor for the progression of non-alcoholic fatty liver disease. The role of pro-inflammatory interleukin (IL)-6 in hepatic steatosis etiology is controversial. We investigated in vivo and in primary hepatocyte cultures whether IL-6 has a modulator role in liver and mitochondria lipid composition and cell death in a choline-deficient (CD) diet rat model of hepatic steatosis. Dietary choline deficiency increased triglycerides and cholesterol, and reduced phosphatidylcholine (PC), phosphatidylethanolamine (PE) and the membrane integrity marker PC:PE ratio in liver. Choline-deficient diet enhanced systemic IL-6, and IL-6 receptor expression and cell death vulnerability in hepatocytes. Derangement of the mitochondrial electron transport chain and of its phospholipid environment was found in CD rat liver mitochondria, which exhibited elevated concentrations of triglycerides, cardiolipin and PC and elevated PC:PE ratio. The cell treatment with IL-6, but not PC, eliminated much of the CD-promoted lipid imbalance in mitochondria but not tumor-necrosis factor (TNF)-alpha-induced cell death. However, PC supplementation prevented the TNF-alpha-induced DNA fragmentation, cytochrome-c release and caspase-3 activity in control and CD hepatocytes. In conclusion, IL-6 ameliorated the mitochondria lipid disturbance in hepatocytes isolated from steatotic animals. Furthermore, PC is identified as a new survival agent that reverses several TNFalpha-inducible responses that are likely to promote steatosis and necrosis.
authors.affiliation: Reina Sofia University Hospital, Cordoba, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Sánchez-Garrido
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Chico
authors.forename: Raúl
authors.initials: R
authors.lastname: González
authors.forename: Isidora
authors.initials: I
authors.lastname: Ranchal
authors.forename: Sandra
authors.initials: S
authors.lastname: González-Rubio
authors.forename: Ana B
authors.initials: AB
authors.lastname: Hidalgo
authors.forename: Cesar
authors.initials: C
authors.lastname: Díaz-López
authors.forename: Guadalupe
authors.initials: G
authors.lastname: Costán
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Padillo
authors.forename: Manuel
authors.initials: M
authors.lastname: De la Mata
authors.forename: Begoña
authors.initials: B
authors.lastname: Ochoa
authors.forename: Jordi
authors.initials: J
authors.lastname: Muntané
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D002796:Choline Deficiency / Q000188:drug therapy / Q000276:immunology* / Q000503:physiopathology; D004032:Diet; D004195:Disease Models, Animal; D018450:Disease Progression; D004579:Electron Transport / Q000187:drug effects / Q000276:immunology; D005234:Fatty Liver / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D022781:Hepatocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015850:Interleukin-6 / Q000378:metabolism* / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects / Q000502:physiology; D010713:Phosphatidylcholines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D019947:Receptors, Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D014280:Triglycerides / Q000096:biosynthesis / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D015850:Interleukin-6; D010713:Phosphatidylcholines; D019947:Receptors, Interleukin-6; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha