title: Metabolic therapy: lessons from liver diseases.
abstract: Fatty liver disease is one of most prevalent metabolic liver diseases, which includes alcoholic (ASH) and nonalcoholic steatohepatitis (NASH). Its initial stage is characterized by fat accumulation in the liver, that can progress to steatohepatitis, a stage of the disease in which steatosis is accompanied by inflammation, hepatocellular death, oxidative stress and fibrosis. Recent evidence in experimental models as well as in patients with steatohepatitis have uncovered a role for cholesterol and sphingolipids, particularly ceramide, in the transition from steatosis to steatohepatitis, insulin resistance and hence disease progression. Cholesterol accumulation and its trafficking to mitochondria sensitizes fatty liver to subsequent hits including inflammatory cytokines, such as TNF/Fas, in a pathway involving ceramide generation by acidic sphingomyelinase (ASMase). Thus, targeting both cholesterol and/or ASMase may represent a novel therapeutic approach of relevance in ASH and NASH, two of the most common forms of liver diseases worldwide.
authors.affiliation: IDIBAPS, Liver Unit-Hospital Clinic, and CIBEREHD, Barcelona, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Garcia-Ruiz
authors.forename: Montserrat
authors.initials: M
authors.lastname: Marí
authors.forename: Anna
authors.initials: A
authors.lastname: Colell
authors.forename: Albert
authors.initials: A
authors.lastname: Morales
authors.forename: Jose C
authors.initials: JC
authors.lastname: Fernandez-Checa
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005234:Fatty Liver / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D005235:Fatty Liver, Alcoholic / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D007333:Insulin Resistance; D050155:Lipogenesis / Q000187:drug effects*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D058990:Molecular Targeted Therapy; D013107:Sphingolipids / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000378:metabolism
chemical_list: D013107:Sphingolipids; D048069:Tumor Necrosis Factors; D002784:Cholesterol