title: Mitochondrial cholesterol accumulation in alcoholic liver disease: Role of ASMase and endoplasmic reticulum stress.
abstract: Alcoholic liver disease (ALD) is a major cause of chronic liver disease and a growing health concern in theworld. While the pathogenesis of ALD is poorly characterized key players identified in experimental models and patients, such as perturbations in mitochondrial structure and function, selective loss of antioxidant defense and susceptibility to inflammatory cytokines, contribute to ALD progression. Both oxidative stress and mitochondrial dysfunction compromise essential cellular functions and energy generation and hence are important pathogenic mechanisms of ALD. An important process mediating the mitochondrial disruption induced by alcohol intake is the trafficking of cholesterol to mitochondria, mediated by acid sphingomyelinase-induced endoplasmic reticulum stress, which contributes to increased cholesterol synthesis and StARD1upregulation. Mitochondrial cholesterol accumulation not only sensitizes to oxidative stress but it can contribute to the metabolic reprogramming in ALD, manifested by activation of the hypoxia inducible transcription factor 1 and stimulation of glycolysis and lactate secretion. Thus, a better understanding of the mechanisms underlying alcohol-mediated mitochondrial impairment and oxidative stress may lead to the identification of novel treatments for ALD. The present review briefly summarizes current knowledge on the cellular and molecular mechanisms contributing to alcohol-induced mitochondrial dysfunction and cholesterol accumulation and provides insights for potential therapeutic targets in ALD.
authors.affiliation: Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB-CSIC), Consejo Superior Investigaciones Científicas (CSIC), IDIBAPS, Liver Unit-Hospital Clínic, CIBEREHD, 08036 Barcelona, Spain. Electronic address: monmari@clinic.ub.es.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Marí
authors.affiliation: Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB-CSIC), Consejo Superior Investigaciones Científicas (CSIC), IDIBAPS, Liver Unit-Hospital Clínic, CIBEREHD, 08036 Barcelona, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Morales
authors.affiliation: Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB-CSIC), Consejo Superior Investigaciones Científicas (CSIC), IDIBAPS, Liver Unit-Hospital Clínic, CIBEREHD, 08036 Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Colell
authors.affiliation: Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB-CSIC), Consejo Superior Investigaciones Científicas (CSIC), IDIBAPS, Liver Unit-Hospital Clínic, CIBEREHD, 08036 Barcelona, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: García-Ruiz
authors.affiliation: Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB-CSIC), Consejo Superior Investigaciones Científicas (CSIC), IDIBAPS, Liver Unit-Hospital Clínic, CIBEREHD, 08036 Barcelona, Spain; Research Center for Alcoholic Liver and Pancreatic Diseases, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA. Electronic address: checa229@yahoo.com.
authors.forename: Jose C
authors.initials: JC
authors.lastname: Fernández-Checa
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008108:Liver Diseases, Alcoholic / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D002784:Cholesterol; D013108:Sphingomyelin Phosphodiesterase; D005978:Glutathione
keywords: Acid sphingomyelinase; ER stress; Lipotoxicity; Mitochondrial GSH; Mitochondrial cholesterol; Mitochondrial respiratory chain