title: Adverse signaling of scavenger receptor class B1 and PGC1s in alcoholic hepatosteatosis and steatohepatitis and protection by betaine in rat.
abstract: Because scavenger receptor class B type 1 is the cholesterol uptake liver receptor, whereas peroxisome proliferator-activated receptor γ coactivator-1β (PGC-1β) and PGC-1α are critical for lipid synthesis and degradation, we investigated the roles of these signaling molecules in the actions of ethanol-polyunsaturated fatty acids and betaine on hepatosteatosis and steatohepatitis. Ethanol-polyunsaturated fatty acid treatment caused the following: i) hepatosteatosis, as evidenced by increased liver cholesterol and triglycerides, lipid score, and decreased serum adiponectin; ii) marked inhibition of scavenger receptor class B type 1 glycosylation, its plasma membrane localization, and its hepatic cholesterol uptake function; and iii) moderate steatohepatitis, as evidenced by histopathological characteristics, increased liver tumor necrosis factor α and IL-6, decreased glutathione, and elevated serum alanine aminotransferase. These actions of ethanol involved up-regulated PGC-1β, sterol regulatory element-binding proteins 1c and 2, acetyl-CoA carboxylase, and HMG-CoA reductase mRNAs/proteins and inactive non-phosphorylated AMP kinase; and down-regulated silence regulator gene 1 and PGC-1α mRNA/proteins and hepatic fatty acid oxidation. Betaine markedly blunted all these actions of ethanol on hepatosteatosis and steatohepatitis. Therefore, we conclude that ethanol-mediated impaired post-translational modification, trafficking, and function of scavenger receptor class B type 1 may account for alcoholic hyperlipidemia. Up-regulation of PGC-1β and lipid synthetic genes and down-regulation of silence regulator gene 1, PGC-1α, adiponectin, and lipid degradation genes account for alcoholic hepatosteatosis. Induction of proinflammatory cytokines and depletion of endogenous antioxidant, glutathione, account for alcoholic steatohepatitis. We suggest betaine as a potential therapeutic agent because it effectively protects against adverse actions of ethanol.
authors.affiliation: Department of Biochemistry and Molecular Medicine, Lipid Research Laboratory, VA Medical Center, The George Washington University, Washington, District of Columbia.
authors.forename: Ravi
authors.initials: R
authors.lastname: Varatharajalu
authors.affiliation: Department of Biochemistry and Molecular Medicine, Lipid Research Laboratory, VA Medical Center, The George Washington University, Washington, District of Columbia.
authors.forename: Mamatha
authors.initials: M
authors.lastname: Garige
authors.affiliation: Department of Biochemistry and Molecular Medicine, Lipid Research Laboratory, VA Medical Center, The George Washington University, Washington, District of Columbia.
authors.forename: Leslie C
authors.initials: LC
authors.lastname: Leckey
authors.affiliation: Department of Biochemistry and Molecular Medicine, Lipid Research Laboratory, VA Medical Center, The George Washington University, Washington, District of Columbia.
authors.forename: Jaime
authors.initials: J
authors.lastname: Arellanes-Robledo
authors.affiliation: Department of Biochemistry and Molecular Medicine, Lipid Research Laboratory, VA Medical Center, The George Washington University, Washington, District of Columbia.
authors.forename: Karina
authors.initials: K
authors.lastname: Reyes-Gordillo
authors.affiliation: Department of Biochemistry and Molecular Medicine, Lipid Research Laboratory, VA Medical Center, The George Washington University, Washington, District of Columbia.
authors.forename: Ruchi
authors.initials: R
authors.lastname: Shah
authors.affiliation: Department of Biochemistry and Molecular Medicine, Lipid Research Laboratory, VA Medical Center, The George Washington University, Washington, District of Columbia. Electronic address: raj.lakshman@va.gov.
authors.forename: M Raj
authors.initials: MR
authors.lastname: Lakshman
mesh_terms: D052242:Adiponectin / Q000097:blood; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001622:Betaine / Q000494:pharmacology*; D059305:Diet, High-Fat; D000431:Ethanol / Q000009:adverse effects; D005234:Fatty Liver / Q000378:metabolism* / Q000473:pathology; D005235:Fatty Liver, Alcoholic / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015850:Interleukin-6 / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000503:physiopathology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011499:Protein Processing, Post-Translational; D017208:Rats, Wistar; D051122:Scavenger Receptors, Class B / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D052242:Adiponectin; D015850:Interleukin-6; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; C495125:Scarb1 protein, rat; D051122:Scavenger Receptors, Class B; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol; D001622:Betaine; D000410:Alanine Transaminase