Adverse Signaling of Scavenger Receptor Class B1 and PGC1s in Alcoholic Hepatosteatosis and Steatohepatitis and Protection by Betaine in Rat

Because scavenger receptor class B type 1 is the cholesterol uptake liver receptor, whereas peroxisome proliferator activated receptor gamma coactivator-1 beta (PGC-1 beta) and PGC-1 alpha 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 glycosytation, its plasma membrane localization, and its hepatic cholesterol uptake function; and iii) moderate steatohepatitis, as evidenced by histopathological characteristics, increased Liver tumor necrosis factor alpha and IL-6, decreased glutathione, and elevated serum alanine aminotransferase. These actions of ethanol involved up-regulated PGC-1 beta, sterol regulatory element-binding proteins 1c and 2, acetyl-CoA carboxylase, and HMG-CoA reductase mRNAs/ proteins and inactive non-phosphorytated AMP kinase; and down-regulated silence regulator gene 1 and PGC-l alpha 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-1 beta and lipid synthetic genes and down-regulation of silence regulator gene 1, PGC-l alpha, 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. (Am J Pathot 2014, 184: 2035-2044;