Predominant role of sterol response element binding proteins (SREBP) lipogenic pathways in hepatic steatosis in the murine intragastric ethanol feeding model Cheng Ji * , Christine Chan, Neil Kaplowitz USC/UCLA Research Center for Alcoholic Liver and Pancreatic Diseases, and USC Research Center for Liver Disease, Department of Medicine, Keck School of Medicine, University of Southern California, HMR-101, 2011 Zonal Avenue, Los Angeles, CA 90033, USA Background/ Aims: Alcohol-induced fatty liver is associated with induction of sterol response element binding proteins (SREBPs), transcription factors which regulate expression of genes of lipid synthesis. The contribution of SREBP-1c to alco- hol-induced fatty liver and injury was studied. Methods: Wild type and SREBP1c null mice were fed alcohol or control diet by intragastric infusion for 4 weeks. H&E and TUNEL staining, real-time PCR, RT-PCR, and immunoblotting were applied to analyze alcohol-induced liver injury. Results: ALT, plasma homocysteine, liver cholesterol, and TUNEL positive hepatocytes were increased in alcohol-fed mice as compared to control in both genotypes. Liver triglycerides were increased 4-fold in alcohol-fed wild type mice (87.2 ± 7.5 vs. control 22.3 ± 3.1 mg/g liver) but 1.8-fold in alcohol-fed null mice (27.9 ± 4 vs. control 14.5 ± 3.8 mg/g liv- er). SREBP-2 and HMG CoA reductase were higher in the null than in wild type. Betaine feeding prevented partially the alcohol-induced changes of hepatic lipids and injury in both genotypes. mRNA of Insig-1 was reduced in both genotypes fed alcohol. No change was detected for the SREBP cleavage-activating protein (Scap) or S1P in either genotype fed alcohol. Conclusions: The predominant mechanism of hepatic triglyceride accumulation in the intragastric alcohol fed mouse requires the participation of SREBP-1c. SREBP-2 regulated cholesterol accumulation still occurs. Ó 2006 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Keywords: Alcohol; Hyperhomocysteinemia; ER stress; Fatty liver 1. Introduction Growing evidence indicates that substantial fat accumulation in the liver at the early stage of heavy alcohol consumption is crucial for the development of severe liver injury [1–6]. A series of experiments have demonstrated that sterol response element bind- ing proteins (SREBPs), a family of endoplasmic retic- ulum (ER) membrane bound transcription factors, are induced in the liver in response to alcohol consump- tion [2,7]. SREBPs have drawn much attention in the field of alcohol-induced hepatic steatosis because of their essential role in hepatic triglyceride and cho- lesterol syntheses. Three SREBPs with overlapping functions control the lipid synthesis in the liver and other tissues of mammals [8]. SREBP-1c and SREBP-2 are expressed in the liver, while SREBP-1a is expressed only at very low levels in the liver of adult mice, rats, and humans. SREBP-1c regulate genes involved in triglyceride synthesis such as activa- tion of glucokinase, acetyl-CoA synthetase and car- boxylase, and steroyl-CoA desaturase and SREBP2 regulates genes involved in cholesterol synthesis such as activation of HMG-CoA synthase and reductase, while SREBP-1a regulates both triglyceride and 0168-8278/$32.00 Ó 2006 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jhep.2006.05.009 Received 19 March 2006; received in revised form 28 April 2006; accepted 12 May 2006; available online 21 June 2006 * Corresponding author. Tel.: +1 323 442 2224; fax: +1 323 442 5425. E-mail address: chengji@usc.edu (C. Ji). www.elsevier.com/locate/jhep Journal of Hepatology 45 (2006) 717–724