Predominant role of sterol response element binding proteins (SREBP) lipogenic pathways in hepatic steatosis in the murine intragastric ethanol feeding model.
OBJECTIVE
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 alcohol-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+/-3.1mg/g liver) but 1.8-fold in alcohol-fed null mice (27.9+/-4 vs. control 14.5+/-3.8 mg/g liver). 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.
Ji
Cheng
C
USC/UCLA Research Center for Alcoholic Liver and Pancreatic Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, HMR-101, 2011 Zonal Avenue, Los Angeles, CA 90033, USA. chengji@usc.edu
Chan
Christine
C
Kaplowitz
Neil
N
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001622:Betaine / Q000494:pharmacology; D053898:Biosynthetic Pathways / Q000187:drug effects / Q000235:genetics; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D004721:Endoplasmic Reticulum / Q000187:drug effects; D000091342:Endoplasmic Reticulum Chaperone BiP; D000431:Ethanol / Q000494:pharmacology*; D005235:Fatty Liver, Alcoholic / Q000378:metabolism* / Q000473:pathology; D006360:Heat-Shock Proteins / Q000378:metabolism; D006710:Homocysteine / Q000097:blood; D020138:Hyperhomocysteinemia / Q000503:physiopathology*; D050155:Lipogenesis / Q000235:genetics / Q000502:physiology*; D008082:Lipotropic Agents / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D018832:Molecular Chaperones / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000187:drug effects / Q000502:physiology*; D051782:Sterol Regulatory Element Binding Protein 2 / Q000187:drug effects / Q000502:physiology*; D014280:Triglycerides / Q000378:metabolism
D002492:Central Nervous System Depressants; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D008082:Lipotropic Agents; D018832:Molecular Chaperones; C497388:Srebf1 protein, mouse; C497391:Srebf2 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D014280:Triglycerides; D006710:Homocysteine; D000431:Ethanol; D001622:Betaine; D000410:Alanine Transaminase