Predominant role of sterol response element binding proteins (SREBP) lipogenic pathways in hepatic steatosis in the murine intragastric ethanol feeding model

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 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 ± 3.1 mg/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. 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. 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. 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 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. 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.