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

J Hepatol. 2006 Nov;45(5):717-24. doi: 10.1016/j.jhep.2006.05.009. Epub 2006 Jun 21.

Abstract

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+/-3.1mg/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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alanine Transaminase / blood
  • Animals
  • Betaine / pharmacology
  • Biosynthetic Pathways / drug effects
  • Biosynthetic Pathways / genetics
  • Central Nervous System Depressants / pharmacology*
  • Endoplasmic Reticulum / drug effects
  • Ethanol / pharmacology*
  • Fatty Liver, Alcoholic / metabolism*
  • Fatty Liver, Alcoholic / pathology
  • Heat-Shock Proteins / metabolism
  • Homocysteine / blood
  • Hyperhomocysteinemia / physiopathology*
  • Lipogenesis / genetics
  • Lipogenesis / physiology*
  • Lipotropic Agents / pharmacology
  • Liver / metabolism
  • Mice
  • Mice, Knockout
  • Models, Animal
  • Molecular Chaperones / metabolism
  • Sterol Regulatory Element Binding Protein 1 / drug effects
  • Sterol Regulatory Element Binding Protein 1 / physiology*
  • Sterol Regulatory Element Binding Protein 2 / drug effects
  • Sterol Regulatory Element Binding Protein 2 / physiology*
  • Triglycerides / metabolism

Substances

  • Central Nervous System Depressants
  • Heat-Shock Proteins
  • Lipotropic Agents
  • Molecular Chaperones
  • Srebf1 protein, mouse
  • Srebf2 protein, mouse
  • Sterol Regulatory Element Binding Protein 1
  • Sterol Regulatory Element Binding Protein 2
  • Triglycerides
  • Homocysteine
  • Ethanol
  • Betaine
  • Alanine Transaminase
  • molecular chaperone GRP78