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

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.

• Authors: Cheng Ji, Christine Chan, Neil Kaplowitz
• Journal: Journal of hepatology (J Hepatol) Vol. 45 Issue 5 Pg. 717-24 (Nov 2006) ISSN: 0168-8278 [Print] Netherlands
• PMID: 16879892 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Central Nervous System Depressants
• Endoplasmic Reticulum Chaperone BiP
• 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

Topics

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