Hepatic fatty acid synthesis is suppressed in mice with fatty livers due to targeted apolipoprotein B38.9 mutation.

Abstract

Humans and genetically engineered mice with hypobetalipoproteinemia due to truncation-producing mutations of the apolipoprotein B (apoB) gene frequently have fatty livers, because the apoB defect impairs the capacity of livers to export triglycerides (TGs). We assessed the adaptation of hepatic lipid metabolism in our apoB-38.9-bearing mice. Hepatic TG contents were 2- and 4-fold higher in heterozygous and homozygous mice, respectively, compared with wild-type mice. Respective in vivo hepatic fatty acid synthetic rates were reduced to 40% and 15% of the wild-type rate. Hepatic mRNAs for sterol regulatory element-binding protein (SREBP)-1c, fatty acid synthase (FAS), and stearoyl coenzyme A desaturase-1 were coordinately decreased. FAS and SREBP-1c mRNA levels were strongly and positively correlated with each other and inversely correlated with hepatic TGs, suggesting that impaired TG export is a potent inhibitor of fatty acid synthesis. In contrast, levels of plasma beta-hydroxybutyrate and of hepatic carnitine palmitoyl transferase and peroxisome proliferator-activated receptor-alpha mRNAs were not altered, implying that beta-oxidation was not affected. Fasting followed by refeeding increased hepatic fatty acid synthesis 56-fold over fasting in normal and heterozygous mice but only 24-fold in homozygous mice. Parallel changes occurred in FAS and SREBP-1c mRNAs. Thus, impairment of very low density lipoprotein export downregulates hepatic fatty acid synthesis, but the adaptation is incomplete, resulting in fatty livers. The signals mediating suppression of FAS and SREBP-1c levels remain to be identified.

• Authors: Xiaobo Lin, Gustav Schonfeld, Pin Yue, Zhouji Chen
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 22 Issue 3 Pg. 476-82 (Mar 01 2002) ISSN: 1524-4636 [Electronic] United States
• PMID: 11884293 (Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Apolipoproteins B
• CCAAT-Enhancer-Binding Proteins
• DNA-Binding Proteins
• Fatty Acids
• RNA, Messenger
• Srebf1 protein, mouse
• Sterol Regulatory Element Binding Protein 1
• Transcription Factors
• Triglycerides
• Fatty Acid Synthases

Topics

• Adaptation, Physiological
• Animals
• Apolipoproteins B (genetics)
• CCAAT-Enhancer-Binding Proteins (biosynthesis, genetics)
• DNA-Binding Proteins (biosynthesis, genetics)
• Fasting
• Fatty Acid Synthases (biosynthesis, genetics)
• Fatty Acids (biosynthesis)
• Female
• Gene Targeting
• Hypobetalipoproteinemias (genetics, metabolism)
• Kinetics
• Liver (metabolism)
• Male
• Mice
• Mutation
• RNA, Messenger (biosynthesis)
• Sterol Regulatory Element Binding Protein 1
• Transcription Factors
• Triglycerides (metabolism)