Hepatic fatty acid synthesis is suppressed in mice with fatty livers due to targeted apolipoprotein B38.9 mutation.
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.
Lin
Xiaobo
X
Division of Atherosclerosis, Nutrition and Lipid Research, Department of Medicine, Washington University School of Medicine, St. Louis, Mo 63110, USA.
Schonfeld
Gustav
G
Yue
Pin
P
Chen
Zhouji
Z
D000222:Adaptation, Physiological; D000818:Animals; D001055:Apolipoproteins B / Q000235:genetics*; D022762:CCAAT-Enhancer-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D005215:Fasting; D064429:Fatty Acid Synthases / Q000096:biosynthesis / Q000235:genetics; D005227:Fatty Acids / Q000096:biosynthesis*; D005260:Female; D018390:Gene Targeting; D006995:Hypobetalipoproteinemias / Q000235:genetics / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D009154:Mutation; D012333:RNA, Messenger / Q000096:biosynthesis; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D014280:Triglycerides / Q000378:metabolism
D001055:Apolipoproteins B; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D005227:Fatty Acids; D012333:RNA, Messenger; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D014280:Triglycerides; D064429:Fatty Acid Synthases