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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:476.)
© 2002 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Hepatic Fatty Acid Synthesis Is Suppressed in Mice With Fatty Livers Due to Targeted Apolipoprotein B38.9 Mutation

Xiaobo Lin; Gustav Schonfeld; Pin Yue; Zhouji Chen

From the Division of Atherosclerosis, Nutrition and Lipid Research, Department of Medicine, Washington University School of Medicine, St. Louis, Mo.

Correspondence to Zhouji Chen, PhD, Division of Atherosclerosis, Nutrition and Lipid Research, Department of Medicine, Washington University School of Medicine, Box 8046, 660 S Euclid Ave, St. Louis, MO 63110. E-mail zchen{at}im.wustl.edu

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 ß-hydroxybutyrate and of hepatic carnitine palmitoyl transferase and peroxisome proliferator-activated receptor- mRNAs were not altered, implying that ß-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.

Key Words: apolipoprotein B • fatty acid synthesis • fatty liver • familial hypobetalipoproteinemia • sterol regulatory element-binding protein 1c

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