Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 22, Issue 3, Pages 476-482Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/hq0302.105271
Keywords
apolipoprotein B; fatty acid synthesis; fatty liver; familial hypobetalipoproteinemia; sterol regulatory element-binding protein 1c
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Funding
- NCI NIH HHS [1P30CA91842-01] Funding Source: Medline
- NCRR NIH HHS [M01RR0036] Funding Source: Medline
- NHLBI NIH HHS [R01 HL-59515, R37 HL-424460] Funding Source: Medline
- NIDDK NIH HHS [1P30DK52574, 5P60DK20579, P30DK56341] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [P30CA091842] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR RESEARCH RESOURCES [M01RR000036] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL059515] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [P60DK020579, P30DK052574, P30DK056341] Funding Source: NIH RePORTER
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Humans and aenetically 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)-Ic, fatty acid synthase (FAS), and stearoyl coenzyme A desaturase-1 were coordinately decreased. FAS and SREBP-Ic 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-Ic 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-Ic levels remain to be identified.
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