Liver fatty acid-binding protein is required for high rates of hepatic fatty acid oxidation but not for the action of PPAR-α in fasting mice
Liver fatty acid-binding protein is required for high rates of hepatic fatty acid oxidation but not for the action of PPAR-α in fasting mice
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DOI：
10.1096/fj.03-0330fje
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发表时间：
2004-02-01
期刊：
影响因子：
4.8
通讯作者：
Binas, Bert
中科院分区：
文献类型：
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作者：
Erol, Erdal;Kumar, Leena S.;Binas, Bert
肝脏脂肪酸结合蛋白（L-FABP）被认为可以限制长链脂肪酸（LCFA）氧化和过氧化物酶体增殖物激活受体α（PPAR-α）的可用性，PPAR-α是一种决定肝脏脂肪酸氧化能力的脂肪酸结合转录因子。在这里，我们使用 L-FABP 缺失小鼠来检验这一假设。在禁食条件下，这种突变降低了β-羟基丁酸（BHB）血浆水平以及分离的肝细胞的BHB释放和棕榈酸氧化。然而，生酮能力并未降低：通过注射辛酸可恢复 BHB 血浆水平；肝匀浆中 BHB 产生和棕榈酸氧化正常；线粒体和线粒体外 LCFA 氧化和生酮的关键 PPAR-α 靶标（MCAD、线粒体 HMG CoA 合酶、ACO、CYP4A3）和其他基因（CPT1、LCAD）的肝脏表达仍保持在野生型水平。在标准饮食期间，L-FABP无效肝脏中线粒体HMG CoA合酶mRNA选择性减少。这些结果表明，在禁食条件下，肝脏 L-FABP 通过非转录机制促进肝脏 LCFA 氧化和生酮，而 L-FABP 可以激活进食小鼠的生酮基因表达。因此，L-FABP 影响脂肪酸氧化的机制可能因生理条件而异。
Liver fatty acid binding protein (L-FABP) has been proposed to limit the availability of long-chain fatty acids (LCFA) for oxidation and for peroxisome proliferator-activated receptor alpha (PPAR-alpha), a fatty acid binding transcription factor that determines the capacity of hepatic fatty acid oxidation. Here, we used L-FABP null mice to test this hypothesis. Under fasting conditions, this mutation reduced beta-hydroxybutyrate (BHB) plasma levels as well as BHB release and palmitic acid oxidation by isolated hepatocytes. However, the capacity for ketogenesis was not reduced: BHB plasma levels were restored by octanoate injection; BHB production and palmitic acid oxidation were normal in liver homogenates; and hepatic expression of key PPAR-alpha target (MCAD, mitochondrial HMG CoA synthase, ACO, CYP4A3) and other (CPT1, LCAD) genes of mitochondrial and extramitochondrial LCFA oxidation and ketogenesis remained at wild-type levels. During standard diet, mitochondrial HMG CoA synthase mRNA was selectively reduced in L-FABP null liver. These results suggest that under fasting conditions, hepatic L-FABP contributes to hepatic LCFA oxidation and ketogenesis by a nontranscriptional mechanism, whereas L-FABP can activate ketogenic gene expression in fed mice. Thus, the mechanisms whereby L-FABP affects fatty acid oxidation may vary with physiological condition.