Kaikaus R M, Chan W K, Ortiz de Montellano P R, Bass N M
Department of Medicine, University of California, San Francisco 94143-0538.
Mol Cell Biochem. 1993;123(1-2):93-100. doi: 10.1007/BF01076479.
Liver fatty acid-binding protein (L-FABP) expression is modulated by developmental, hormonal, dietary, and pharmacological factors. The most pronounced induction is seen after treatment with peroxisome proliferators, which induce L-FABP coordinately with microsomal cytochrome P-450 4A1 and the enzymes of peroxisomal fatty acid beta-oxidation. These effects of peroxisome proliferators may be mediated by a receptor which has been shown to be activated by peroxisome proliferators in mammalian cell transfection studies. However, the peroxisome proliferators tested thus far do not bind to this receptor, known as the peroxisome proliferator-activated receptor (PPAR), and its endogenous ligand(s) also remain unknown. Peroxisome proliferators inhibit mitochondrial beta-oxidation, and one hypothesis is that the dicarboxylic fatty acid metabolites of accumulated LCFA, formed via the P-450 4A1 omega-oxidation pathway, serve as primary inducers of L-FABP and peroxisomal beta-oxidation. We have tested this hypothesis in primary hepatocyte cultures exposed to clofibrate (CF). Inhibition of P-450 4A1 markedly diminished, via a pre-translational mechanism, the CF induction of L-FABP and peroxisomal beta-oxidation. In further experiments, long-chain dicarboxylic acids, the final products of the P-450 4A1 omega-oxidation pathway, but not LCFA, induced L-FABP and peroxisomal beta-oxidation pre-translationally. These results suggest a role, in part, for long-chain dicarboxylic acids in mediating the peroxisome proliferator induction of L-FABP and peroxisomal beta-oxidation. We also found that LCFA, which undergo rapid hepatocellular metabolism, could become inducers of L-FABP and peroxisomal beta-oxidation under conditions where their metabolism was inhibited.(ABSTRACT TRUNCATED AT 250 WORDS)
肝脏脂肪酸结合蛋白（L-FABP）的表达受发育、激素、饮食和药理因素的调节。在用过氧化物酶体增殖剂处理后，可观察到最显著的诱导作用，过氧化物酶体增殖剂可使L-FABP与微粒体细胞色素P-450 4A1以及过氧化物酶体脂肪酸β氧化酶协同诱导。过氧化物酶体增殖剂的这些作用可能由一种受体介导，在哺乳动物细胞转染研究中已表明该受体可被过氧化物酶体增殖剂激活。然而，迄今为止所测试的过氧化物酶体增殖剂并不与这种称为过氧化物酶体增殖物激活受体（PPAR）的受体结合，其内源性配体也仍然未知。过氧化物酶体增殖剂抑制线粒体β氧化，一种假说是，通过P-450 4A1ω氧化途径形成的累积长链脂肪酸（LCFA）的二羧酸脂肪酸代谢产物，作为L-FABP和过氧化物酶体β氧化的主要诱导剂。我们在暴露于氯贝丁酯（CF）的原代肝细胞培养物中测试了这一假说。通过翻译前机制，对P-450 4A1的抑制显著减弱了CF对L-FABP和过氧化物酶体β氧化的诱导作用。在进一步的实验中，P-450 4A1ω氧化途径的终产物长链二羧酸，但不是LCFA，在翻译前诱导了L-FABP和过氧化物酶体β氧化。这些结果部分表明长链二羧酸在介导过氧化物酶体增殖剂对L-FABP和过氧化物酶体β氧化的诱导中起作用。我们还发现，经历快速肝细胞代谢的LCFA，在其代谢受到抑制的条件下，可能成为L-FABP和过氧化物酶体β氧化的诱导剂。（摘要截取自250字）
