Steatohepatitis, spontaneous peroxisome proliferation and liver tumors in mice lacking peroxisomal fatty acyl-CoA oxidase -: Implications for peroxisome proliferator-activated receptor α natural ligand metabolism
Steatohepatitis, spontaneous peroxisome proliferation and liver tumors in mice lacking peroxisomal fatty acyl-CoA oxidase -: Implications for peroxisome proliferator-activated receptor α natural ligand metabolism
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DOI：
10.1074/jbc.273.25.15639
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发表时间：
1998-06-19
影响因子：
4.8
通讯作者：
Reddy, JK
中科院分区：
文献类型：
--
作者：
Fan, CY;Pan, J;Reddy, JK
过氧化物酶体β-氧化系统由fc、ur连续反应组成，优先代谢极长链脂肪酸。该系统的第一步由酰基辅酶A氧化酶（AOX）催化，将脂肪酰基辅酶A转化为2-反式烯酰基辅酶A。在此，我们发现AOX缺陷的小鼠表现出脂肪性肝炎，肝脏H2 O2水平升高，肝细胞再生，导致6至8个月大的脂肪变化完全逆转。具有再生肝细胞的AOX-/-小鼠的肝脏显示出广泛的自发性过氧化物酶体增殖和由过氧化物酶体增殖物激活受体α（PPAR α）调节的基因的mRNA水平增加。AOX-/-小鼠在15月龄时由于持续激活PPAR α而发生肝腺瘤和肝癌。这些观察结果暗示酰基辅酶A和AOX的其他假定底物作为PPAR α的生物配体;因此，正常AOX基因对于PPAR α的生理调节是不可或缺的。
Peroxisomal beta-oxidation system consists of fc,ur consecutive reactions to preferentially metabolize very long chain fatty acids. The first step of this system, catalyzed by acyl-CoA oxidase (AOX), converts fatty acyl-CoA to 2-trans-enoyl-CoA. Herein, we show that mice deficient in AOX exhibit steatohepatitis, increased hepatic H2O2 levels, and hepatocellular regeneration, leading to a complete reversal of fatty change by 6 to 8 months of age. The liver of AOX-/- mice with regenerated hepatocytes displays profound generalized spontaneous peroxisome proliferation and increased mRNA levels of genes that are regulated by peroxisome proliferator-activated receptor alpha (PPAR alpha). Hepatic adenomas and carcinomas develop in AOX-/- mice by 15 months of age due to sustained activation of PPAR alpha. These observations implicate acyl-CoA and other putative substrates for AOX, as biological ligands for PPAR alpha; thus, a normal AOX gene is indispensable for the physiological regulation of PPAR alpha.