Steatogenesis in adult-onset type II citrullinemia is associated with down-regulation of PPARα.
Steatogenesis in adult-onset type II citrullinemia is associated with down-regulation of PPARα.
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DOI：
10.1016/j.bbadis.2014.12.011
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发表时间：
2015-03
期刊：
影响因子：
--
通讯作者：
Aoyama T
中科院分区：
文献类型：
--
作者：
Komatsu M;Kimura T;Yazaki M;Tanaka N;Yang Y;Nakajima T;Horiuchi A;Fang ZZ;Joshita S;Matsumoto A;Umemura T;Tanaka E;Gonzalez FJ;Ikeda S;Aoyama T
SLC 25 A13（瓜氨酸或谷氨酸盐-谷氨酸载体2）位于肝脏的线粒体膜上，其遗传缺陷导致成人发作的II型瓜氨酸血症（CTLN 2）。CTLN 2是一种尿素循环障碍，其特征在于由于降低的氨基琥珀酸合成酶活性而引起的突发性高氨血症。在没有肥胖和酒精消耗的情况下，这种疾病经常伴有脂肪肝。然而，脂肪生成的确切机制仍不清楚。使用从16名CTLN 2患者获得的肝脏样品检测与脂肪酸（FA）和甘油三酯（TG）代谢相关的基因的表达，并与7名健康个体进行比较。虽然与脂肪生成和TG水解相关的肝脏基因表达没有改变，但编码FA氧化相关酶/蛋白质的mRNA（肉毒碱棕榈酰辅酶A转移酶1α、中链和极长链酰基辅酶A转移酶和酰基辅酶A氧化酶1）、极低密度脂蛋白分泌（微粒体TG转移蛋白）和FA转运（CD 36和FA结合蛋白1）在CTLN 2患者中明显受到抑制。这些患者的血清酮体浓度也降低，表明线粒体β-氧化活性降低。与这些发现一致，过氧化物酶体增殖物激活受体α（PPARα）的表达，肝脏脂质代谢的主要调节因子，显着下调。肝脏PPARα表达与脂肪变性的严重程度、循环氨和瓜氨酸水平呈负相关。此外，CTLN 2肝脏中c-Jun-N-末端激酶的磷酸化增强，这可能与较低的肝脏PPARα相关。总的来说，PPARα的下调与CTLN 2患者的脂肪生成相关。这些发现提供了尿素循环障碍、脂质代谢和PPARα之间的新联系。
SLC25A13 (citrin or aspartate-glutamate carrier 2) is located in the mitochondrial membrane in the liver and its genetic deficiency causes adult-onset type II citrullinemia (CTLN2). CTLN2 is one of the urea cycle disorders characterized by sudden-onset hyperammonemia due to reduced argininosuccinate synthase activity. This disorder is frequently accompanied with hepatosteatosis in the absence of obesity and ethanol consumption. However, the precise mechanism of steatogenesis remains unclear. The expression of genes associated with fatty acid (FA) and triglyceride (TG) metabolism was examined using liver samples obtained from 16 CTLN2 patients and compared with 7 healthy individuals. Although expression of hepatic genes associated with lipogenesis and TG hydrolysis was not changed, the mRNAs encoding enzymes/proteins involved in FA oxidation (carnitine palmitoyl-CoA transferase 1α, medium- and very-long-chain acyl-CoA dehydrogenases, and acyl-CoA oxidase 1), very-low-density lipoprotein secretion (microsomal TG transfer protein), and FA transport (CD36 and FA-binding protein 1), were markedly suppressed in CTLN2 patients. Serum concentrations of ketone bodies were also decreased in these patients, suggesting reduced mitochondrial β-oxidation activity. Consistent with these findings, the expression of peroxisome proliferator-activated receptor α (PPARα), a master regulator of hepatic lipid metabolism, was significantly down-regulated. Hepatic PPARα expression was inversely correlated with severity of steatosis and circulating ammonia and citrulline levels. Additionally, phosphorylation of c-Jun-N-terminal kinase was enhanced in CTLN2 livers, which was likely associated with lower hepatic PPARα. Collectively, down-regulation of PPARα is associated with steatogenesis in CTLN2 patients. These findings provide a novel link between urea cycle disorder, lipid metabolism, and PPARα.
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影响因子：
1.2
作者：
Fukushima, Kazuhiro;Yazaki, Masahide;Ikeda, Shu-ichi
通讯作者：
Ikeda, Shu-ichi
影响因子：
3.1
作者：
Kimura, Takefumi;Shinji, Akihiro;Tanaka, Eiji
通讯作者：
Tanaka, Eiji
影响因子：
3.9
作者：
Kawashima, H;Naganuma, T;Kishimoto, T
通讯作者：
Kishimoto, T
影响因子：
13.5
作者：
Badizadegan, K;PerezAtayde, AR
通讯作者：
PerezAtayde, AR
影响因子：
4.2
作者：
Iacobazzi V;Infantino V;Palmieri F
通讯作者：
Palmieri F