Komatsu Michiharu, Kimura Takefumi, Yazaki Masahide, Tanaka Naoki, Yang Yang, Nakajima Takero, Horiuchi Akira, Fang Zhong-Ze, Joshita Satoru, Matsumoto Akihiro, Umemura Takeji, Tanaka Eiji, Gonzalez Frank J, Ikeda Shu-Ichi, Aoyama Toshifumi
Department of Medicine (Gastroenterology), Shinshu University School of Medicine, Japan.
Department of Medicine (Gastroenterology), Shinshu University School of Medicine, Japan; Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, Japan.
Biochim Biophys Acta. 2015 Mar;1852(3):473-81. doi: 10.1016/j.bbadis.2014.12.011. Epub 2014 Dec 20.
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.
溶质载体家族25成员13（柑橘素或天冬氨酸-谷氨酸载体2）位于肝脏的线粒体膜中，其基因缺陷会导致成人发作的II型瓜氨酸血症（CTLN2）。CTLN2是尿素循环障碍之一，其特征是由于精氨琥珀酸合成酶活性降低而突然发作高氨血症。这种疾病在没有肥胖和饮酒的情况下经常伴有肝脂肪变性。然而，脂肪生成的确切机制仍不清楚。使用从16例CTLN2患者获得的肝脏样本检查了与脂肪酸（FA）和甘油三酯（TG）代谢相关的基因表达，并与7名健康个体进行了比较。尽管与脂肪生成和TG水解相关的肝脏基因表达没有变化，但编码参与FA氧化（肉碱棕榈酰辅酶A转移酶1α、中链和极长链酰基辅酶A脱氢酶以及酰基辅酶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（CD36和FA结合蛋白1）的酶/蛋白的mRNA在CTLN2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，肝脏脂质代谢的主要调节因子过氧化物酶体增殖物激活受体α（PPARα）的表达显著下调。肝脏PPARα表达与脂肪变性的严重程度以及循环氨和瓜氨酸水平呈负相关。此外，CTLN2肝脏中c-Jun氨基末端激酶的磷酸化增强，这可能与较低的肝脏PPARα有关。总体而言，PPARα的下调与CTLN2患者的脂肪生成有关。这些发现为尿素循环障碍、脂质代谢和PPARα之间提供了新的联系。
