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肝脏线粒体脂肪酸氧化增加可降低大鼠血浆和肝脏甘油三酯水平，并与解偶联蛋白（UCPs）和载脂蛋白C-III（APOC-III）的调节有关。

Increased hepatic mitochondrial FA oxidation reduces plasma and liver TG levels and is associated with regulation of UCPs and APOC-III in rats.

作者信息

Lindquist Carine, Bjørndal Bodil, Rossmann Christine Renate, Tusubira Deusdedit, Svardal Asbjørn, Røsland Gro Vatne, Tronstad Karl Johan, Hallström Seth, Berge Rolf Kristian

机构信息

Departments of Clinical Science University of Bergen, Bergen, Norway; Department of Heart Disease, Haukeland University Hospital, Bergen, Norway.

Departments of Clinical Science University of Bergen, Bergen, Norway.

出版信息

J Lipid Res. 2017 Jul;58(7):1362-1373. doi: 10.1194/jlr.M074849. Epub 2017 May 4.

DOI:10.1194/jlr.M074849
PMID:28473603
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5496034/
Abstract

Hepatic mitochondrial function, APOC-III, and LPL are potential targets for triglyceride (TG)-lowering drugs. After 3 weeks of dietary treatment with the compound 2-(tridec-12-yn-1-ylthio)acetic acid (1-triple TTA), the hepatic mitochondrial FA oxidation increased more than 5-fold in male Wistar rats. Gene expression analysis in liver showed significant downregulation of APOC-III and upregulation of LPL and the VLDL receptor. This led to lower hepatic (53%) and plasma (73%) TG levels. Concomitantly, liver-specific biomarkers related to mitochondrial biogenesis and function (mitochondrial DNA, citrate synthase activity, and cytochrome c and TFAM gene expression) were elevated. Interestingly, 1-triple TTA lowered plasma acetylcarnitine levels, whereas the concentration of β-hydroxybutyrate was increased. The hepatic energy state was reduced in 1-triple TTA-treated rats, as reflected by increased AMP/ATP and decreased ATP/ADP ratios, whereas the energy state remained unchanged in muscle and heart. The 1-triple TTA administration induced gene expression of uncoupling protein (UCP)2 and UCP3 in liver. In conclusion, the 1-triple TTA-mediated clearance of blood TG may result from lowered APOC-III production, increased hepatic LPL gene expression, mitochondrial FA oxidation, and (re)uptake of VLDL facilitating drainage of FAs to the liver for β-oxidation and production of ketone bodies as extrahepatic fuel. The possibility that UCP2 and UCP3 mediate a moderate degree of mitochondrial uncoupling should be considered.

摘要

肝线粒体功能、载脂蛋白C-III（APOC-III）和脂蛋白脂肪酶（LPL）是降低甘油三酯（TG）药物的潜在靶点。在用化合物2-（十三碳-12-炔-1-基硫代）乙酸（1-三TTA）进行3周饮食治疗后，雄性Wistar大鼠的肝线粒体脂肪酸氧化增加了5倍多。肝脏基因表达分析显示APOC-III显著下调，LPL和极低密度脂蛋白受体上调。这导致肝脏TG水平降低53%，血浆TG水平降低73%。同时，与线粒体生物发生和功能相关的肝脏特异性生物标志物（线粒体DNA、柠檬酸合酶活性以及细胞色素c和线粒体转录因子A（TFAM）基因表达）升高。有趣的是，1-三TTA降低了血浆乙酰肉碱水平，而β-羟基丁酸的浓度增加。1-三TTA治疗的大鼠肝脏能量状态降低，表现为腺苷酸/三磷酸腺苷（AMP/ATP）增加和三磷酸腺苷/二磷酸腺苷（ATP/ADP）比值降低，而肌肉和心脏的能量状态保持不变。给予1-三TTA可诱导肝脏中解偶联蛋白（UCP）2和UCP3的基因表达。总之，1-三TTA介导的血液TG清除可能是由于APOC-III生成减少、肝脏LPL基因表达增加、线粒体脂肪酸氧化以及极低密度脂蛋白的（再）摄取促进脂肪酸向肝脏引流以进行β-氧化并产生酮体作为肝外燃料。应考虑UCP2和UCP3介导一定程度线粒体解偶联的可能性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a2c/5496034/4c16521e5977/1362fig12.jpg
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