Department of Medical Biotechnology and Translational Medicine, Center for Study and Research on Obesity, University of Milan , Milan , Italy.
Department of Clinical and Experimental Sciences, University of Brescia , Brescia , Italy.
Am J Physiol Gastrointest Liver Physiol. 2018 May 1;314(5):G566-G582. doi: 10.1152/ajpgi.00231.2017. Epub 2018 Jan 25.
Chronic alcohol consumption promotes mitochondrial dysfunction, oxidative stress, defective protein metabolism, and fat accumulation in hepatocytes (liver steatosis). Inadequate amino acid metabolism is worsened by protein malnutrition, frequently present in alcohol-consuming patients, with reduced circulating branched-chain amino acids (BCAAs). Here we asked whether dietary supplementation with a specific amino acid mixture, enriched in BCAAs (BCAAem) and able to promote mitochondrial function in muscle of middle-aged rodents, would prevent mitochondrial dysfunction and liver steatosis in Wistar rats fed on a Lieber-DeCarli ethanol (EtOH)-containing liquid diet. Supplementation of BCAAem, unlike a mixture based on the amino acid profile of casein, abrogated the EtOH-induced fat accumulation, mitochondrial impairment, and oxidative stress in liver. These effects of BCAAem were accompanied by normalization of leucine, arginine, and tryptophan levels, which were reduced in liver of EtOH-consuming rats. Moreover, although the EtOH exposure of HepG2 cells reduced mitochondrial DNA, mitochondrial transcription factors, and respiratory chain proteins, the BCAAem but not casein-derived amino acid supplementation halted this mitochondrial toxicity. Nicotinamide adenine dinucleotide levels and sirtuin 1 (Sirt1) expression, as well as endothelial nitric oxide (eNOS) and mammalian/mechanistic target of rapamycin (mTOR) signaling pathways, were downregulated in the EtOH-exposed HepG2 cells. BCAAem reverted these molecular defects and the mitochondrial dysfunction, suggesting that the mitochondrial integrity obtained with the amino acid supplementation could be mediated through a Sirt1-eNOS-mTOR pathway. Thus a dietary activation of the mitochondrial biogenesis and function by a specific amino acid supplement protects against the EtOH toxicity and preserves the liver integrity in mammals. NEW & NOTEWORTHY Dietary supplementation of a specific amino acid formula prevents both fat accumulation and mitochondrial dysfunction in hepatocytes of alcohol-consuming rats. These effects are accompanied also by increased expression of anti-reactive oxygen species genes. The amino acid-protective effects likely reflect activation of sirtuin 1-endothelial nitric oxide synthase-mammalian target of rapamycin pathway able to regulate the cellular energy balance of hepatocytes exposed to chronic, alcoholic damage.
慢性酒精摄入会导致肝细胞中线粒体功能障碍、氧化应激、蛋白质代谢缺陷和脂肪堆积（肝脂肪变性）。在经常饮酒的患者中，由于蛋白质营养不良导致氨基酸代谢不足，循环中支链氨基酸（BCAA）减少，情况会进一步恶化。在这里，我们想知道，在给予富含支链氨基酸（BCAA）并能促进中年啮齿动物肌肉中线粒体功能的特定氨基酸混合物的饮食补充后，是否可以预防长期摄入酒精的 Wistar 大鼠的线粒体功能障碍和肝脂肪变性。与基于酪蛋白氨基酸组成的混合物不同，BCAAem 的补充消除了酒精引起的脂肪堆积、肝线粒体损伤和氧化应激。BCAAem 的这些作用伴随着亮氨酸、精氨酸和色氨酸水平的正常化，这些氨基酸在酒精消耗大鼠的肝脏中减少。此外，尽管 HepG2 细胞暴露于乙醇会降低线粒体 DNA、线粒体转录因子和呼吸链蛋白，但 BCAAem 而不是酪蛋白衍生氨基酸的补充阻止了这种线粒体毒性。烟酰胺腺嘌呤二核苷酸（NAD+）水平和 Sirtuin 1（Sirt1）表达以及内皮型一氧化氮合酶（eNOS）和哺乳动物/雷帕霉素靶蛋白（mTOR）信号通路在 HepG2 细胞暴露于乙醇后均下调。BCAAem 逆转了这些分子缺陷和线粒体功能障碍，表明通过 Sirt1-eNOS-mTOR 途径，氨基酸补充获得的线粒体完整性可能介导。因此，通过特定氨基酸补充剂激活线粒体生物发生和功能可以防止酒精毒性并保护哺乳动物的肝脏完整性。新的和值得注意的是，特定氨基酸配方的饮食补充可防止饮酒大鼠肝细胞中的脂肪堆积和线粒体功能障碍。这些作用还伴随着抗氧化应激基因表达的增加。氨基酸的保护作用可能反映了 Sirtuin 1-内皮型一氧化氮合酶-mTOR 通路的激活，该通路能够调节暴露于慢性酒精损伤的肝细胞的细胞能量平衡。
