Guazzelli Pedro Arend, Cittolin-Santos Giordano Fabricio, Meira-Martins Leo Anderson, Grings Mateus, Nonose Yasmine, Lazzarotto Gabriel S, Nogara Daniela, da Silva Jussemara S, Fontella Fernanda U, Wajner Moacir, Leipnitz Guilhian, Souza Diogo O, de Assis Adriano Martimbianco
Post-graduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil.
Department of Biochemistry, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil.
Front Mol Neurosci. 2020 Jan 10;12:327. doi: 10.3389/fnmol.2019.00327. eCollection 2019.
Acute liver failure (ALF) implies a severe and rapid liver dysfunction that leads to impaired liver metabolism and hepatic encephalopathy (HE). Recent studies have suggested that several brain alterations such as astrocytic dysfunction and energy metabolism impairment may synergistically interact, playing a role in the development of HE. The purpose of the present study is to investigate early alterations in redox status, energy metabolism and astrocytic reactivity of rats submitted to ALF. Adult male Wistar rats were submitted either to subtotal hepatectomy (92% of liver mass) or sham operation to induce ALF. Twenty-four hours after the surgery, animals with ALF presented higher plasmatic levels of ammonia, lactate, ALT and AST and lower levels of glucose than the animals in the sham group. Animals with ALF presented several astrocytic morphological alterations indicating astrocytic reactivity. The ALF group also presented higher mitochondrial oxygen consumption, higher enzymatic activity and higher ATP levels in the brain (frontoparietal cortex). Moreover, ALF induced an increase in glutamate oxidation concomitant with a decrease in glucose and lactate oxidation. The increase in brain energy metabolism caused by astrocytic reactivity resulted in augmented levels of reactive oxygen species (ROS) and Poly [ADP-ribose] polymerase 1 (PARP1) and a decreased activity of the enzymes superoxide dismutase and glutathione peroxidase (GSH-Px). These findings suggest that in the early stages of ALF the brain presents a hypermetabolic state, oxidative stress and astrocytic reactivity, which could be in part sustained by an increase in mitochondrial oxidation of glutamate.
急性肝衰竭（ALF）意味着严重且迅速的肝功能障碍，可导致肝脏代谢受损和肝性脑病（HE）。最近的研究表明，一些脑功能改变，如星形胶质细胞功能障碍和能量代谢受损，可能协同相互作用，在HE的发生发展中起作用。本研究的目的是调查急性肝衰竭大鼠氧化还原状态、能量代谢和星形胶质细胞反应性的早期变化。成年雄性Wistar大鼠接受次全肝切除术（切除92%的肝脏）或假手术以诱导急性肝衰竭。手术后24小时，急性肝衰竭动物的血浆氨、乳酸、谷丙转氨酶（ALT）和谷草转氨酶（AST）水平高于假手术组动物，而血糖水平低于假手术组动物。急性肝衰竭动物出现了几种星形胶质细胞形态学改变，表明星形胶质细胞具有反应性。急性肝衰竭组在大脑（额顶叶皮质）中还表现出线粒体氧消耗增加、酶活性升高和ATP水平升高。此外，急性肝衰竭导致谷氨酸氧化增加，同时葡萄糖和乳酸氧化减少。星形胶质细胞反应性引起的脑能量代谢增加导致活性氧（ROS）和聚[ADP-核糖]聚合酶1（PARP1）水平升高，超氧化物歧化酶和谷胱甘肽过氧化物酶（GSH-Px）的活性降低。这些发现表明，在急性肝衰竭的早期阶段，大脑呈现高代谢状态、氧化应激和星形胶质细胞反应性，这可能部分由谷氨酸线粒体氧化增加所维持。
