Ramirez Teresa, Tong Ming, Ayala Carol A, Monfils Paul R, McMillan Paul N, Zabala Valerie, Wands Jack R, de la Monte Suzanne M
Liver Research Center and Departments of Medicine, Pathology, Neurology, and Neurosurgery, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, USA.
J Clin Exp Pathol. 2012 Jun;2(4). doi: 10.4172/2161-0681.1000114.
Chronic alcoholic liver disease is associated with hepatic insulin resistance, inflammation, oxidative and ER stress, mitochondrial dysfunction, and DNA damage. Peroxisome-proliferator activated receptor (PPAR) agonists are insulin sensitizers that have anti-inflammatory/anti-oxidant effects. We previously showed that PPAR agonists can restore hepatic insulin responsiveness in chronic ethanol-fed rats with steatohepatitis. Herein, we furthered our investigations by characterizing the histological and ultrastructural changes mediated by PPAR agonist rescue of alcohol-induced steatohepatitis. Adult male Long Evans rats were pair fed with isocaloric liquid diets containing 0% or 37% ethanol (caloric) for 8 weeks. After 3 weeks on the diets, rats were treated with vehicle, or a PPAR-α, PPAR-δ, or PPAR-γ agonist twice weekly by i.p. injection. Ethanol-fed rats developed steatohepatitis with disordered hepatic chord architecture, mega-mitochondria, disruption of the RER, increased apoptosis, and increased 4-hydroxynonenal (HNE) and 3-nitrotyrosine (NTyr) immunoreactivity. PPAR-δ and PPAR-γ agonists reduced the severity of steatohepatitis, and restored the hepatic chord-like architectural, mitochondrial morphology, and RER organization, and the PPAR-δ agonist significantly reduced hepatic HNE. On the other hand, prominent RER tubule dilation, which could reflect ER stress, persisted in ethanol-exposed, PPAR-γ treated but not PPAR-δ treated livers. The PPAR-α agonist exacerbated both steatohepatitis and formation of mega-mitochondria, and it failed to restore RER architecture or lower biochemical indices of oxidative stress. In conclusion, improved hepatic insulin responsiveness and decreased inflammation resulting from PPAR-δ or PPAR-γ agonist treatments of alcohol-induced steatohepatitis are likely mediated by enhanced signaling through metabolic pathways with attendant reductions in ER stress, oxidative stress, and mitochondrial dysfunction.
慢性酒精性肝病与肝脏胰岛素抵抗、炎症、氧化应激和内质网应激、线粒体功能障碍以及DNA损伤相关。过氧化物酶体增殖物激活受体（PPAR）激动剂是具有抗炎/抗氧化作用的胰岛素增敏剂。我们之前表明，PPAR激动剂可恢复患有脂肪性肝炎的慢性乙醇喂养大鼠的肝脏胰岛素反应性。在此，我们通过描述PPAR激动剂对酒精性脂肪性肝炎的挽救所介导的组织学和超微结构变化，进一步开展了研究。成年雄性Long Evans大鼠以含0%或37%乙醇（热量）的等热量液体饮食配对喂养8周。在饮食3周后，大鼠每周经腹腔注射给予赋形剂、PPAR-α激动剂、PPAR-δ激动剂或PPAR-γ激动剂两次。乙醇喂养的大鼠出现脂肪性肝炎，伴有肝索结构紊乱、巨型线粒体、粗面内质网破坏、细胞凋亡增加以及4-羟基壬烯醛（HNE）和3-硝基酪氨酸（NTyr）免疫反应性增加。PPAR-δ和PPAR-γ激动剂减轻了脂肪性肝炎的严重程度，并恢复了肝索样结构、线粒体形态和粗面内质网结构，且PPAR-δ激动剂显著降低了肝脏HNE。另一方面，可能反映内质网应激的显著粗面内质网小管扩张在乙醇暴露且经PPAR-γ处理而非PPAR-δ处理的肝脏中持续存在。PPAR-α激动剂加剧了脂肪性肝炎和巨型线粒体的形成，且未能恢复粗面内质网结构或降低氧化应激的生化指标。总之，PPAR-δ或PPAR-γ激动剂治疗酒精性脂肪性肝炎导致的肝脏胰岛素反应性改善和炎症减轻，可能是通过代谢途径增强信号传导，并伴随内质网应激、氧化应激和线粒体功能障碍的减轻来介导的。
