Liver Research Center and Department of Medicine, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, Rhode Island 02903, USA.
J Gastroenterol Hepatol. 2013 Jan;28(1):179-87. doi: 10.1111/j.1440-1746.2012.07256.x.
Chronic alcoholic liver disease is associated with hepatic insulin resistance, dysregulated lipid metabolism with increased toxic lipid (ceramide) accumulation, lipid peroxidation, and oxidative and endoplasmic reticulum (ER) stress. Peroxisome-proliferator activated receptor (PPAR) agonists are insulin sensitizers that can restore hepatic insulin responsiveness in both alcohol and non-alcohol-related steatohepatitis. Herein, we demonstrate that treatment with a PPAR-δ agonist enhances insulin signaling and reduces the severities of ER stress and ceramide accumulation in an experimental model of ethanol-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 PPAR-δ agonist twice weekly by i.p. injection.
Ethanol-fed rats developed steatohepatitis with inhibition of signaling through the insulin and insulin-like growth factor-1 receptors, and Akt activated pathways. Despite continued ethanol exposure, PPAR-δ agonist co-treatments increased Akt activation, reduced multiple molecular indices of ER stress and steatohepatitis.
These results suggest that PPAR-δ agonist rescue of chronic alcoholic liver disease is mediated by enhancement of insulin signaling through Akt/metabolic pathways that reduce lipotoxicity and ER stress.
慢性酒精性肝病与肝胰岛素抵抗有关，表现为脂质代谢失调、毒性脂质（神经酰胺）积累增加、脂质过氧化、氧化和内质网（ER）应激。过氧化物酶体增殖物激活受体（PPAR）激动剂是胰岛素增敏剂，可恢复酒精和非酒精性脂肪性肝炎中肝胰岛素的反应性。在此，我们证明在乙醇诱导的脂肪性肝炎的实验模型中，PPAR-δ 激动剂的治疗可增强胰岛素信号传导并降低 ER 应激和神经酰胺积累的严重程度。
成年雄性 Long Evans 大鼠用含 0%或 37%（热量）乙醇的等热量液体饮食进行配对喂养 8 周。在饮食上 3 周后，大鼠每周两次通过腹腔注射接受载体或 PPAR-δ 激动剂治疗。
乙醇喂养的大鼠发生脂肪性肝炎，导致胰岛素和胰岛素样生长因子-1 受体以及 Akt 激活途径的信号转导受到抑制。尽管持续暴露于乙醇，PPAR-δ 激动剂联合治疗仍可增加 Akt 的激活，减少多种 ER 应激和脂肪性肝炎的分子指标。
这些结果表明，PPAR-δ 激动剂通过增强 Akt/代谢途径的胰岛素信号转导来拯救慢性酒精性肝病，从而减轻脂肪毒性和 ER 应激。
