Glucagon-like peptide-1 receptor activation stimulates hepatic lipid oxidation and restores hepatic signalling alteration induced bya high-fat diet in nonalcoholic steatohepatitis
Glucagon-like peptide-1 receptor activation stimulates hepatic lipid oxidation and restores hepatic signalling alteration induced bya high-fat diet in nonalcoholic steatohepatitis
复制标题
DOI：
10.1111/j.1478-3231.2011.02462.x
复制
发表时间：
2011-10-01
影响因子：
6.7
通讯作者：
Gastaldelli, Amalia
中科院分区：
文献类型：
--
作者：
Svegliati-Baroni, Gianluca;Saccomanno, Stefania;Gastaldelli, Amalia
背景/目的：高脂肪饮食摄入和低体力活动会导致胰岛素抵抗、非酒精性脂肪肝（NAFLD）和非酒精性脂肪性肝炎（NASH）。最近的研究表明，胰高血糖素样肽-1 (GLP-1) 对肝脏葡萄糖代谢有影响，尽管在人类肝脏中尚未发现 GLP-1 受体 (GLP-1r)。本研究的目的是调查肝脏 GLP-1r 的存在以及艾塞那肽（一种 GLP-1 类似物）对肝脏信号传导的影响。方法：在人类肝活检和高脂饮食治疗的大鼠肝脏中评估 GLP-1r 的表达。在高脂饮食喂养 3 个月的大鼠肝细胞中评估了艾塞那肽 (100 nM) 的作用。结果：GLP-1r 在人类肝细胞中表达，但在 NASH 患者中表达减少。同样，在 3 个月高脂饮食导致 NASH 的大鼠中，我们发现 GLP-1r 和过氧化物酶体增殖物激活受体 γ (PPAR γ) 的表达降低，并且过氧化物酶体增殖物激活受体 α (PPAR α) 活性降低。肝细胞与艾塞那肽一起孵育可增加 PPAR γ 表达，同时通过减少 JNK 磷酸化发挥胰岛素增敏作用。此外，艾塞那肽可增加蛋白激酶 A (PKA) 活性、Akt 和 AMPK 磷酸化，并确定 PPAR α 活性的 PKA 依赖性增加。结论：GLP-1 通过激活参与脂肪酸 β 氧化和胰岛素敏感性的基因，对肝细胞产生直接影响。 GLP-1 类似物可能是改善 NAFLD/NASH 患者肝脏胰岛素抵抗的一种有前景的治疗方法。
Background/Aims: High-fat dietary intake and low physical activity lead to insulin resistance, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Recent studies have shown an effect of glucagon-like peptide-1 (GLP-1) on hepatic glucose metabolism, although GLP-1 receptors (GLP-1r) have not been found in human livers. The aim of this study was to investigate the presence of hepatic GLP-1r and the effect of exenatide, a GLP-1 analogue, on hepatic signalling. Methods: The expression of GLP-1r was evaluated in human liver biopsies and in the livers of high-fat diet-treated rats. The effect of exenatide (100 nM) was evaluated in hepatic cells of rats fed 3 months with the high-fat diet. Results: GLP-1r is expressed in human hepatocytes, although reduced in patients with NASH. Similarly, in rats with NASH resulted from 3 months of the high-fat diet, we found a decreased expression of GLP-1r and peroxisome proliferator-activated receptor gamma (PPAR gamma), and reduced peroxisome proliferator-activated receptor alpha (PPAR alpha) activity. Incubation of hepatocytes with exenatide increased PPAR gamma expression, which also exerted an insulin-sensitizing action by reducing JNK phosphorylation. Moreover, exenatide increased protein kinase A (PKA) activity, Akt and AMPK phosphorylation and determined a PKA-dependent increase of PPAR alpha activity. Conclusions: GLP-1 has a direct effect on hepatocytes, by activating genes involved in fatty acid beta-oxidation and insulin sensitivity. GLP-1 analogues could be a promising treatment approach to improve hepatic insulin resistance in patients with NAFLD/NASH.