Modelling porcine NAFLD by deletion of leptin and defining the role of AMPK in hepatic fibrosis.
Modelling porcine NAFLD by deletion of leptin and defining the role of AMPK in hepatic fibrosis.
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DOI：
10.1186/s13578-023-01124-1
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发表时间：
2023-09-13
影响因子：
7.5
通讯作者：
Xing, Yiming
中科院分区：
文献类型：
--
作者：
Tan, Tan;Song, Zhiyuan;Li, Wenya;Wang, Runming;Zhu, Mingli;Liang, Zuoxiang;Bai, Yilina;Wang, Qi;Wu, Hanyu;Hu, Xiaoxiang;Xing, Yiming
非酒精性脂肪性肝病（NAFLD）是慢性肝病最常见的原因，并导致非酒精性脂肪性肝炎（NASH），其进展为纤维化和肝硬化。虽然瘦素缺乏的啮齿动物模型被广泛用于代谢综合征和肥胖的研究，但它们不像患者那样发生肝损伤。由于与人类的高度相似性，我们产生了瘦素缺陷（瘦素-/-）猪，以研究瘦素引起的肥胖和NAFLD的机制和临床试验。Leptin−/−猪在12个月大时表现出增加的体脂和显著的胰岛素抵抗。此外，Leptin-/-猪随着年龄的增长会出现脂肪肝、非酒精性脂肪性肝炎和肝纤维化。在猪中缺乏瘦素降低了JAK 2-STAT 3和AMPK的磷酸化。JAK 2-STAT 3和AMPK的失活分别增强了脂肪酸β-氧化和导致线粒体自噬，两者都有助于增加肝细胞的氧化应激。与Leptin−/−猪相反，尽管大鼠肝脏中Leptin缺失抑制JAK 2-STAT 3磷酸化，但AMPK通路的激活可能防止肝损伤。因此，在Leptin−/−大鼠肝脏中未发生β-氧化、线粒体自噬和肝纤维化。瘦素缺陷猪提供了一个理想的模型来说明人类NAFLD的全谱。AMPK信号通路的活性为NAFLD的诊断和治疗提供了新的靶点。在线版本包含补充材料，可通过10.1186/s13578-023-01124-1获得。
Non-alcoholic fatty liver disease (NAFLD) is the most prevalent cause of chronic hepatic disease and results in non-alcoholic steatohepatitis (NASH), which progresses to fibrosis and cirrhosis. Although the Leptin deficient rodent models are widely used in study of metabolic syndrome and obesity, they fail to develop liver injuries as in patients. Due to the high similarity with humans, we generated Leptin-deficient (Leptin−/−) pigs to investigate the mechanisms and clinical trials of obesity and NAFLD caused by Leptin. The Leptin−/− pigs showed increased body fat and significant insulin resistance at the age of 12 months. Moreover, Leptin−/− pig developed fatty liver, non-alcoholic steatohepatitis and hepatic fibrosis with age. Absence of Leptin in pig reduced the phosphorylation of JAK2-STAT3 and AMPK. The inactivation of JAK2-STAT3 and AMPK enhanced fatty acid β-oxidation and leaded to mitochondrial autophagy respectively, and both contributed to increased oxidative stress in liver cells. In contrast with Leptin−/− pig, although Leptin deletion in rat liver inhibited JAK2-STAT3 phosphorylation, the activation of AMPK pathway might prevent liver injury. Therefore, β-oxidation, mitochondrial autophagy and hepatic fibrosis did not occurred in Leptin−/− rat livers. The Leptin-deficient pigs presents an ideal model to illustrate the full spectrum of human NAFLD. The activity of AMPK signaling pathway suggests a potential target to develop new strategy for the diagnosis and treatment of NAFLD. The online version contains supplementary material available at 10.1186/s13578-023-01124-1.
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影响因子：
12.8
作者：
Jeon SM
通讯作者：
Jeon SM
影响因子：
5.6
作者：
Ghosh, Asish K.;Vaughan, Douglas E.
通讯作者：
Vaughan, Douglas E.
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作者：
Hossain, Israt Ara;Akter, Salima;Ali, Liaquat
通讯作者：
Ali, Liaquat
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25.7
作者：
Leung, Tung-Ming;Nieto, Natalia
通讯作者：
Nieto, Natalia
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25.7
作者：
Machado, Mariana;Marques-Vidal, Pedro;Cortez-Pinto, Helena
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Cortez-Pinto, Helena