Modelling porcine NAFLD by deletion of leptin and defining the role of AMPK in hepatic fibrosis

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13578-023-01124-1.