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

Abstract

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.

Association between triglyceride to high-density lipoprotein cholesterol ratio and nonalcoholic fatty liver disease and liver fibrosis in American adults: an observational study from the National Health and Nutrition Examination Survey 2017–2020

“…Recently, a strong association between IR and leptin secretion has been reported ( 50 ). Leptin is a protein-like hormone secreted by adipose tissue, and the degree of hepatic steatosis is positively correlated to its expression level ( 50 ).…”

“…Recently, a strong association between IR and leptin secretion has been reported ( 50 ). Leptin is a protein-like hormone secreted by adipose tissue, and the degree of hepatic steatosis is positively correlated to its expression level ( 50 ). Persistent hyperleptinemia has therefore been linked to steatosis, liver fibrosis, and hepatocellular cancer in several observational clinical investigations, indicating that hyperleptinemia is a reliable indicator of the onset or development of NAFLD ( 51 – 53 ).…”

Underlying Mechanisms behind the Brain–Gut–Liver Axis and Metabolic-Associated Fatty Liver Disease (MAFLD): An Update

“…Furthermore, it also positively regulates the expression of CD14 in Kupffer cells-endotoxic bacterial lipopolysaccharide (LPS) receptor, which, when positive, causes greater sensitization of cells to harmful stimuli and, consequently, more significant oxidative stress, progression of steatohepatitis and fibrosis [41,56]. In summary, it is possible to point out that the link between leptin and the inflammatory component of MAFLD is summarized in the discovery that leptin increases pro-inflammatory and pro-fibrotic effects [147][148][149][150][151].…”

Novel perspectives on autophagy-oxidative stress-inflammation axis in the orchestration of adipogenesis

“…Conversely, the interplay between autophagy and ROS influences the transcriptional regulation of adipose regulatory factors, ultimately affecting the differentiation of preadipocytes. Recently, a research group established a LEPTIN-deletion pig obesity model ( 114 ). LEPTIN deletion in pigs causes type II diabetes and non-alcoholic fatty liver disease.…”