The adiponectin receptor agonist AdipoRon alleviates lipotoxic injury in LMH cells

Avian fatty liver disease is a metabolic disease characterized by hepatocellular steatosis caused by fat deposition due to lipid metabolism disorders in poultry. AdipoRon, an adiponectin receptor agonist, has various biological effects, such as regulating glucose and lipid metabolism disorders, increasing insulin sensitivity, improving liver fat accumulation, and preventing inflammation and oxidative stress. Our previous study revealed that AdipoRon protected against liver injury induced by a high-fat diet and lipopolysaccharide in poultry. In this study, leghorn male hepatoma (LMH) cells were used to construct a lipotoxic injury model with mixed fatty acids (oleic acid + palmitic acid), and AdipoRon was subsequently used to intervene, followed by inhibition and activation of AMPK signaling pathways using an antagonist and agonist of AMPK, respectively, to detect lipid content and lipid deposition, hepatocyte injury-related transaminase activity, and the expression levels of lipid metabolism-related genes and key signaling molecules that regulate lipid metabolism, as well as the cellular lipid composition in LMH cells. AdipoRon promoted fatty acid oxidation, reduced lipid synthesis and deposition, and alleviated mixed fatty acid-induced lipotoxic injury through the regulation of the expression of adiponectin receptors, AMPK, PPARα, and key genes involved in lipid metabolism. The inhibition or activation of AMPK signaling pathways could regulate the expression of AdipoR1, AdipoR2, AMPK and p-AMPK, thereby altering the expression of lipid metabolism-related genes and antagonizing or synergistically increasing the ameliorative effects of AdipoRon on cellular lipid metabolism disorders, lipid deposition and cell injury. Lipidomic analysis further suggested that AdipoRon could regulate the metabolism of lipids such as sphingolipids, glycerophospholipids, acylcarnitines, and glycerolipids; reduce the accumulation of lipids such as ceramides, sphingomyelins, triacylglycerol, and acylcarnitines; maintain the metabolic homeostasis of phosphatidylamine and phosphatidylcholine, as well as cell membrane structural integrity and functional stability; and mitigate lipotoxic injury in LMH cells. This study provides new insights into targeted interventions involving adiponectin and its receptors to prevent and treat avian fatty liver disease.