211-OR: Chemerin Affects Mitochondrial Function by Modulating PPARγ/PGC-1α/UCP2 Signaling Pathway to Promote Metabolic Dysfunction-Associated Fatty Liver Disease

Introduction and Objective: Previous studies have found that chemerin knockout mice are less susceptible to fatty liver when fed high-fat diet, but the underlying mechanisms remain unknown. Therefore, this study explores the role of chemerin in metabolic dysfunction-associated fatty liver disease and its mechanisms. Methods: 8-week-old male wild-type mice (WT) and adipose chemerin-specific knockout mice (chemerin-/-) were divided into 4 groups: WT plus normal diet, WT plus high-fat diet, chemerin-/- plus normal diet, chemerin-/- plus high-fat diet group, high-fat feeding for 12 weeks. The occurrence of fatty liver as well as the morphological and functional indexes of liver mitochondria were observed. AML12 was interfered with chemerin overexpression plasmid and sh-RNA to observe lipid deposition in hepatocytes and mitochondrial function indexes. Results: 1) chemerin-/- mice were less likely to develop fatty liver after high-fat feeding. Overexpression of chemerin in hepatocytes increased lipid deposition, while knockdown of chemerin were reversed. 2) chemerin-/- mice with HFD showed increased ATP and membrane potential in liver, increased number of mitochondria, and reduced mitochondrial edema compared with HFD WT mice. ATP levels and membrane potential were decreased in AML12 cells overexpressing chemerin, and these were reversed with knockdown of chemerin. 3) The protein levels of PPARγ, PGC-1α and UCP2 in the liver of chemerin-/- mice were increased under high-fat feeding. In AML12 cells with overexpression of chemerin, PPARγ, PGC-1α and UCP2 were decreased, while they were increased with knockdown of chemerin. 4) AML12 cells treated with PPARγ agonist increased ATP and membrane potential. However, those effects were reversed by PPARγ inhibitor. Conclusion: Chemerin induces fatty liver by affecting mitochondrial function, which is related to the regulation of the PPARγ/PGC-1α/UCP2 pathway. Disclosure X. Lin: None. H. Chen: None. S. Qu: None.