Loss of DDB2 in type II diabetes mellitus induces dysregulated ubiquitination of KMT2A in lipid metabolism disorders.

The disorders of glucose and lipid metabolism contribute to severe diseases, including cardiovascular disease, diabetes, and fatty liver. Here, we identified DNA damage-binding protein 2 (DDB2), an E3 ubiquitin ligase, as a pivotal regulator of lipid metabolism disorders in type II diabetes mellitus (T2DM). A mouse model of T2DM and primary mouse hepatocytes with steatosis were induced. DDB2 overexpression alone or in combination with lysine N-methyltransferase 2 A (KMT2A) overexpression vectors were delivered into db/db mice and in vitro hepatocytes. DDB2 was expressed poorly, while KMT2A was expressed highly in liver tissues and primary hepatocytes of db/db mice. DDB2 ameliorated glucose intolerance and insulin resistance, decreased liver/body weight ratio, downregulated expression of lipogenesis-associated proteins (SREBP1, FASN, and SCD1) and gluconeogenesis-related proteins (PEPCK and G6Pase) in liver tissues and cells, and decreased triglyceride and total cholesterol levels in steatotic hepatocytes. DDB2 reduced KMT2A expression through ubiquitination modification. Overexpression of KMT2A promoted insulin resistance, lipogenesis and lipid deposition, and glycogen accumulation in the presence of DDB2. Overall, our data demonstrate that DDB2 alleviates hepatic lipogenesis and lipid deposition via degradation of KMT2A, thereby repressing lipid metabolism disorders in T2DM.