Loss of CCDC3 alleviates MAFLD and metabolic aging of mice through enhanced AGXT-associated hepatocyte glycine metabolism

Coiled-coil domain-containing protein 3 (CCDC3), a protein secreted from adipose tissues and endothelial cells, was suggested to play a possible role in aging-associated hepatic steatosis. However, its role in unhealthy diet-associated liver diseases and the underlying molecular events remain completely unknown. By employing Ccdc-3 knockout mice, we found that loss of Ccdc3 not only improves the metabolic aging of mice under a chow diet, but also significantly delays the western diet-induced obesity, insulin resistance, and inert metabolism, as well as alleviates western diet-induced metabolic dysfunction-associated fatty liver disease (MAFLD) progression and liver fibrosis in mice. Our RNA sequencing combined with metabolomic analysis of mouse liver samples revealed that Ccdc3 deletion induced the expression of alanine-glyoxylate aminotransferase (AGXT, AGT), a hepatocyte-specific enzyme that can catalyze glycine synthesis. Consistently, glycine level and glutathione production were elevated, and bile acid turnover and homeostasis were enhanced, while inflammation and lipogenesis were alleviated, in Ccdc3-deleted mouse liver. These improvements were also observed by supplementing glycine to human liver cancer cells and mouse hepatocytes incubated in CCDC3-conditioned medium. Hence, our study reveals that CCDC3 regulates the progression of MAFLD by directing AGXT-associated glycine metabolism in hepatocytes, identifying CCDC3 as a potential target for MAFLD therapy.