Hepatocyte-specific DDAH1 regulates fasting-induced hepatic lipid metabolism via modulating FABP1 expression and...

Under nutrient deprivation conditions, the liver maintains systemic energy homeostasis by mobilizing lipid reserves, a process often accompanied by hepatic lipid accumulation. Dimethylarginine dimethylaminohydrolase 1 (DDAH1), a key metabolizing enzyme for asymmetric dimethylarginine (ADMA), has been demonstrated to exert a protective effect in the pathogenesis of nonalcoholic fatty liver disease (NAFLD), yet its role in fasting-induced hepatic metabolic adaptation remains incompletely elucidated. In this article, we explored the function of DDAH1 in fasting-induced liver lipid accumulation using hepatocyte-specific Ddah1 knockout (Ddah1 ^HKO) mice. Compared with control mice (Ddah1 ^f/f), Ddah1 ^HKO mice exhibited significantly attenuated hepatic steatosis after fasting. Lipidomic analysis of the liver revealed decreased levels of most lipid species (e.g., triglycerides and free fatty acids) in Ddah1 ^HKO mice. Further mechanistic studies demonstrated that Ddah1 deletion downregulated the protein level of hepatic fatty acid binding protein 1 (FABP1) and activated the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling pathway, thereby enhancing autophagic flux and promoting lipid droplet degradation under fasting conditions. Hepatic overexpression of FABP1 reversed the anti-steatotic phenotype of Ddah1 ^HKO mice, while treatment with the AMPK inhibitor Compound C suppressed autophagy and increased hepatic lipid accumulation. In addition, overexpression of DDAH1 in hepatocytes exacerbated hepatic steatosis in fasted mice, coinciding with FABP1 upregulation and autophagy inhibition. Collectively, this article reveals that DDAH1 plays a critical role in hepatic lipid metabolism under fasting conditions by modulating FABP1 expression and AMPK/mTOR-mediated autophagy.