The liver plays a central role in maintaining systemic energy homeostasis during fasting by mobilizing lipid reserves, a process often accompanied by transient hepatic steatosis. Dimethylarginine dimethylaminohydrolase 1 (DDAH1), a key enzyme metabolizing asymmetric dimethylarginine (ADMA), has been shown to protect against NAFLD under nutrient-overload conditions. However, its role in the physiological context of fasting remained elusive.

To address this question, a recent study published in Life Metabolism reveals a novel, nutrient-state-dependent function of hepatocyte DDAH1. The research team led by Prof. Zhongbing Lu from Chinese Academy of Sciences found that contrary to its protective role in obesity, hepatocyte-specific deletion of Ddah1 (Ddah1^HKO) in mice significantly attenuated fasting-induced hepatic steatosis. Conversely, hepatic overexpression of DDAH1 exacerbated lipid accumulation. Lipidomic and transcriptomic analyses revealed a comprehensive remodeling of hepatic lipid metabolism in fasted Ddah1^HKO mice, characterized by reduced levels of most lipid species and downregulation of genes involved in fatty acid oxidation and ketogenesis (Figure 1).

Mechanistically, the study identified the regulatory role of DDAH1 both in fatty acid-binding protein 1 (FABP1) and in AMPK/mTOR signaling pathway. On the one hand, DDAH1 deficiency led to a marked decrease in the protein level of FABP1, specifically under fasting conditions. This downregulation impaired cellular fatty acid uptake. Crucially, hepatic overexpression of FABP1 in Ddah1^HKO mice reversed the anti-steatotic phenotype, confirming FABP1 as a key downstream effector of DDAH1. On the other hand, DDAH1 deletion activated the AMPK/mTOR signaling pathway, thereby enhancing autophagic flux (increased LC3-II/LC3-I ratio, decreased p62). Pharmacological inhibition of AMPK using Compound C suppressed this enhanced autophagy and abolished the protective effect against hepatic steatosis in fasted Ddah1^HKO mice. Furthermore, FABP1 overexpression suppressed AMPK/mTOR signaling pathway, positioning FABP1 as the upstream of AMPK in this regulatory axis.

Taken together, this work delineates a novel DDAH1-FABP1-AMPK/mTOR-autophagy axis that fine-tunes hepatic lipid homeostasis during fasting. DDAH1 promotes lipid accumulation by simultaneously increasing fatty acid uptake via upregulating FABP1 and inhibiting lipid droplet degradation via suppressing AMPK/mTOR-mediated autophagy. These findings highlight the complex, context-dependent nature of metabolic regulators and identify the DDAH1-centered pathway as a potential therapeutic target for managing dyslipidemia in metabolic liver diseases.
DOI
10.1093/lifemeta/loaf042