Amino Acid Downregulate SIRT4 to Detoxify Ammonia
HU Songhua, FENG Yuyang, XU Wei, ZHAO Shimin*
Amino acids are one of the major sources of cellular energy, yet ammonia produced from amino acid catabolism has serious neurotoxicity. The urea cycle (ornithine cycle) is the primary metabolic pathway involved in ammonia detoxification, but the processes underlying the regulation of ammonia removal by amino acids remain unclear. SIRT4 acts as a decarbamylase that responds to amino acid sufficiency and regulates ammonia removal. Mechanistically, amino acids-derived CP (carbamoyl phosphate) promotes lysine 307 carbamylation (OTC K307-CP) of OTC (ornithine transcarbamylase), which activates OTC and the urea cycle. SIRT4 expression was transcriptionally upregulated by the amino acid insufficiency-activated GCN2-Eif2A-ATF4 axis, leading to decarbamylation of OTC and inactivation of urea cycle. Based on this mechanism, Sirt4 ablation decreased mouse blood ammonia levels and ameliorated CCl4-induced hepatic encephalopathy phenotypes. This study uncovers a novel role of SIRT4 in ammonia detoxification, which could be harnessed to develop a new strategy to cure hepatic encephalopathy.
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