The Molecular Mechanism Of SWI/SNF Complex Subunit BAF60a Inhibiting Hepatic Urea Production

The blood levels of ammonia in mammals are precisely controlled,thus enough ammonia is provided in the body to synthesize essential chemicals such as proteins,while ammonia toxicity is avoided.Of note,hepatic ureagenesis plays an important role in the regulation of ammonia homeostasis.The urea cycle converts toxic ammonia into non-toxic urea through five enzymatic reactions and it is excreted by the kidneys.Among them,carbamoyl phosphate synthase 1(CPS1)is the rate-limiting enzyme of the urea cycle.Given the importance of ammonia clearance,disruption of ureagenesis will lead to the development of hyperammonaemia,accompanied with hepatic encephalopathy and liver fibrosis induced by hepatic stellate cell(HSC)activation.Recent studies have shown that hepatic ureagenesis is a process that responds to nutritional signals,and it plays a vital role in maintaining ammonia homeostasis in mammals.Such as,during prolonged fasted,amino acids catabolism becomes the main pathway in supplying the energy,which leads to an increase in blood ammonia concentration.At the same time,a variety of hormones work together to increase the ability of ureagenesis.Conversely,in the case of overnutrition,severe damage to the urea cycle leads to hyperammonaemia,which accelerates liver damage and fibrosis.Although these findings are informative,it is still unknown how excess ammonia is produced by the steatotic hepatocytes.Therefore,intensive investigation of the molecular mechanism underlying ureagenesis will shed some light on the pathology of metabolic diseases related to ammonia dysregulation.The SWI/SNF complex subunit BAF60 a is a transcription factor that can respond to nutritional signals and regulate various metabolic pathways.Previous studies have shown that BAF60 a can respond to the Fasted signal,and then regulate fatty acid β oxidation by combining PPARα and peroxisome proliferator-activated receptor γ coactivator-1α(PGC-1α).In addition,high-fat diet(HFD)signal can induce BAF60 a combined with CAR to regulate the synthesis of cholic acid and cholesterol homeostasis in the body.It is not difficult to find that there is an inextricable link among nutritional signals,BAF60 a and metabolic processes.Therefore,we hypothesized that BAF60 a is likely to be a key regulatory factor connecting nutrient signals and the urea cycle.Here,we demonstrated that BAF60 a,a chromatin-remodeling complex subunit,was induced in the liver of both fasted and HFD-feeding mice,while the hepatic m RNA expression of BAF60 a in HFD-mice negatively correlated with ureagenesis-associated genes.Gain-and loss-of function studies indicated that BAF60 a inhibited hepatic ureagenesis,leading to the increase of serum ammonia levels and the activation of HSCs.Mechanistically,BAF60 a repressed the transcription of Cps1,a rate-limiting enzyme in the ureagenesis,through interacting with Y-box protein 1(YB-1)and switching the chromatin structure of Cps1 promoter into an inhibitory state.More importantly,we found that in response to different nutrient states,PGC-1α(as a transcriptional coactivator)and YB-1 competitively binds to BAF60 a,thus selectively regulates hepatic fatty acid β-oxidation and ureagenesis.Taken together,the BAF60a-YB-1 axis represses hepatic ureagenesis,thereby contributing to hyperammonemia under overnutrient status.Therefore,therapeutic intervention targeting BAF60 a in the liver may be a promising strategy to treat hyperammonaemia and HSC activation-induced fibrosis in the patients with nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.