SWI/SNF complex subunit BAF60a represses hepatic ureagenesis through a crosstalk between YB-1 and PGC-1α

Wenxiang Zhang,Zhewen Dong,Mengyi Xu,Shiyao Zhang,Chang Liu,Siyu Chen

doi:10.1016/j.molmet.2019.12.007

Wenxiang Zhang, Zhewen Dong + Show 4 more

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https://doi.org/10.1016/j.molmet.2019.12.007

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Journal: Molecular Metabolism	Publication Date: Dec 20, 2019
Citations: 5	License type: cc-by

Affiliation: China Pharmaceutical University

Abstract

ObjectiveUreagenesis predominantly occurs in the liver and functions to remove ammonia, and the dysregulation of ureagenesis leads to the development of hyperammonemia. Recent studies have shown that ureagenesis is under the control of nutrient signals, but the mechanism remains elusive. Therefore, intensive investigation of the molecular mechanism underlying ureagenesis will shed some light on the pathology of metabolic diseases related to ammonia imbalance. MethodsMice were fasted for 24 h or fed a high-fat diet (HFD) for 16 weeks. For human evaluation, we obtained a public data set including 41 obese patients with and without hepatic steatosis. We analyzed the expression levels of hepatic BAF60a under different nutrient status. The impact of BAF60a on ureagenesis and hyperammonemia was assessed by using gain- and loss-of-function strategies. The molecular chaperons mediating the effects of BAF60a on ureagenesis were validated by molecular biological strategies. ResultsBAF60a was induced in the liver of both fasted and HFD-fed mice and was positively correlated with body mass index in obese patients. Liver-specific overexpression of BAF60a inhibited hepatic ureagenesis, leading to the increase of serum ammonia levels. Mechanistically, BAF60a repressed the transcription of Cps1, a rate-limiting enzyme, through interaction with Y-box protein 1 (YB-1) and by switching the chromatin structure of Cps1 promoter into an inhibitory state. More importantly, in response to different nutrient status, PGC-1α (as a transcriptional coactivator) and YB-1 competitively bound to BAF60a, thus selectively regulating hepatic fatty acid β-oxidation and ureagenesis. ConclusionThe BAF60a-YB-1 axis represses hepatic ureagenesis, thereby contributing to hyperammonemia under overnutrient status. Therefore, hepatic BAF60a may be a novel therapeutic target for the treatment of overnutrient-induced urea cycle disorders and their associated diseases.

Highlights

Hepatic ureagenesis plays a predominant role in maintaining nitrogen and ammonia homeostasis in mammals [1]
We found that while carbamoyl phosphate synthetase 1 (CPS1) expression was inhibited in the liver of high-fat diet (HFD)-fed mice, BAF60a expression was still increased in response to overnutrient signals (Figure 1B and Fig. S1D)
We explored the relevance of BAF60a and ureagenesis in humans

Summary

Introduction

Hepatic ureagenesis plays a predominant role in maintaining nitrogen and ammonia homeostasis in mammals [1]. Pathological signals, such as overnutrient states induced by consumption of a high-fat diet (HFD) and high-fat/high-cholesterol (HFHC) diets, impair ureagenesis and cause hyperammonemia [6]. These findings are informative, it is still unknown how excess ammonia is produced by the steatotic hepatocytes. Ureagenesis is controlled by five enzymatic reactions that occur sequentially in the mitochondrial matrix and cytoplasm of hepatocytes These enzymes are carbamoyl phosphate synthetase 1 (CPS1), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL), and arginase (ARG) [1].

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Conclusion