| First Author | Zhang T | Year | 2019 |
| Journal | Hepatology | Volume | 70 |
| Issue | 5 | Pages | 1770-1784 |
| PubMed ID | 31016736 | Mgi Jnum | J:340403 |
| Mgi Id | MGI:7529313 | Doi | 10.1002/hep.30675 |
| Citation | Zhang T, et al. (2019) Reverse Erythroblastosis Virus alpha Antagonism Promotes Homocysteine Catabolism and Ammonia Clearance. Hepatology 70(5):1770-1784 |
| abstractText | Metabolic homeostasis of amino acids is essential for human health. Here, we aimed to investigate a potential role for the clock component reverse erythroblastosis virus alpha (Rev-erbalpha) in circadian regulation of amino acid metabolism. RNA-seq with Rev-erbalpha(-/-) mice showed expression changes in genes involved in amino acid metabolism, particularly, the urea cycle and methionine metabolism. Rev-erbalpha ablation increased hepatic mRNA, protein, and enzymatic activity of betaine homocysteine methyltransferase (Bhmt), cystathionine beta-synthase (Cbs), and cystathionine gamma-lyase (Cth) and decreased the levels of plasma and liver homocysteine in mice. Cell-based assays confirmed negative regulation of these three genes by Rev-erbalpha. Combined luciferase reporter, mobility-shift, and chromatin immunoprecipitation assays identified Rev-erbalpha as a transcriptional repressor of Bhmt, Cbs, and Cth. Rev-erbalpha ablation or antagonism alleviated chemical-induced hyperhomocysteinemia in mice. This was accompanied by elevated expressions of Bhmt, Cbs, and Cth. Moreover, Rev-erbalpha ablation or antagonism promoted urea production and ammonia clearance. Of urea cycle-related genes, arginase 1 (Arg1), ornithine transcarbamylase (Otc), and carbamoyl-phosphate synthase 1 (Cps1) expressions were up-regulated in Rev-erbalpha(-/-) mice. Negative regulation of these urea cycle genes by Rev-erbalpha was validated using cell-based experiments. Mechanistic studies revealed that Rev-erbalpha inhibited CCAAT-enhancer-binding protein alpha transactivation to repress the transcription of Arg1, Cps1, and Otc. Conclusion: Rev-erbalpha antagonism alleviates hyperhomocysteinemia and promotes ammonia clearance. Targeting Rev-erbalpha represents an approach for the management of homocysteine- and ammonia-related diseases. |
