Hepatology of Jin Baojian Research Group of Jinan University discovered the key role of circadian clock gene in amino acid metabolism
Amino acid metabolism homeostasis is essential for human health. Professor Wu Baojian from the School of Pharmacy of Jinan University published an article entitled "REV-ERBα antagonism promotes homocysteine ​​catabolism and ammonia clearance" and found that the clock gene REV-ERBα is in amino acids. Metabolic circadian rhythm plays an important role in its antagonism to alleviate hyperhomocysteinemia and promote ammonia clearance, helping scientists to find a new management of homocysteine ​​and ammonia-related diseases. method.
The study was published in the April issue of Hepatology and was led by Professor Wu Baojian from the School of Pharmacy of Jinan University.
The human body follows a certain circadian rhythm to live and work. This rhythm is called the biological clock of the human body. The biological clock not only helps people to better adapt to life and stay healthy, but also helps control the production and use of various nutrients by cells in the human body. Previous studies have found a protein that controls intracellular fat synthesis and also controls the recycling process of intracellular nutrients (including autophagy) called REV-ERBα and REV-ERBβ.
Although these two factors have similar functions in maintaining circadian rhythms and regulating lipid/glucose metabolism, REV-ERBα appears to play a more important role. Moreover, REV-ERBα is also involved in the regulation of breast cancer, aging, and myocardial damage.
Previous studies by Professor Wu's research group showed that the loss of REV-ERBα leads to the destruction of circadian rhythm in mice. At the same time, it also regulates the expression of metabolic genes, thereby correlating circadian rhythms with cellular metabolism.
A variety of amino acids (such as homocysteine) and products (such as ammonia and urea) are associated with circadian rhythm oscillations in the body, suggesting that the circadian clock has potential regulation of amino acid metabolism. However, whether and how the clock gene such as REV-ERBα regulates amino acid metabolism is still unknown.
In this article, the researchers discovered the key role of Rev-erbα in regulating amino acid metabolism. They used Rev-erbα knockout mice prepared by Guangzhou Saiye Biotechnology , and found that mice lacking Rev-erbα showed changes in the expression of amino acid metabolism-related genes, especially in the urea cycle and methionine metabolism genes. Expression changes. Moreover, the study also pointed out that Rev-erbα deletion increased liver mRNA, protein and enzyme activity of Bhmt, Cbs and Cth, and decreased plasma and liver homocysteine ​​levels in mice. In addition, cell experiments confirmed Rev-erbα. Negative regulation of these three genes.
In this study, the researchers demonstrated that Rev-erbα is a transcriptional repressor of Bhmt, Cbs, and Cth by binding to luciferase reporter genes, mobility changes, and chromatin immunoprecipitation assays. Rev-erbα antagonism attenuates chemically induced hyperhomocysteinemia in mice with elevated expression of Bhmt, Cbs and Cth.
In addition, Rev-erbα antagonism also promotes urea production and ammonia clearance. Among the urea cycle-related genes, Arg1, Otc and Cps1 expression were up-regulated in Rev-erb-deficient mice. Cell experiments demonstrated the negative regulation of these urea cycle genes by Rev-erbα; mechanistic studies indicated that Rev-erbα inhibited C/EBPα transactivation and inhibited the transcription of Arg1, Cps1 and Otc.
These data all indicate the key role of Rev-erbα in regulating amino acid metabolism, so it can be used as a new target for the treatment of hyperhomocysteinemia and hyperammonemia.
Note:
Hyperhomocysteinemia, also known as homocysteineuria, is a rare autosomal recessive disorder caused by the absence or deficiency of cystathionine beta synthase, which causes homocysteine ​​accumulation in the blood. , a disease in which the homocysteine ​​is excessive in the urine. The disease mainly has the following clinical features: developmental delay, osteoporosis, ocular abnormalities, horse-like syndrome, thromboembolic disease and premature atherosclerosis. According to statistics, the incidence of global homocysteine ​​is 1/344,000.
About the Author:
Wu Baojian, male, doctor, professor of pharmacy, doctoral tutor at Jinan University. In 2004, 2007 and 2011, he received a bachelor's degree in pharmacy from Fudan University, a master's degree in pharmacy from Fudan University, and a doctorate in pharmacy from the University of Houston. After graduating from the University of Baylor College of Medicine, he did postdoctoral research (biochemistry and molecular biology). Returning to China in September 2012, he is engaged in teaching and research at the School of Pharmacy of Jinan University.
Original title:
REVâ€ERBα antagonism promotes homocysteine ​​catabolism and ammonia clearance
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