Scientists discover a new mechanism by which proline hydroxylation modification regulates type 2 diabetes

Researchers from Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Affiliated Hospital of Southwest Medical University and Qingdao University were the first to analyze the new mechanism of proline hydroxylation modification regulating the progression of type 2 diabetes, revealing that proline hydroxylase 3 (PHD3) increases the nuclear localization and activity of CRTC2, a key transcription factor of gluconeogenesis, through hydroxylation, which in turn increases hepatic gluconeogenic gene expression and glucose production. The study was published online May 30 in the Proceedings of the National Academy of Sciences (PNAS).

As an important endocrine organ, liver glucose metabolism plays an important role in maintaining blood glucose homeostasis. Excessive increase in hepatic gluconeogenesis is an important cause of high blood sugar and type 2 diabetes. The secretion of glucagon will promote the binding of CREB to its transcriptional cofactor CRTC2 by activating the PKA pathway and increasing the phosphorylation of CREB, thereby promoting the expression of PEPCK and G6Pase, the key rate-limiting enzymes of gluconeogenesis, and increasing the level of gluconeogenesis. Proline hydroxylase PHD3 is able to regulate the hydroxylation level of the hypoxia-inducible factor HIF by sensing changes in oxygen content, thereby affecting its activity. However, it is unclear whether PHD3 can sense changes in other physiological states of the body and regulate glucose metabolism and blood glucose homeostasis.

In order to explore whether PHD3 can sense changes in the body’s energy, the researchers first measured the protein level of PHD3 in the liver of mice under normal feeding and fasting, and found that fasting can significantly increase the protein expression of PHD3. PHD3 hepatocytes-specific knockout mice were fed with fasting and high-fat and high-sucrose diets, and it was found that PHD3 hepatocyte-specific knockout could reduce the expression level of key enzymes of gluconeogenesis in the liver of mice and reduce glucose production, whether in the physiological state of fasting or the pathological state of obesity. Secondly, in order to explore whether the role of PHD3 is exerted by its hydroxylase activity, the researchers further constructed a gene knock-in (KI) mouse model of loss of hydroxylase activity in PHD3 hepatocytes, and obtained results consistent with PHD3 hepatocyte-specific knockout mice, indicating that PHD3 participates in the regulatory process of gluconeogenesis and depends on its hydroxylase activity. Further mechanistic studies have found that PHD3 promotes the binding of CRTC2 to CREB by hydroxylating the Pro129 and Pro625 sites of CRTC2, increasing the nuclear translocation and transcriptional activity of CRTC2, thereby increasing gluconeogenic gene transcription and glucose production. In addition, the hydroxylation level of CRTC2 Pro615 site increased significantly in the liver tissues of fasted mice, obese, obese diabetic mice, and diabetic patients, indicating that PHD3-mediated CRTC2 hydroxylation modification may play an important role in the regulation of blood glucose homeostasis in mice and humans under physiological and pathological conditions.

The study found that CRTC2, the key transcription factor of gluconeogenesis, is a new downstream substrate of PHD3, and hydroxylation modification enhances the nuclear translocation and activity of CRTC2, thereby increasing the expression of gluconeogenic genes and hepatic glucose output. At the same time, the study suggests that inhibition of liver PHD3 or CRTC2 hydroxylation may be a new strategy for treating hyperglycemia and type 2 diabetes. Post-translational modification of proteins is strongly associated with the onset and progression of metabolic diseases such as type 2 diabetes. Previous studies in Li’s research group found that AMPK inhibits hepatic lipid oversynthesis and nonalcoholic fatty liver disease by phosphorylation modifying lipid anabolic key factors Insig and SREBP (Nat Commun, 2019; Cell Metab, 2013)。 These studies reveal the molecular mechanism of protein post-translational modification key enzymes (such as PHD3 and AMPK) in regulating glucose and lipid metabolism disorders, and provide new ideas and treatment methods for the prevention and treatment of metabolic diseases such as type 2 diabetes mellitus and fatty liver.

Professor Li Yu of Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Professor Fu Wenguang of the Affiliated Hospital of Southwest Medical University, Professor Fang Jing of Qingdao University are the corresponding authors of this paper, and Dr. Xue Yaqian and Associate Professor Cui Aoyuan of Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences are the first authors of this paper. The research was supported by the Key R&D Program of the Ministry of Science and Technology of the People’s Republic of China, the National Natural Science Foundation of China, the Shanghai Municipal Major Project, the Sichuan Provincial Key Laboratory of Metabolic Vascular Diseases, the Natural Science Foundation of Shandong Province, the China Postdoctoral Science Foundation, and the Public Technology Center of the Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences. (Source: Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences)

Related paper information:

PHD3 activates hepatic gluconeogenesis pattern map by non-classical CRTC2 hydroxylation modification

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