Researchers determine novel mechanism of hepatic gluconeogenesis through PHD3-mediated hydroxylation of CRTC2

A staff led by Prof. Li Yu from the Shanghai Institute of Diet and Well being (SINH) of the Chinese language Academy of Sciences (CAS), in collaboration with Prof. Fu Wenguang and Prof. Fang Jing, recognized a novel mechanism for the HIF prolyl hydroxylase area protein 3 (PHD3)-dependent proline hydroxylation of cAMP responsive component binding protein (CREB)-regulated transcriptional coactivator 2 (CRTC2) within the regulation of hepatic gluconeogenesis. This research was revealed on-line in PNAS on Could 30.

Elevated gluconeogenesis and extreme glucose manufacturing within the liver contribute to hyperglycemia and sort 2 diabetes. Prolyl hydroxylase (PHD)-mediated protein hydroxylation is concerned within the regulation of mobile adaptation to hypoxia. Nevertheless, whether or not it’s regulated by dietary or hormonal indicators and modulates hepatic gluconeogenesis stays largely unknown.

This research demonstrated that PHD3 acts as a novel regulator in regulating hepatic gluconeogenesis and glucose homeostasis, and that protein ranges of PHD3 are potently induced within the liver and hepatocyte in response to fasting indicators.

To research whether or not PHD3 and its hydroxylase exercise is required for hepatic glucose metabolism, liver-specific knockout of PHD3 or prolyl hydroxylase-deficient knockin mice had been generated. The mice confirmed attenuated fasting gluconeogenic genes, glycaemia and hepatic capability to provide glucose throughout fasting or when fed with high-fat, high-sucrose weight loss program.

Mechanistically, the catalytic area of PHD3 particularly binds to and immediately hydroxylates the CREB coactivator CRTC2 at two amino acid residues proline 129 and 615 (Pro129 and Pro615), and hydroxylation of CRTC2 will increase its affiliation with CREB and nuclear translocation, which results in enhanced transcription of gluconeogenic gene.

Importantly, Pro615 hydroxylation of CRTC2 by PHD3 is elevated in livers of fasted mice, diet-induced insulin resistance or genetically overweight ob/ob mice and people with diabetes.

These findings enhance the understanding of molecular mechanisms linking protein hydroxylation to gluconeogenesis, and will provide therapeutic potential for treating extreme gluconeogenesis, hyperglycemia and sort 2 diabetes.