Hepatic PHD2/HIF‐1α axis is involved in postexercise systemic energy homeostasis. Issue 9 (30th March 2018)

• Record Type: Journal Article
• Authors: Luo2, Beibei; Xiang, Dao; Wu, Die; Liu, Changcheng; Fang, Yiqun; Chen, Peijie; Hu, Yi-Ping
• Is Part Of: FASEB journal. Volume 32:Issue 9(2018)
• Page Start: 4670
• Page End: 4680
• Publication Date: 2018-03-30
• Subjects: liver -- swimming -- metabolic chamber -- hypoxia -- energy metabolism; Biology -- Periodicals; Biology, Experimental -- Periodicals; 570
• DOI: 10.1096/fj.201701139R
• Languages: English
• ISSNs: 0892-6638

Abstract

ABSTRACT: Exercise plays an important role in the prevention and treatment of chronic liver disease and associated metabolic disorders. A single bout of exercise induces tissue blood flow redistribution, which decreases splanchnic circulation and leads to physiologic hypoxia in the gastrointestinal system and liver. The transcription factor, hypoxia inducible factor‐1 α (HIF‐1 α ), and its regulator, prolylhydroxylase 2 (PHD2), play pivotal roles in the response to oxygen flux by regulating downstream gene expression levels in the liver. We hypothesized that exercise increases the HIF‐1 α levels in the liver, and that the hepatic PHD2/HIF‐1 α axis is involved in postexercise restoration of systemic energy homeostasis. Through constant O2 consumption, CO2 production, food and water intake, and physical activity detection with metabolic chambers, we observed that one 30‐min session of swimming exercise enhances systemic energy metabolism in mice. By using the noninvasive bioluminescence imaging ROSA26 oxygen‐dependent domain Luc mouse model, we reveal that exercise increases in vivo HIFa levels in the liver. Intraperitoneal injections of the PHD inhibitor, dimethyloxalylglycine, mimicked exercise‐induced HIF α increase, whereas the HIF‐1 α inhibitor, PX‐478, blocked this effect. We next constructed liver‐specific knockout (LKO) mouse models with albumin‐ Cre ‐mediated, hepatocyte‐specific Hifla and Phd2 deletion. Compared with their controls, Hifla‐LKO and Phd2‐LKO mice exhibited distinct patterns of hepatic metabolism‐related gene expression profiles. Moreover, Hifla‐LKO mice failed to restore systemic energy homeostasis after exercise. In conclusion, the current study demonstrates that a single bout of exercise disrupts systemic energy homeostasis, increasing the HIF‐1a levels in the liver. These findings also provide evidence that the hepatic PHD2/HIF‐1 α axis is involved in postexercise systemic metabolic homeostasis.—Luo, B., Xiang, D., Wu, D., Liu, C., Fang, Y., Chen, P., Hu, Y.‐P. Hepatic PHD2/HIF‐1α axis is involved in postexercise systemic energy homeostasis. FASEB J. 32, 4670–4680 (2018). www.fasebj.org