Hepatic PHD2/HIF‐1α axis is involved in postexercise systemic energy homeostasis

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-1α (HIF-1α), 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-1α levels in the liver, and that the hepatic PHD2/HIF-1α axis is involved in postexercise restoration of systemic energy homeostasis. Through constant O consumption, CO 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 HIFα levels in the liver. Intraperitoneal injections of the PHD inhibitor, dimethyloxalylglycine, mimicked exercise-induced HIFα increase, whereas the HIF-1α inhibitor, PX-478, blocked this effect. We next constructed liver-specific knockout (LKO) mouse models with albumin- Cre-mediated, hepatocyte-specific Hif1a and Phd2 deletion. Compared with their controls, Hif1a-LKO and Phd2-LKO mice exhibited distinct patterns of hepatic metabolism-related gene expression profiles. Moreover, Hif1a-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-1α levels in the liver. These findings also provide evidence that the hepatic PHD2/HIF-1α 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.

Hypoxia, Hypoxia-Inducible Factors and Liver Fibrosis

“…VHL deletion in hepatocytes, which is preventing the proteasome degradation of HIFα subunits, resulted in the overexpression of both HIF1α and HIF2α and then in the rapid development of an impressive fatty liver associated with an impairment of fatty acid oxidation [ 104 ]. Almost homologous results were obtained in other studies employing mice carrying hepatocyte conditional deletion of genes encoding for either PHD2 or PHD3 [ 105 , 106 ]. It should be noted, however, that fatty liver developed in all these transgenic mice in the absence of any induction of liver injury or metabolic alteration, and substantially so in an oxygen-independent way.…”

Cold-induced protein RBM3 orchestrates neurogenesis via modulating Yap mRNA stability in cold stress

“…2, C–F). To detect which changes occurred in the gene expression level in the embryonic brain leading to the abnormal development during maternal cold stress, according to the previous studies, the indicated genes clusters were tested, including genes associated with low temperature sensitivity (RBM3 [Danno et al, 1997, Cirbp [Nishiyama et al, 1997], trpm8 [Palkar et al, 2018], and trpa1 [Moore et al, 2018]), metabolic sensitivity (HIF1a [Luo et al, 2018] and Ucp1 and Ucp2 [Margaryan et al, 2017]), and high temperature sensitivity (trpm2, trpv1, and trpv3 [Tan and McNaughton, 2016]; Fig. 2 G).…”

The role of hypoxia-inducible factors in metabolic diseases

“…Early evidence for a role of HIFs in metabolic diseases was provided by hepatocyte-specific disruption of VHL 63 , PHD2 (REF. 64 ) or PHD3 (REF. 65 ), which triggered the O 2 -independent overexpression of both HIF1α and HIF2α and induced hepatic steatosis.…”