Molecular mechanism of hypoxia‐mediated hepatic gluconeogenesis by transcriptional regulation

Abstract

Until now, it is known that hypoxia increases the glycolytic enzyme expression at the transcriptional level. Here, we show evidence that hypoxia increases hepatic glucose output and HIF-1 and ATF-2-mediated transactivation of phosphoenolpyruvate carboxykinase (PEPCK), which plays a critical role as a rate-limiting enzyme in gluconeogenesis, gene in liver. HIF-1 directly bound to the specific PEPCK promoter region through its cognate binding element and found as an active complex with coactivator CBP. Additionally, ATF-2 was also involved to regulate hypoxia-dependent PEPCK transcription in the transcriptional complex with HIF-1 and CBP. Interestingly, retinoic acid (RA) signaling induced the recruitment of HIF-1 on the PEPCK promoter, resulting from the functional interaction of HIF-1 and ATF-2 with coactivator CBP. Taken together, these results suggest that hypoxia signaling leads the hepatic glucose production and release via the increased gene expression of gluconeogenic enzymes, possibly playing a role in providing glucose to other tissues, such as endothelial, brain and muscle cells.

Exposure to an acute hypoxic stimulus during early life affects the expression of glucose metabolism-related genes at first-feeding in trout

“…These compensations are mainly achieved by upregulating genes encoding for glucose transporters (especially glut1 and glut3 ) 21, 47 and glycolytic enzymes 16, 24, 25 in a Hif-1 dependent manner. Meanwhile, the increase in the mRNA levels of gluconeogenetic fbp1b1 and g6pcb2b in fish subjected to 2.5 mg·L −1 O 2 hypoxia seems paradoxical, but such a phenomenon has also been reported in previous studies 48–50 . A few genes were also differentially affected depending on the developmental stage at which they received the hypoxic stimulus ( i .…”

Expression of fructose 1,6-bisphosphatase and phosphofructokinase is induced in hepatopancreas of the white shrimp Litopenaeus vannamei by hypoxia

“…In this context, hypoxia-inducible factors (HIFs) are transcriptional activators that function as master regulators of oxygen homeostasis in all metazoan species (Semenza, 2012). From studies in mammals we now know that HIF-1 directly binds to the specific PEPCK promoter region inducing transcription in hypoxic conditions (Choi et al, 2005). HIF-1 binds a core sequence of the Hypoxia Response Elements (HRE) in the promoters of hypoxia-responsive genes and induces their expressions (Lee et al, 2004).…”

Oxygen restriction as challenge test reveals early high-fat-diet-induced changes in glucose and lipid metabolism

“…OxR induced gluconeogenesis, de novo lipogenesis, and an antioxidant response in liver tissue of HF mice Exposure to a similar level of ambient normobaric hypoxia leads to an almost threefold reduction in oxygen saturation in mouse liver tissue [45]. OxR may, therefore, result in an increase in glycolytic flux and peripheral lactate production and clearance by the liver [10]. OxR can, furthermore, induce an increase in oxidative stress at tissue level, which leads to an increase in the expression of genes involved in oxidative stress.…”

“…A switch to glycolytic ATP production also explains the increase in blood glucose levels that were induced by OxR in both groups of mice. OxR is known to increase blood glucose and insulin levels [12,38,45], which is presumably caused by the conversion of lactate to glucose in liver tissue [10] or by-or in combination witha reduction in insulin and glucose sensitivity that is frequently observed after exposure to OxR [30,37,45].…”