HIF-1α is necessary to support gluconeogenesis during liver regeneration

Tajima, T; Goda, Nobuhito; Fujiki, Natsuko; Hishiki, Takako; Nishiyama, Y; Senoo‐Matsuda, Nanami; Shimazu, Motohide; Soga, Tomoyoshi; Yoshimura, Yasunori; Johnson, Randall S.; Suematsu, Makoto

doi:10.1016/j.bbrc.2009.07.115

Cited by 61 publications

(57 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…HIF1 also participates in hepatic glucose homeostasis under different circumstances (15,34). Evidences favoring a critical role for HIF1 in the correction or prevention of hypoglycemia came from a study conducted in liver-specific HIF1 mutant mice (34). Data presented here coincide with these findings and further suggest that in the absence of high iNOS levels, HIF1 promotes hepatic glucose uptake and possibly glycogenogenesis, while concurrently induction of HIF1 and iNOS, under inflammatory conditions, supports glycogenolysis and glucose release into the circulation.…”

supporting

confidence: 75%

“…HIF1 mediates cell survival through alterations in cellular energy metabolism. HIF1 particularly involves in glucose homeostasis by mediating glucose utilization and/or production (15,34). Currently, whether iNOS/HIF1 axis is involved in glucose homeostasis in steatotic livers during endotoxemia is yet to be determined.…”

mentioning

confidence: 99%

“…Thus, finding presented here corroborate the significance of iNOS on HIF1a accumulation in vivo. HIF1 also participates in hepatic glucose homeostasis under different circumstances (15,34). Evidences favoring a critical role for HIF1 in the correction or prevention of hypoglycemia came from a study conducted in liver-specific HIF1 mutant mice (34).…”

mentioning

confidence: 99%

See 2 more Smart Citations

A Novel Antihypoglycemic Role of Inducible Nitric Oxide Synthase in Liver Inflammatory Response Induced by Dietary Cholesterol and Endotoxemia

Anavi

Hahn-Obercyger

Margalit

et al. 2013

Antioxidants & Redox Signaling

View full text Add to dashboard Cite

Aims: The current study aim was to elucidate the antihypoglycemic role and mechanism of inducible nitric oxide synthase (iNOS) under inflammatory stress. Methods: Liver inflammatory stress was induced in wild-type (WT) and iNOS-knockout (iNOS -/ -) mice by lipopolysaccharide (LPS) (5 mg/kg) with and without the background of nonalcoholic steatohepatitis (NASH)-Induced by high cholesterol diet (HCD, 6 weeks). Results: HCD led to steatohepatitis in WT and iNOS -/ -mice. LPS administration caused marked liver inflammatory damage only in cholesterol-fed mice, which was further exacerbated in the absence of iNOS. Glucose homeostasis was significantly impaired and included fatal hypoglycemia and inhibition of glycogen decomposition. In iNOS -/ -hypoxia-inducible factor-1 (HIF1), signaling was impaired compared to control WT. Using hydrodynamic gene transfer method HIF1a was expressed in the livers of iNOS -/ -mice, and significantly ameliorated cholesterol and LPS-induced liver damage. WT mice overexpressing HIF1a exhibited higher blood glucose levels and lower glycogen contents after LPS injection. Conversely, induction of HIF1a was not effective in preventing LPSinduced glucose lowering effect in iNOS -/ -mice. The critical role of NO signaling in hepatocytes glucose output mediated by HIF1 pathway was also confirmed in vitro. Results also demonstrated increased oxidative stress and reduced heme oxygenase-1 mRNA in the livers of iNOS -/ -mice. Furthermore, the amounts of plasma tumor necrosis factor-a (TNFa) and intrahepatic TNFa mRNA were significantly elevated in the absence of iNOS. Innovation and Conclusion: These data highlight the essential role of iNOS in the glycemic response to LPS in NASH conditions and argues for the beneficial effects of iNOS.

show abstract

supporting

confidence: 75%

mentioning

confidence: 99%

See 1 more Smart Citation

A Novel Antihypoglycemic Role of Inducible Nitric Oxide Synthase in Liver Inflammatory Response Induced by Dietary Cholesterol and Endotoxemia

Anavi

Hahn-Obercyger

Margalit

et al. 2013

Antioxidants & Redox Signaling

View full text Add to dashboard Cite

show abstract

“…As a result, hypoxic conditions may develop in that setting, and HIF1␣-mediated pathways play an important metabolic role (54,59,60). Moreover, HIF1␣ has also been shown to play a role in liver metabolism by regulating hepatic glucose homeostasis (61). Even though neither of these organs displays hypoxia under conditions of HFD exposure, we cannot exclude the possibility that PX-478-mediated effects in muscle and liver contribute to the metabolic improvements observed.…”

Section: Discussionmentioning

confidence: 93%

Selective Inhibition of Hypoxia-Inducible Factor 1α Ameliorates Adipose Tissue Dysfunction

Sun

Halberg

Khan

et al. 2013

Molecular and Cellular Biology

200

175

View full text Add to dashboard Cite

Hypoxia-inducible factor 1␣ (HIF1␣) induction in adipocytes is a critical component of the "fibrotic response," directly linked to metabolic dysfunction in adipose tissues under hypoxic conditions. We reasoned that inhibition of HIF1␣ may ameliorate the negative aspects of the obesity-associated fat pad expansion. We used the selective HIF1␣ inhibitor PX-478, whose effectiveness has previously been established in tumor models. We demonstrate that PX-478 treatment effectively suppresses the high-fat-diet (HFD)-induced HIF1␣ activation in adipose tissue. HIF1␣ inhibition causes a reduction of weight gain in mice on an HFD but not on a chow diet. Treatment increases energy expenditure and prompts resistance to HFD-mediated deterioration of metabolic parameters. Moreover, PX-478-treated mice have reduced fibrosis and fewer inflammatory infiltrates in their adipose tissues. We confirm the metabolic effects obtained with PX-478 treatment using an adipose tissue-specific, doxycycline-inducible dominant negative HIF1␣ mutant (dn-HIF1␣). Consistent with the pharmacological results, genetic inhibition of endogenous HIF1␣ activity prompts similar metabolic improvements in HFD-fed mice. Collectively, our results demonstrate that HIF1␣ inhibition in the adipocyte leads to significant metabolic improvements, suggesting that selective HIF1␣ inhibition in adipose tissue may be an effective therapeutic avenue in the context of metabolic dysfunction.

show abstract

“…Preterm lambs developing respiratory distress syndrome display upregulation of PHDs with a reciprocal fall in HIF-α isoforms and HIF-dependent VEGF [53]. Th is observation implies that PHD inhibitors might have therapeutic potential in this clinical setup.…”

Section: Lung Injurymentioning

confidence: 97%