2014
DOI: 10.2337/db14-0472
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HIF Prolyl 4-Hydroxylase-2 Inhibition Improves Glucose and Lipid Metabolism and Protects Against Obesity and Metabolic Dysfunction

Abstract: Obesity is a major public health problem, predisposing subjects to metabolic syndrome, type 2 diabetes, and cardiovascular diseases. Specific prolyl 4-hydroxylases (P4Hs) regulate the stability of the hypoxia-inducible factor (HIF), a potent governor of metabolism, with isoenzyme 2 being the main regulator. We investigated whether HIF-P4H-2 inhibition could be used to treat obesity and its consequences. Hif-p4h-2–deficient mice, whether fed normal chow or a high-fat diet, had less adipose tissue, smaller adipo… Show more

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Cited by 107 publications
(153 citation statements)
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“…HIF is a regulator of energy metabolism, and amelioration of dyslipidemia by daprodustat is consistent with recent observations by other groups [24,25] . This effect may be mediated by increased HMG-CoA reductase degradation [26] and increased expression of the very low-density lipoprotein receptor [27] by HIF activation.…”
Section: Discussionsupporting
confidence: 80%
“…HIF is a regulator of energy metabolism, and amelioration of dyslipidemia by daprodustat is consistent with recent observations by other groups [24,25] . This effect may be mediated by increased HMG-CoA reductase degradation [26] and increased expression of the very low-density lipoprotein receptor [27] by HIF activation.…”
Section: Discussionsupporting
confidence: 80%
“…For example, liver specific PHD2 deletion has been shown to induce HIF-1α, whereas PHD3 deletion promoted primarily HIF-2α induction which is in line with findings from mice where simultaneous genetic inactivation of PHD1, PHD2, and PHD3 in mice reactivates hepatic expression of the HIF-2 target gene erythropoietin and stimulates red blood cell synthesis [59]. With respect to metabolism it was found that PHD2 inhibition improves glucose and lipid metabolism as well as protects against obesity and metabolic dysfunction [60].…”
Section: Hypoxia-inducible Transcription Factors (Hifs)supporting
confidence: 70%
“…Because chemical inhibitors usually only partly suppress enzymatic activity and their efficacy can be regulated by dosage, chemical compounds that inhibit PHDs have been tested in clinical trials for renal anemia (14). Additionally, it was recently reported that treating mice with a PHD inhibitor (FG4497) improves metabolic dysfunction, including hepatic steatosis (70). This evidence indicates that renal anemia can be treated with PHD inhibitors.…”
Section: Discussionmentioning
confidence: 96%