Deficiency of the oxygen sensor prolyl hydroxylase 1 attenuates hypercholesterolaemia, atherosclerosis, and hyperglycaemia

Marsch, Elke; Demandt, J A F; Theelen, Thomas; Tullemans, Bibian M. E.; Wouters, Kristiaan; Boon, Mariëtte R.; Dijk, Theo H. van; Gijbels, Marion J.J.; Dubois, Ludwig; Meex, Steven J.R.; Mazzone, Massimiliano; Hung, Gene; Fisher, Edward A.; Biessen, Erik A. L.; Daemen, Mat J.A.P.; Rensen, Patrick C.N.; Carmeliet, Peter; Groen, Albert K.; Sluimer, Judith C.

doi:10.1093/eurheartj/ehw156

Cited by 44 publications

(43 citation statements)

References 13 publications

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“…1), mice with systemic HIF-P4H-1 (PHD1/EglN2) deficiency lowered their skeletal muscle O2 consumption through activation of PPARα as well as HIF2α-mediated development of hypoxia tolerance [17] but had no difference in body weight [18]. These mice also displayed reduced LDL-C levels, less circulating immune cells, and an improved glucose tolerance [9] (Fig. 4).…”

Section: Hypoxia Hifs and Hif-p4hs In Obesity Metabolic Syndrome Anmentioning

confidence: 97%

“…Since HIFs regulate many processes beyond erythropoiesis ( Fig. 1), HIF-P4H inhibition has been exploited widely in preclinical conditions, and indeed found beneficial in ischemic and inflammatory conditions (for reviews see [3,4]) and lately in metabolic diseases [4][5][6][7][8][9]. However, there exists concern about the use of HIF-P4H inhibitors.…”

Section: Hif-p4h Inhibitors and Renal Anemia -What About Beyond?mentioning

confidence: 99%

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Hypoxia-Inducible Factor Prolyl 4-Hydroxylases and Metabolism

Koivunen

Kietzmann

2018

Trends in Molecular Medicine

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Hypoxia-inducible factor prolyl 4-hydroxylases (HIF-P4Hs, also known as PHDs or EglNs) are enzymes that act as cellular oxygen sensors. Inhibition of HIF-P4Hs leads to stabilization of hypoxiainducible transcription factors (HIFs) which initiate a gene expression program that allows to cope with low oxygen levels and to restore tissue oxygenation. This involves for example upregulation of erythropoiesis and angiogenesis, modulation of inflammatory responses and reprogramming of metabolism. Currently, several pharmacological HIF-P4H inhibitors are in clinical trials mainly for renal anemia. However, recent data suggest that HIF-P4H inhibitors could also be considered to treat metabolic disorders. Here we will discuss the potential of targeting HIF-P4Hs and the HIF pathway for the treatment of obesity, metabolic syndrome, atherosclerosis and fatty liver diseases. Highlights Inhibition of HIF-P4Hs, which act as molecular oxygen sensors, is the so far best understood mechanism to regulate the oxygen sensing pathway. Several HIF-P4H inhibitors are currently in phase 3 randomized clinical trials for treatment of renal anemia with no reported serious side effects until now. Recent data from preclinical, clinical and epidemiological studies support that besides anemia activation of the hypoxia response via HIF-P4H inhibition is a powerful tool to regulate metabolism and may be beneficial for conditions such as obesity, metabolic syndrome, T2D, NAFLD/NASH or liver fibrosis.

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Section: Hypoxia Hifs and Hif-p4hs In Obesity Metabolic Syndrome Anmentioning

confidence: 97%

Section: Hif-p4h Inhibitors and Renal Anemia -What About Beyond?mentioning

confidence: 99%

Hypoxia-Inducible Factor Prolyl 4-Hydroxylases and Metabolism

Koivunen

Kietzmann

2018

Trends in Molecular Medicine

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“…The first-in-class small-molecule HIF-P4H inhibitor that activates the hypoxia response has been approved for treatment of renal anemia and several others are in clinical trials [10,11]. Recent data suggest that besides anemia, HIF-P4H inhibition and hypoxia are powerful tools for promoting metabolic health [10,[12][13][14][15][16][17]. We have previously shown that genetic HIF-P4H-2 deficiency protects the Hif-p4h-2 gt/gt mice against metabolic disorder-related hepatic steatosis and chemically induced HCC [14,18], and against alcoholic liver disease (ALD) by downregulating hepatic lipogenesis and improving the elimination of harmful ethanol metabolites and reactive oxygen species [19].…”

Section: Introductionmentioning

confidence: 99%

HIF-P4H-2 inhibition enhances intestinal fructose metabolism and induces thermogenesis protecting against NAFLD

et al. 2020

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Non-alcoholic fatty liver disease (NAFLD) parallels the global obesity epidemic with unmet therapeutic needs. We investigated whether inhibition of hypoxia-inducible factor prolyl 4-hydroxylase-2 (HIF-P4H-2), a key cellular oxygen sensor whose inhibition stabilizes HIF, would protect from NAFLD by subjecting HIF-P4H-2-deficient (Hif-p4h-2 gt/gt ) mice to a high-fat, highfructose (HFHF) or high-fat, methionine-choline-deficient (HF-MCD) diet. On both diets, the Hif-p4h-2 gt/gt mice gained less weight and had less white adipose tissue (WAT) and its inflammation, lower serum cholesterol levels, and lighter livers with less steatosis and lower serum ALT levels than the wild type (WT). The intake of fructose in majority of the Hif-p4h-2 gt/gt tissues, including the liver, was 15-35% less than in the WT. We found upregulation of the key fructose transporter and metabolizing enzyme mRNAs, Slc2a2, Khka, and Khkc, and higher ketohexokinase activity in the Hif-p4h-2 gt/gt small intestine relative to the WT, suggesting enhanced metabolism of fructose in the former. On the HF-MCD diet, the Hif-p4h-2 gt/gt mice showed more browning of the WAT and increased thermogenesis. A pharmacological pan-HIF-P4H inhibitor protected WT mice on both diets against obesity, metabolic dysfunction, and liver damage. These data suggest that HIF-P4H-2 inhibition could be studied as a novel, comprehensive treatment strategy for NAFLD. Key messages• HIF-P4H-2 inhibition enhances intestinal fructose metabolism protecting the liver.• HIF-P4H-2 inhibition downregulates hepatic lipogenesis.• Induced browning of WAT and increased thermogenesis can also mediate protection.• HIF-P4H-2 inhibition offers a novel, comprehensive treatment strategy for NAFLD.

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“…PHD1 deficiency has recently been linked to lowered serum cholesterol levels, resistance to hyperglycaemia and an impaired development of atherosclerotic plaques in mice (Marsch et al . ). Intriguingly, in a rat model of gestational hypertension, PHD1 was associated with a reduction in blood pressure after physical exercise (Gilbert et al .…”

Section: Molecular Oxygen Sensing In Metazoan Cellsmentioning

confidence: 97%

The PHD1 oxygen sensor in health and disease

Kennel

Burmeister

Schneider

et al. 2018

The Journal of Physiology

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The hypoxia-inducible factor (HIF) co-ordinates the adaptive transcriptional response to hypoxia in metazoan cells. The hypoxic sensitivity of HIF is conferred by a family of oxygen-sensing enzymes termed HIF hydroxylases. This family consists of three prolyl hydroxylases (PHD1-3) and a single asparagine hydroxylase termed factor inhibiting HIF (FIH). It has recently become clear that HIF hydroxylases are functionally non-redundant and have discrete but overlapping physiological roles. Furthermore, altered abundance or activity of these enzymes is associated with a number of pathologies. Pharmacological HIF-hydroxylase inhibitors have recently proven to be both tolerated and therapeutically effective in patients. In this review, we focus on the physiology, pathophysiology and therapeutic potential of the PHD1 isoform, which has recently been implicated in diseases including inflammatory bowel disease, ischaemia and cancer.

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Deficiency of the oxygen sensor prolyl hydroxylase 1 attenuates hypercholesterolaemia, atherosclerosis, and hyperglycaemia

Cited by 44 publications

References 13 publications

Hypoxia-Inducible Factor Prolyl 4-Hydroxylases and Metabolism

Hypoxia-Inducible Factor Prolyl 4-Hydroxylases and Metabolism

HIF-P4H-2 inhibition enhances intestinal fructose metabolism and induces thermogenesis protecting against NAFLD

The PHD1 oxygen sensor in health and disease

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