Dataset Information

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

ABSTRACT:

Aims

Normalization of hypercholesterolaemia, inflammation, hyperglycaemia, and obesity are main desired targets to prevent cardiovascular clinical events. Here we present a novel regulator of cholesterol metabolism, which simultaneously impacts on glucose intolerance and inflammation.

Methods and results

Mice deficient for oxygen sensor HIF-prolyl hydroxylase 1 (PHD1) were backcrossed onto an atherogenic low-density lipoprotein receptor (LDLR) knockout background and atherosclerosis was studied upon 8 weeks of western-type diet. PHD1^-/-LDLR^-/- mice presented a sharp reduction in VLDL and LDL plasma cholesterol levels. In line, atherosclerotic plaque development, as measured by plaque area, necrotic core expansion and plaque stage was hampered in PHD1^-/-LDLR^-/- mice. Mechanistically, cholesterol-lowering in PHD1 deficient mice was a result of enhanced cholesterol excretion from blood to intestines and ultimately faeces. Additionally, flow cytometry of whole blood of these mice revealed significantly reduced counts of leucocytes and particularly of Ly6C^high pro-inflammatory monocytes. In addition, when studying PHD1^-/- in diet-induced obesity (14 weeks high-fat diet) mice were less glucose intolerant when compared with WT littermate controls.

Conclusion

Overall, PHD1 knockout mice display a metabolic phenotype that generally is deemed protective for cardiovascular disease. Future studies should focus on the efficacy, safety, and gender-specific effects of PHD1 inhibition in humans, and unravel the molecular actors responsible for PHD1-driven, likely intestinal, and regulation of cholesterol metabolism.

SUBMITTER: Marsch E

PROVIDER: S-EPMC5081036 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Publications

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

Marsch Elke E Demandt Jasper A F JA Theelen Thomas L TL Tullemans Bibian M E BM Wouters Kristiaan K Boon Mariëtte R MR van Dijk Theo H TH Gijbels Marion J MJ Dubois Ludwig J LJ Meex Steven J R SJ Mazzone Massimiliano M Hung Gene G Fisher Edward A EA Biessen Erik A L EA Daemen Mat J A P MJ Rensen Patrick C N PC Carmeliet Peter P Groen Albert K AK Sluimer Judith C JC

European heart journal 20160428 39

<h4>Aims</h4>Normalization of hypercholesterolaemia, inflammation, hyperglycaemia, and obesity are main desired targets to prevent cardiovascular clinical events. Here we present a novel regulator of cholesterol metabolism, which simultaneously impacts on glucose intolerance and inflammation.<h4>Methods and results</h4>Mice deficient for oxygen sensor HIF-prolyl hydroxylase 1 (PHD1) were backcrossed onto an atherogenic low-density lipoprotein receptor (LDLR) knockout background and atheroscleros ...[more]

PMID: 27125949

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Project description:The oxygen sensor PHD2 (prolyl hydroxylase domain 2) plays an important role in cell hypoxia adaptation by regulating the stability of HIF proteins (HIF1α and HIF2α) in numerous cell types including T lymphocytes. The role of oxygen sensor on immune cells, in particular on regulatory T cell (Treg) function, has not been fully elucidated. The purpose of our study was to evaluate the role of PHD2 in the regulation of Treg phenotype and function. We demonstrate herein that selective ablation of PHD2 expression in Treg (PHD2ΔTreg mice) leads to a spontaneous systemic inflammatory syndrome, as evidenced by weight loss, development of a rectal prolapse, splenomegaly, shortening of the colon and elevated expression of IFN-γ in the mesenteric lymph nodes, intestine and spleen. PHD2 deficiency in Tregs led to an increased number of activated CD4 conventional T cells expressing an effector/Th1-like phenotype. Concomitantly, the expression of innate-type cytokines such as IL1-β, IL-12p40, IL-12p35 and TNF-α was found to be elevated in peripheral (gut) tissues and spleen. PHD2ΔTreg mice also displayed an enhanced sensitivity to DSS-induced colitis and to toxoplasmosis, suggesting that PHD2-deficient Tregs do not efficiently control inflammatory response in vivo, in particular immune responses characterized by IFN-γ production. Further analysis revealed that Treg dysregulation is largely prevented in PHD2-HIF2α (PHD2-HIF2αΔTreg mice), but not in PHD2-HIF1α (PHD2-HIF1αΔTreg mice) double KOs, suggesting an important and possibly selective role of the PHD2-HIF2α axis in the control of Treg function. Finally, the transcriptomic analysis of PHD2-deficient Tregs revealed an altered expression of several chemokine receptors including CXCR3, a finding corroborated by the altered in vivo localization of PHD2-deficient Tregs in splenic tissues. Collectively, these findings uncover an important role of the PHD2-HIF2α axis in regulatory T cell positioning and trafficking.

Dataset Information

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

Aims

Methods and results

Conclusion

Publications

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

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