Adipocyte Hypoxia-Inducible Factor 2α Suppresses Atherosclerosis by Promoting Adipose Ceramide Catabolism

Zhang, Xingzhong; Zhang, Yangming; Wang, Pengcheng; Zhang, Song-Yang; Dong, Yongqiang; Zeng, Guangyi; Yan, Yu; Sun, Lulu; Wu, Qing; Liu, Huiying; Liu, Bo; Kong, Wei; Wang, Xian; Jiang, Changtao

doi:10.1016/j.cmet.2019.09.016

Cited by 112 publications

(97 citation statements)

References 73 publications

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“…ACER2 is expressed in the placenta, pancreas, and heart [39]. ACER2 expression is regulated by the tumor suppressor p53 and hypoxia-inducible factor 2α [41][42][43][44]. Hence, ACER2 mRNA expression has been found to be increased in human cancer tissue in the liver and colon when compared to samples of healthy individuals [39].…”

Section: Alkaline Ceramidasesmentioning

confidence: 99%

Role of Ceramidases in Sphingolipid Metabolism and Human Diseases

Parveen

Bender

Law

et al. 2019

Cells

102

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Human pathologies such as Alzheimer’s disease, type 2 diabetes-induced insulin resistance, cancer, and cardiovascular diseases have altered lipid homeostasis. Among these imbalanced lipids, the bioactive sphingolipids ceramide and sphingosine-1 phosphate (S1P) are pivotal in the pathophysiology of these diseases. Several enzymes within the sphingolipid pathway contribute to the homeostasis of ceramide and S1P. Ceramidase is key in the degradation of ceramide into sphingosine and free fatty acids. In humans, five different ceramidases are known—acid ceramidase, neutral ceramidase, and alkaline ceramidase 1, 2, and 3—which are encoded by five different genes (ASAH1, ASAH2, ACER1, ACER2, and ACER3, respectively). Notably, the neutral ceramidase N-acylsphingosine amidohydrolase 2 (ASAH2) shows considerable differences between humans and animals in terms of tissue expression levels. Besides, the subcellular localization of ASAH2 remains controversial. In this review, we sum up the results obtained for identifying gene divergence, structure, subcellular localization, and manipulating factors and address the role of ASAH2 along with other ceramidases in human diseases.

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Section: Alkaline Ceramidasesmentioning

confidence: 99%

Role of Ceramidases in Sphingolipid Metabolism and Human Diseases

Parveen

Bender

Law

et al. 2019

Cells

102

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“…In addition, one recent study showed FG-4592 ameliorated the cisplatin-induced acute kidney injury through regulating apoptosis and inflammation ( Yang et al., 2018 ). FG-4592 also had protective effects against atherosclerosis and high glucose-induced glomerular endothelial cells injury through upregulating HIF ( Xie et al., 2019 ; Zhang et al., 2019 ). For cancer cells, HIFs increases the proliferation and metastasis of cancer cells by regulating the expression of some target genes ( Keith et al., 2011 ).…”

Section: Introductionmentioning

confidence: 98%

Antianemia Drug Roxadustat (FG-4592) Protects Against Doxorubicin-Induced Cardiotoxicity by Targeting Antiapoptotic and Antioxidative Pathways

Long

Chen

et al. 2020

Front. Pharmacol.

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Doxorubicin (DOX) is broadly used in treating various malignant tumors. However, its cardiotoxicity limits its clinical use. Roxadustat (FG-4592) is a new hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) inhibitor and has been approved for treating anemia in chronic kidney diseases (CKD) patients. However, the role of FG-4592 in DOX-induced cardiotoxicity remains unknown. In this study, mouse cardiac function was evaluated by echocardiography, plasma LDH/CK-MB, and heart HE staining. Cell viability, apoptosis, oxidative stress, inflammation, and HIF-target genes were evaluated in mouse cardiac tissue and cardiac cells exposed to DOX with FG-4592 pretreatment. DOX-sensitive HepG2 and MCF-7 cell lines were used to evaluate FG-4592 effect on the anticancer activity of DOX. We found that FG-4592 alleviated DOX-induced cardiotoxicity shown by the protection against cardiac dysfunction, cardiac apoptosis, and oxidative stress without the effect on inflammatory response. FG-4592 alone did not change the cardiac function, cardiomyocyte morphology, oxidative stress, and inflammation in vivo. FG-4592 could protect cardiomyocytes against DOX-induced apoptosis and ROS production in line with the upregulation of HIF-1a and its target genes of Bcl-2 and SOD2. Importantly, FG-4592 displayed anticancer property in cancer cells treated with or without DOX. These findings highlighted the protective effect of FG-4592 on DOX-induced cardiotoxicity possibly through upregulating HIF-1a and its target genes antagonizing apoptosis and oxidative stress.

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“…Furthermore, other researchers found that in the process of atherosclerosis, HIF-1 has an effect on macrophages and vascular cells, which is used as a target for treating atherosclerosis (Jain et al 2018). However, as a member of HIF family, the HIF-2 had a protective effect on atherosclerosis by inhibiting adipose, plasma ceramide, and plasma cholesterol levels (Zhang et al 2019). Fig.…”

Section: Discussionmentioning

confidence: 97%

A Functional Polymorphism in HIF-3α Is Related to an Increased Risk of Ischemic Stroke

Tang

Zeng

et al. 2020

J Mol Neurosci

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Hypoxia-inducible factor-3α (HIF-3α), a member of HIF family, can mediate adaptive responses to low oxygen and ischemia. It is believed that HIF plays crucial roles in stroke-related diseases. However, there are no reports on the association between HIF-3α genetic variants and ischemic stroke (IS) susceptibility. Therefore, we examined the association between HIF-3α gene polymorphisms (rs3826795, rs2235095, and rs3764609) and IS risk. The study population included 302 controls and 310 patients with ischemic stroke. Three polymorphisms in HIF-3α (rs3826795, rs2235095, and rs3764609) were genotyped using SNPscan technique. Our study showed a strong association of rs3826795 in HIF-3α with the risk of IS. The genotype and allele frequencies were shown to differ between the two groups. The rs3826795 in an intron of HIF-3α was related to a prominent increased IS risk (AA vs GG adjusted odd ratio [OR], 2.21; 95% confidence intervals [95% CI], 1.10–4.44; P = 0.03; AA vs AG/GG OR = 1.74, 95% CI, 1.02–2.97, P = 0.04; A vs G OR = 1.48, 95% CI, 1.05–2.07, P = 0.02). Logistic regression analysis suggested that rs3826795 posed a risk factor for IS in addition to common factors. Furthermore, when compared to controls, increased levels of homocysteic acid and level of non-esterified fatty acid were found in the cases (P < 0.01). However, no significant association was found between rs2235095 or rs3264609 and IS risk. These findings indicated that the rs3826795 polymorphism may be a potential target for predicting the risk of IS.

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Adipocyte Hypoxia-Inducible Factor 2α Suppresses Atherosclerosis by Promoting Adipose Ceramide Catabolism

Abstract: Highlights d Moderate cold exposure activates adipose HIF-2a signaling d Deficiency of adipocyte HIF-2a exacerbates Western-dietinduced atherosclerosis d Adipocyte HIF-2a enhances ceramide degradation by targeting ACER2 d Pharmacological activation of adipose HIF-2a reduces atherosclerosis

Cited by 112 publications

References 73 publications

Role of Ceramidases in Sphingolipid Metabolism and Human Diseases

Role of Ceramidases in Sphingolipid Metabolism and Human Diseases

Antianemia Drug Roxadustat (FG-4592) Protects Against Doxorubicin-Induced Cardiotoxicity by Targeting Antiapoptotic and Antioxidative Pathways

A Functional Polymorphism in HIF-3α Is Related to an Increased Risk of Ischemic Stroke

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