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Ullah K, Ai L, Humayun Z, Wu R. Targeting Endothelial HIF2α/ARNT Expression for Ischemic Heart Disease Therapy. BIOLOGY 2023; 12:995. [PMID: 37508425 PMCID: PMC10376750 DOI: 10.3390/biology12070995] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 07/07/2023] [Accepted: 07/07/2023] [Indexed: 07/30/2023]
Abstract
Ischemic heart disease (IHD) is a major cause of mortality and morbidity worldwide, with novel therapeutic strategies urgently needed. Endothelial dysfunction is a hallmark of IHD, contributing to its development and progression. Hypoxia-inducible factors (HIFs) are transcription factors activated in response to low oxygen levels, playing crucial roles in various pathophysiological processes related to cardiovascular diseases. Among the HIF isoforms, HIF2α is predominantly expressed in cardiac vascular endothelial cells and has a key role in cardiovascular diseases. HIFβ, also known as ARNT, is the obligate binding partner of HIFα subunits and is necessary for HIFα's transcriptional activity. ARNT itself plays an essential role in the development of the cardiovascular system, regulating angiogenesis, limiting inflammatory cytokine production, and protecting against cardiomyopathy. This review provides an overview of the current understanding of HIF2α and ARNT signaling in endothelial cell function and dysfunction and their involvement in IHD pathogenesis. We highlight their roles in inflammation and maintaining the integrity of the endothelial barrier, as well as their potential as therapeutic targets for IHD.
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Affiliation(s)
- Karim Ullah
- Section of Cardiology, Department of Medicine, Biological Sciences Division, University of Chicago, Chicago, IL 60637, USA
| | - Lizhuo Ai
- Section of Cardiology, Department of Medicine, Biological Sciences Division, University of Chicago, Chicago, IL 60637, USA
- The Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Zainab Humayun
- Section of Cardiology, Department of Medicine, Biological Sciences Division, University of Chicago, Chicago, IL 60637, USA
| | - Rongxue Wu
- Section of Cardiology, Department of Medicine, Biological Sciences Division, University of Chicago, Chicago, IL 60637, USA
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Zhang J, Jia Q, Li Y, He J. The Function of Xenobiotic Receptors in Metabolic Diseases. Drug Metab Dispos 2023; 51:237-248. [PMID: 36414407 DOI: 10.1124/dmd.122.000862] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 09/01/2022] [Accepted: 11/09/2022] [Indexed: 11/23/2022] Open
Abstract
Metabolic diseases are a series of metabolic disorders that include obesity, diabetes, insulin resistance, hypertension, and hyperlipidemia. The increased prevalence of metabolic diseases has resulted in higher mortality and mobility rates over the past decades, and this has led to extensive research focusing on the underlying mechanisms. Xenobiotic receptors (XRs) are a series of xenobiotic-sensing nuclear receptors that regulate their downstream target genes expression, thus defending the body from xenobiotic and endotoxin attacks. XR activation is associated with the development of a number of metabolic diseases such as obesity, nonalcoholic fatty liver disease, type 2 diabetes, and cardiovascular diseases, thus suggesting an important role for XRs in modulating metabolic diseases. However, the regulatory mechanism of XRs in the context of metabolic disorders under different nutrient conditions is complex and remains controversial. This review summarizes the effects of XRs on different metabolic components (cholesterol, lipids, glucose, and bile acids) in different tissues during metabolic diseases. As chronic inflammation plays a critical role in the initiation and progression of metabolic diseases, we also discuss the impact of XRs on inflammation to comprehensively recognize the role of XRs in metabolic diseases. This will provide new ideas for treating metabolic diseases by targeting XRs. SIGNIFICANCE STATEMENT: This review outlines the current understanding of xenobiotic receptors on nutrient metabolism and inflammation during metabolic diseases. This work also highlights the gaps in this field, which can be used to direct the future investigations on metabolic diseases treatment by targeting xenobiotic receptors.
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Affiliation(s)
- Jinhang Zhang
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy (J.Z., Y.L., J.H.) and Department of Endocrinology and Metabolism (Q.J.), West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Qingyi Jia
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy (J.Z., Y.L., J.H.) and Department of Endocrinology and Metabolism (Q.J.), West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yanping Li
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy (J.Z., Y.L., J.H.) and Department of Endocrinology and Metabolism (Q.J.), West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Jinhan He
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy (J.Z., Y.L., J.H.) and Department of Endocrinology and Metabolism (Q.J.), West China Hospital, Sichuan University, Chengdu, Sichuan, China
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Xiang J, Deng YY, Liu HX, Pu Y. LncRNA MALAT1 Promotes PPARα/CD36-Mediated Hepatic Lipogenesis in Nonalcoholic Fatty Liver Disease by Modulating miR-206/ARNT Axis. Front Bioeng Biotechnol 2022; 10:858558. [PMID: 35769097 PMCID: PMC9234139 DOI: 10.3389/fbioe.2022.858558] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 05/16/2022] [Indexed: 01/21/2023] Open
Abstract
Long non-coding RNAs (lncRNAs) are known to play crucial roles in nonalcoholic fatty liver disease (NAFLD). This research sought to explore mechanisms by which lncRNA MALAT1 regulates the progression of NAFLD. Thus, in order to detect the function of MALAT1 in NAFLD, in vitro and in vivo model of NAFLD were established. Then, fatty acid uptake and triglyceride level were investigated by BODIPY labeled-fatty acid uptake assay and Oil red O staining, respectively. The expressions of MALAT1, miR-206, ARNT, PPARα and CD36 were detected by western blotting and qPCR. Dual luciferase, RIP and ChIP assay were used to validate the relation among MALAT1, miR-206, ARNT and PPARα. The data revealed expression of MALAT1 was up-regulated in vitro and in vivo in NAFLD, and knockdown of MALAT1 suppressed FFA-induced lipid accumulation in hepatocytes. Meanwhile, MALAT1 upregulated the expression of ARNT through binding with miR-206. Moreover, miR-206 inhibitor reversed MALAT1 knockdown effects in decreased lipid accumulation in FFA-treated hepatocytes. Furthermore, ARNT could inhibit the expression of PPARα via binding with PPARα promoter. Knockdown of MALAT1 significantly upregulated the level of PPARα and downregulated the expression of CD36, while PPARα knockdown reversed these phenomena. MALAT1 regulated PPARα/CD36 -mediated hepatic lipid accumulation in NAFLD through regulation of miR-206/ARNT axis. Thus, MALAT1/miR-206/ARNT might serve as a therapeutic target against NAFLD.
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Affiliation(s)
- Juan Xiang
- Endocrinology Subspecialty of Geriatrics, Xiangya Hospital of Central South University, Changsha, China
| | - Yuan-Yuan Deng
- Endocrinology Subspecialty of Geriatrics, Xiangya Hospital of Central South University, Changsha, China
| | - Hui-Xia Liu
- Endocrinology Subspecialty of Geriatrics, Xiangya Hospital of Central South University, Changsha, China
| | - Ying Pu
- Endocrinology Subspecialty of Geriatrics, Xiangya Hospital of Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital of Central South University, Changsha, China
- *Correspondence: Ying Pu,
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AhR promotes phosphorylation of ARNT isoform 1 in human T cell malignancies as a switch for optimal AhR activity. Proc Natl Acad Sci U S A 2022; 119:e2114336119. [PMID: 35290121 PMCID: PMC8944900 DOI: 10.1073/pnas.2114336119] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The aryl hydrocarbon receptor nuclear translocator (ARNT) is a transcription factor present in immune cells as a long and short isoform, referred to as isoforms 1 and 3, respectively. However, investigation into potential ARNT isoform–specific immune functions is lacking despite the well-established heterodimerization requirement of ARNT with, and for the activity of, the aryl hydrocarbon receptor (AhR), a critical mediator of immune homeostasis. Here, using global and targeted transcriptomics analyses, we show that the relative ARNT isoform 1:3 ratio in human T cell lymphoma cells dictates the amplitude and direction of AhR target gene regulation. Specifically, shifting the ARNT isoform 1:3 ratio lower by suppressing isoform 1 enhances, or higher by suppressing isoform 3 abrogates, AhR responsiveness to ligand activation through preprograming a cellular genetic background that directs explicit gene expression patterns. Moreover, the fluctuations in gene expression patterns that accompany a decrease or increase in the ARNT isoform 1:3 ratio are associated with inflammation or immunosuppression, respectively. Molecular studies identified the unique casein kinase 2 (CK2) phosphorylation site within isoform 1 as an essential parameter to the mechanism of ARNT isoform–specific regulation of AhR signaling. Notably, CK2-mediated phosphorylation of ARNT isoform 1 is dependent on ligand-induced AhR nuclear translocation and is required for optimal AhR target gene regulation. These observations reveal ARNT as a central modulator of AhR activity predicated on the status of the ARNT isoform ratio and suggest that ARNT-based therapies are a viable option for tuning the immune system to target immune disorders.
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Hypoxia, Hypoxia-Inducible Factors and Liver Fibrosis. Cells 2021; 10:cells10071764. [PMID: 34359934 PMCID: PMC8305108 DOI: 10.3390/cells10071764] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 07/07/2021] [Accepted: 07/08/2021] [Indexed: 12/18/2022] Open
Abstract
Liver fibrosis is a potentially reversible pathophysiological event, leading to excess deposition of extracellular matrix (ECM) components and taking place as the net result of liver fibrogenesis, a dynamic and highly integrated process occurring during chronic liver injury of any etiology. Liver fibrogenesis and fibrosis, together with chronic inflammatory response, are primarily involved in the progression of chronic liver diseases (CLD). As is well known, a major role in fibrogenesis and fibrosis is played by activated myofibroblasts (MFs), as well as by macrophages and other hepatic cell populations involved in CLD progression. In the present review, we will focus the attention on the emerging pathogenic role of hypoxia, hypoxia-inducible factors (HIFs) and related mediators in the fibrogenic progression of CLD.
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Alharthi J, Latchoumanin O, George J, Eslam M. Macrophages in metabolic associated fatty liver disease. World J Gastroenterol 2020; 26:1861-1878. [PMID: 32390698 PMCID: PMC7201150 DOI: 10.3748/wjg.v26.i16.1861] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 03/10/2020] [Accepted: 04/17/2020] [Indexed: 02/06/2023] Open
Abstract
Metabolic associated fatty liver disease (MAFLD), formerly named non-alcoholic fatty liver disease is the most common liver disorder in many countries. The inflammatory subtype termed steatohepatitis is a driver of disease progression to cirrhosis, hepatocellular carcinoma, liver transplantation, and death, but also to extrahepatic complications including cardiovascular disease, diabetes and chronic kidney disease. The plasticity of macrophages in response to various environmental cues and the fact that they can orchestrate cross talk between different cellular players during disease development and progression render them an ideal target for drug development. This report reviews recent advances in our understanding of macrophage biology during the entire spectrum of MAFLD including steatosis, inflammation, fibrosis, and hepatocellular carcinoma, as well as for the extra-hepatic manifestations of MAFLD. We discuss the underlying molecular mechanisms of macrophage activation and polarization as well as cross talk with other cell types such as hepatocytes, hepatic stellate cells, and adipose tissue. We conclude with a discussion on the potential translational implications and challenges for macrophage based therapeutics for MAFLD.
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Affiliation(s)
- Jawaher Alharthi
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney 2145, NSW, Australia
| | - Olivier Latchoumanin
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney 2145, NSW, Australia
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney 2145, NSW, Australia
| | - Mohammed Eslam
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney 2145, NSW, Australia
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