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Wang H, Zhang L, Chen X, Hong L, Zhao J, Qian W, Pham LK, Willard B, Li X, Bulek K, Li X. Adipocyte-specific Steap4 deficiency reduced thermogenesis and energy expenditure in mice. iScience 2025; 28:111903. [PMID: 39995871 PMCID: PMC11848796 DOI: 10.1016/j.isci.2025.111903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 11/21/2024] [Accepted: 01/22/2025] [Indexed: 02/26/2025] Open
Abstract
Six-transmembrane protein of prostate 4 (Steap4), highly expressed in adipose tissue, is associated with metabolic homeostasis. Dysregulated adipose and mitochondrial metabolism contributes to obesity, highlighting the need to understand their interplay. Whether and how Steap4 influences mitochondrial function, adipocytes, and energy expenditure remain unclear. Adipocyte-specific Steap4-deficient mice exhibited increased fat mass and severe insulin resistance in our high-fat diet model. Mass spectrometry identified two classes of Steap4 interactomes: mitochondrial proteins and proteins involved in splicing. RNA sequencing (RNA-seq) analysis of white adipose tissue demonstrated that Steap4 deficiency altered RNA splicing patterns with enriched mitochondrial functions. Indeed, Steap4 deficiency impaired respiratory chain complex activity, causing mitochondrial dysfunction in white adipose tissue. Consistently, brown adipocyte-specific Steap4 deficiency impaired mitochondrial function, increased brown fat whitening, reduced energy expenditure, and exacerbated insulin resistance in a high-fat model. Overall, our study highlights Steap4's critical role in modulating adipocyte mitochondrial function, thereby controlling thermogenesis, energy expenditure, and adiposity.
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Affiliation(s)
- Han Wang
- Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
- Center for RNA Science and Therapeutics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA
| | - Lizi Zhang
- Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
- Center for RNA Science and Therapeutics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Xing Chen
- Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
- Center for RNA Science and Therapeutics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Lingzi Hong
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA
| | - Junjie Zhao
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA
| | - Wen Qian
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA
| | - Lam Khue Pham
- Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
- Center for RNA Science and Therapeutics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Belinda Willard
- Proteomics and Metabolomics Core, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA
| | - Xiaoxia Li
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA
| | - Katarzyna Bulek
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA
| | - Xiao Li
- Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
- Center for RNA Science and Therapeutics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
- Department of Computer and Data Sciences, School of Engineering, Case Western Reserve University, Cleveland,OH 44106, USA
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Fang ZX, Chen WJ, Wu Z, Hou YY, Lan YZ, Wu HT, Liu J. Inflammatory response in gastrointestinal cancers: Overview of six transmembrane epithelial antigens of the prostate in pathophysiology and clinical implications. World J Clin Oncol 2024; 15:9-22. [PMID: 38292664 PMCID: PMC10823946 DOI: 10.5306/wjco.v15.i1.9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 11/24/2023] [Accepted: 12/19/2023] [Indexed: 01/23/2024] Open
Abstract
Chronic inflammation is known to increase the risk of gastrointestinal cancers (GICs), the common solid tumors worldwide. Precancerous lesions, such as chronic atrophic inflammation and ulcers, are related to inflammatory responses in vivo and likely to occur in hyperplasia and tumorigenesis. Unfortunately, due to the lack of effective therapeutic targets, the prognosis of patients with GICs is still unsatisfactory. Interestingly, it is found that six transmembrane epithelial antigens of the prostate (STEAPs), a group of metal reductases, are significantly associated with the progression of malignancies, playing a crucial role in systemic metabolic homeostasis and inflammatory responses. The structure and functions of STEAPs suggest that they are closely related to intracellular oxidative stress, responding to inflammatory reactions. Under the imbalance status of abnormal oxidative stress, STEAP members are involved in cell transformation and the development of GICs by inhibiting or activating inflammatory process. This review focuses on STEAPs in GICs along with exploring their potential molecular regulatory mechanisms, with an aim to provide a theoretical basis for diagnosis and treatment strategies for patients suffering from these types of cancers.
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Affiliation(s)
- Ze-Xuan Fang
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Wen-Jia Chen
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Zheng Wu
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Yan-Yu Hou
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Yang-Zheng Lan
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Hua-Tao Wu
- Department of General Surgery, First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Jing Liu
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
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Xie B, Zhong B, Zhao Z, Hu J, Yang J, Xie Y, Zhang J, Long J, Yang X, Li H. STEAP4 inhibits cisplatin-induced chemotherapy resistance through suppressing PI3K/AKT in hepatocellular carcinoma. Cancer Metab 2023; 11:26. [PMID: 38111065 PMCID: PMC10726618 DOI: 10.1186/s40170-023-00323-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Accepted: 11/04/2023] [Indexed: 12/20/2023] Open
Abstract
Chemotherapy resistance is the leading cause for hepatocellular carcinoma (HCC)-induced death. Exploring resistance generation mechanism is an urgent need for HCC therapy. Here, we found STEAP4 was significantly downregulated in HCC patients with recurrence. Patients with low STEAP4 had poor outcome, suggesting STEAP4 might inhibit chemotherapy resistance. Cell viability assay, colony formation assay, apoptosis assay, soft agar growth assay, and tumor animal model showed STEAP4 inhibited cisplatin resistance. Mechanism analysis showed STEAP4 inhibited PI3K/AKT pathway through directly interacting with AKT. Double knockdown of STEP4 and AKT significantly inhibited cisplatin resistance. We also found STEAP4 expression was negatively correlated with PI3K/AKT pathway activity in clinic specimens. In summary, our findings suggested STEAP4 inhibited cisplatin resistance through suppressing PI3K/AKT pathway activity, providing a target for HCC therapy.
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Affiliation(s)
- Binhui Xie
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, People's Republic of China
- Ganzhou Key Laboratory of Hepatocellular Carcinoma, the First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, People's Republic of China
| | - Baiyin Zhong
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, People's Republic of China
- Ganzhou Key Laboratory of Hepatocellular Carcinoma, the First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, People's Republic of China
| | - Zhenxian Zhao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, People's Republic of China
| | - Jie Hu
- Department of Medical Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, People's Republic of China
| | - Jianqiong Yang
- Department of Clinical Research Center, the First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, People's Republic of China
| | - Yuankang Xie
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, People's Republic of China
- Ganzhou Key Laboratory of Hepatocellular Carcinoma, the First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, People's Republic of China
| | - Jianhong Zhang
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, People's Republic of China
- Ganzhou Key Laboratory of Hepatocellular Carcinoma, the First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, People's Republic of China
| | - Jianting Long
- Department of Medical Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, People's Republic of China.
| | - Xuewei Yang
- Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510000, People's Republic of China.
| | - Heping Li
- Department of Medical Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, People's Republic of China.
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Ju MH, Jang EJ, Kang SH, Roh YH, Jeong JS, Han SH. Six-Transmembrane Epithelial Antigen of Prostate 4: An Indicator of Prognosis and Tumor Immunity in Hepatocellular Carcinoma. J Hepatocell Carcinoma 2023; 10:643-658. [PMID: 37101765 PMCID: PMC10124562 DOI: 10.2147/jhc.s394973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 03/14/2023] [Indexed: 04/28/2023] Open
Abstract
Purpose The six-transmembrane epithelial antigen of prostate 4 (STEAP4) has been linked to tumor progression via its involvement in inflammatory responses, oxidative stress, and metabolism. However, STEAP4 has rarely been studied in hepatocellular carcinoma (HCC). We explored STEAP4 expression associated with tumor prognosis to understand its role in tumor biology in HCC. Patients and Methods STEAP4 mRNA and protein expressions were primarily analyzed using bioinformatics tools based on The Cancer Genome Atlas database to understand the expression pattern, molecular mechanism, prognostic impact, and association with immune cell infiltration. We further investigated the association between STEAP4 protein expression and clinicopathological parameters and their predictive value in HCC patients using immunohistochemical staining of tissue microarrays. Results The expression of STEAP4 mRNA and protein in HCC tissues was significantly lower than in normal liver tissues. Reduced expression of STEAP4 was linked to advanced HCC stages, poor recurrence-free survival (RFS), and overall survival. Furthermore, reduced STEAP4 expression was a significant predictor of worse RFS in univariate and multivariate analyses in the immunohistochemical cohort. GO, KEGG, and GSEA analyses revealed that STEAP4 is related to numerous biological processes and pathways, including drug metabolism, DNA replication, RNA metabolism, and immune response. In terms of the immune system, the decreased level of STEAP4 was correlated with the immunosuppressive microenvironment. Conclusion Our data indicated that reduced STEAP4 expression was significantly associated with tumor aggressiveness and poor prognosis, possibly because of its link to various biological processes and induction of HCC immune evasion. Therefore, STEAP4 expression may serve as a potential prognostic biomarker for cancer progression and immunity, as well as a therapeutic target in HCC.
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Affiliation(s)
- Mi Ha Ju
- Department of Pathology, Dong-A University College of Medicine, Busan, Republic of Korea
| | - Eun Jeong Jang
- Department of Surgery, Dong-A University College of Medicine, Busan, Republic of Korea
| | - Sung Hwa Kang
- Department of Surgery, Dong-A University College of Medicine, Busan, Republic of Korea
| | - Young Hoon Roh
- Department of Surgery, Dong-A University College of Medicine, Busan, Republic of Korea
| | - Jin Sook Jeong
- Department of Pathology, Dong-A University College of Medicine, Busan, Republic of Korea
| | - Song-Hee Han
- Department of Pathology, Dong-A University College of Medicine, Busan, Republic of Korea
- Correspondence: Song-Hee Han, Department of Pathology, Dong-A University College of Medicine, 26, Daesingongwon-ro, Seo-gu, Busan, 49201, Republic of Korea, Tel +82-51-240-2863, Fax +82-51-240-7396, Email
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Kim HY, Yoo YH. The Role of STAMP2 in Pathogenesis of Chronic Diseases Focusing on Nonalcoholic Fatty Liver Disease: A Review. Biomedicines 2022; 10:biomedicines10092082. [PMID: 36140186 PMCID: PMC9495648 DOI: 10.3390/biomedicines10092082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 08/16/2022] [Accepted: 08/24/2022] [Indexed: 11/16/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a major health issue. NAFLD can progress from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH). NASH can progress to cirrhosis or hepatocellular carcinoma. Unfortunately, there is no currently approved pharmacologic therapy for NAFLD patients. The six transmembrane protein of prostate 2 (STAMP2), a metalloreductase involved in iron and copper homeostasis, is well known for its critical role in the coordination of glucose/lipid metabolism and inflammation in metabolic tissues. We previously demonstrated that hepatic STAMP2 could be a suitable therapeutic target for NAFLD. In this review, we discuss the emerging role of STAMP2 in the dysregulation of iron metabolism events leading to NAFLD and suggest therapeutic strategies targeting STAMP2.
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Zhao M, Yang S, Su X, Hung TC, Liu Y, Zheng W. Hepatitis B Virus Infection and Increased Risk of Gestational Diabetes Regardless of Liver Function Status: A Xiamen Area Population-Based Study. Front Physiol 2022; 13:938149. [PMID: 35899024 PMCID: PMC9309327 DOI: 10.3389/fphys.2022.938149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Accepted: 06/06/2022] [Indexed: 11/13/2022] Open
Abstract
Background & Aims: Hepatitis B virus (HBV) infection is a significant cause of liver function damage. However, previous studies on HBV mainly aimed at ordinary people, and there is a lack of consensus on the relationship between HBV infection and gestational diabetes mellitus (GDM) and whether HBV-infected pregnant women should undergo antiviral treatment. In addition, systematic studies on the impact of HBV infection on GDM have rarely been studied directly. Therefore, the overall goal of this study was to pursue the association between HBV infection, liver function, and GDM using Xiamen area gestational big data.Methods: Using the Xiamen Primary Health Information System-maternal and child health information system, the data on participants (138,867 in total) expected confinement between 2008 and 2018 were included. Using univariate and multivariate logistic regressions, we constructed models to determine the role of HBV infection and liver function status in GDM. In addition, an analysis of variance tests was performed to study whether the relationship between HBsAg and GDM differed in the normal liver function and the abnormal liver function subgroups.Results: HBsAg's positive status showed a substantial correlation with GDM onset in univariate and multivariate logistic regressions (p < 0.001). Subgroup analysis among HBsAg, liver function, and GDM suggests that both HBsAg and liver function affect the onset of GDM and have the highest prevalence of both abnormalities. Furthermore, ANOVA was used to investigate the association of HBsAg positive (p < 0.001), abnormal liver function (p < 0.001), and their interaction (p = 0.302) on the onset of GDM. This result showed that HBsAg is an independent factor of GDM pathogenesis, regardless of liver function status.Conclusion: HBsAg and liver function are independent factors in GDM. Therefore, regarding these results, while clinicians consider the traditional risk factors of GDM, it is necessary to consider the HBV infection status. Conducting a dietary intervention for HBsAg-positive pregnant women at the early stage of pregnancy is conducive to reducing the adverse effects.
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Affiliation(s)
- Min Zhao
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- Computer Management Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen, China
- *Correspondence: Min Zhao,
| | - Shuyu Yang
- National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen, China
- Research Studio of Traditional Chinese Medicine, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Xiaojie Su
- Computer Management Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Tzu-Chieh Hung
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | | | - Wenjie Zheng
- Computer Management Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
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Liu D, Zhou L, Zhang X, Zeng Y, Bai L, Wu D, Tang H. Significantly Decreased Islet β Cell Function is Closely Associated with Hyperglycemia in Chronic Hepatitis B Patients. Int J Endocrinol 2021; 2021:1264707. [PMID: 34497643 PMCID: PMC8421157 DOI: 10.1155/2021/1264707] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Accepted: 08/12/2021] [Indexed: 02/06/2023] Open
Abstract
AIM This study is aimed at the characteristics of glucose metabolism and islet β cell function evaluated by the homeostasis model assessment of β cell function (HOMA-β) value and its risk factors in chronic hepatitis B (CHB) patients. METHOD This cross-sectional study recruited 110 CHB patients (CHB group) and 110 patients without hepatitis B virus (non-HBV group); the groups were matched according to sex, age, and body mass index under the same glucose metabolism status. The risk factors, characteristics, and differences in glucose metabolism and HOMA-β values between the two groups were analyzed. RESULTS The abnormal glucose metabolism rate was higher in CHB patients with liver cirrhosis (LC) or hepatitis B envelope antigen (HBeAg) (-) status. In addition, under the same glucose metabolism status, the fasting plasma glucose (FPG) levels and 2-hour postprandial plasma glucose (2h-PG) levels in the CHB group were higher, while the HOMA-β values were significantly lower and the homeostasis model assessment of insulin resistance (HOMA-IR) value was not higher than that in the non-HBV group (all P < 0.0001). Further analyses revealed that the main risk factors for abnormal glucose metabolism were HBeAg (-) status and hepatitis B envelope antibody levels. But HBV serological and virological indicators had no effects on the HOMA-β values. CONCLUSION Islet β cell function in patients with CHB was compromised, which is closely associated with fasting and postprandial hyperglycemia in chronic hepatitis B patients. Further research should be done to verify the compromised islet β cell function and then to investigate the mechanisms behind the effect of hepatitis B virus infection on islet β cell function in CHB patients.
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Affiliation(s)
- Dafeng Liu
- Center of Infectious Diseases, Sichuan University West China Hospital, Chengdu, China
- Department of Internal Medicine, The Public and Health Clinic Centre of Chengdu, Chengdu, China
| | - Lingyun Zhou
- Center of Infectious Diseases, Sichuan University West China Hospital, Chengdu, China
| | - Xinyi Zhang
- Department of Endocrinology and Metabolism, Sichuan University West China Hospital, Chengdu, China
| | - Yilan Zeng
- Department of Internal Medicine, The Public and Health Clinic Centre of Chengdu, Chengdu, China
| | - Lang Bai
- Center of Infectious Diseases, Sichuan University West China Hospital, Chengdu, China
| | - Dongbo Wu
- Center of Infectious Diseases, Sichuan University West China Hospital, Chengdu, China
| | - Hong Tang
- Center of Infectious Diseases, Sichuan University West China Hospital, Chengdu, China
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Fay EJ, Aron SL, Macchietto MG, Markman MW, Esser-Nobis K, Gale M, Shen S, Langlois RA. Cell type- and replication stage-specific influenza virus responses in vivo. PLoS Pathog 2020; 16:e1008760. [PMID: 32790753 PMCID: PMC7447048 DOI: 10.1371/journal.ppat.1008760] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 08/25/2020] [Accepted: 06/29/2020] [Indexed: 12/22/2022] Open
Abstract
Influenza A viruses (IAVs) remain a significant global health burden. Activation of the innate immune response is important for controlling early virus replication and spread. It is unclear how early IAV replication events contribute to immune detection. Additionally, while many cell types in the lung can be infected, it is not known if all cell types contribute equally to establish the antiviral state in the host. Here, we use single-cycle influenza A viruses (scIAVs) to characterize the early immune response to IAV in vitro and in vivo. We found that the magnitude of virus replication contributes to antiviral gene expression within infected cells prior to the induction of a global response. We also developed a scIAV that is only capable of undergoing primary transcription, the earliest stage of virus replication. Using this tool, we uncovered replication stage-specific responses in vitro and in vivo. Using several innate immune receptor knockout cell lines, we identify RIG-I as the predominant antiviral detector of primary virus transcription and amplified replication in vitro. Through a Cre-inducible reporter mouse, we used scIAVs expressing Cre-recombinase to characterize cell type-specific responses in vivo. Individual cell types upregulate unique sets of antiviral genes in response to both primary virus transcription and amplified replication. We also identified antiviral genes that are only upregulated in response to direct infection. Altogether, these data offer insight into the early mechanisms of antiviral gene activation during influenza A infection.
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Affiliation(s)
- Elizabeth J. Fay
- Biochemistry, Molecular Biology and Biophysics Graduate Program, University of Minnesota, Minneapolis MN, United States of America
- Center for Immunology, University of Minnesota, Minneapolis MN, United States of America
| | - Stephanie L. Aron
- Department of Microbiology and Immunology, University of Minnesota, Minneapolis MN, United States of America
| | - Marissa G. Macchietto
- Institute for Health Informatics, University of Minnesota, Minneapolis MN, United States of America
| | - Matthew W. Markman
- Department of Microbiology and Immunology, University of Minnesota, Minneapolis MN, United States of America
| | - Katharina Esser-Nobis
- Department of Immunology and Center for Innate Immunity and Immune Disease, University of Washington, Seattle WA, United States of America
| | - Michael Gale
- Department of Immunology and Center for Innate Immunity and Immune Disease, University of Washington, Seattle WA, United States of America
| | - Steven Shen
- Institute for Health Informatics, University of Minnesota, Minneapolis MN, United States of America
| | - Ryan A. Langlois
- Biochemistry, Molecular Biology and Biophysics Graduate Program, University of Minnesota, Minneapolis MN, United States of America
- Center for Immunology, University of Minnesota, Minneapolis MN, United States of America
- Department of Microbiology and Immunology, University of Minnesota, Minneapolis MN, United States of America
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Oh YJ, Kim HY, Lee MH, Suh SH, Choi Y, Nam TG, Kwon WY, Lee SY, Yoo YH. Cilostazol Improves HFD-Induced Hepatic Steatosis by Upregulating Hepatic STAMP2 Expression through AMPK. Mol Pharmacol 2018; 94:1401-1411. [PMID: 30366981 DOI: 10.1124/mol.118.113217] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Accepted: 10/05/2018] [Indexed: 12/29/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is an increasingly studied condition that can progress to end-stage liver disease. Although NAFLD was first described in 1980, a complete understanding of the mechanism and causes of this disease is still lacking. Six-transmembrane protein of prostate 2 (STAMP2) plays a role in integrating inflammatory and nutritional signals with metabolism. Our previous study suggested that STAMP2 may be a suitable target for treating NAFLD. In the current study, we performed a focused drug-screening and found that cilostazol could be a potential STAMP2 enhancer. Thus, we examined whether cilostazol alleviates NAFLD through STAMP2. The in vivo and in vitro pharmacological efficacies of cilostazol on STAMP2 expression and lipid accumulation were analyzed in NAFLD mice induced by high-fat diet (HFD) and in HepG2 cell lines treated by oleic acid (OA), respectively. Cilostazol increased the expression of STAMP2 through transcriptional regulation in vivo and in vitro. Cilostazol also dampened the STAMP2 downregulation caused by the HFD and by OA in vivo and in vitro, respectively. Cilostazol activated AMP-activated protein kinase (AMPK) in vivo and in vitro, and AMPK functions upstream of STAMP2, and reversed downregulation of STAMP2 expression through AMPK in the NAFLD model. Cilostazol ameliorates hepatic steatosis by enhancing hepatic STAMP2 expression through AMPK. Enhancing STAMP2 expression with cilostazol represents a potential therapeutic avenue for treatment of NAFLD.
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Affiliation(s)
- Yoo Jin Oh
- Departments of Anatomy and Cell Biology (Y.J.O., H.Y.K., M.H.L., W.Y.K., Y.H.Y.), Endocrinology Medicine (S.H.S.), and Rheumatology (S.Y.L.), Dong-A University College of Medicine, Busan, Republic of Korea; Gyeonggi Bio Center, Gyeonggi-do Business and Science Accelerator, Suwon, Republic of Korea (Y.C.); and Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Republic of Korea (T.-G.N.)
| | - Hye Young Kim
- Departments of Anatomy and Cell Biology (Y.J.O., H.Y.K., M.H.L., W.Y.K., Y.H.Y.), Endocrinology Medicine (S.H.S.), and Rheumatology (S.Y.L.), Dong-A University College of Medicine, Busan, Republic of Korea; Gyeonggi Bio Center, Gyeonggi-do Business and Science Accelerator, Suwon, Republic of Korea (Y.C.); and Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Republic of Korea (T.-G.N.)
| | - Mi Hwa Lee
- Departments of Anatomy and Cell Biology (Y.J.O., H.Y.K., M.H.L., W.Y.K., Y.H.Y.), Endocrinology Medicine (S.H.S.), and Rheumatology (S.Y.L.), Dong-A University College of Medicine, Busan, Republic of Korea; Gyeonggi Bio Center, Gyeonggi-do Business and Science Accelerator, Suwon, Republic of Korea (Y.C.); and Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Republic of Korea (T.-G.N.)
| | - Sung Hwan Suh
- Departments of Anatomy and Cell Biology (Y.J.O., H.Y.K., M.H.L., W.Y.K., Y.H.Y.), Endocrinology Medicine (S.H.S.), and Rheumatology (S.Y.L.), Dong-A University College of Medicine, Busan, Republic of Korea; Gyeonggi Bio Center, Gyeonggi-do Business and Science Accelerator, Suwon, Republic of Korea (Y.C.); and Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Republic of Korea (T.-G.N.)
| | - Yongmun Choi
- Departments of Anatomy and Cell Biology (Y.J.O., H.Y.K., M.H.L., W.Y.K., Y.H.Y.), Endocrinology Medicine (S.H.S.), and Rheumatology (S.Y.L.), Dong-A University College of Medicine, Busan, Republic of Korea; Gyeonggi Bio Center, Gyeonggi-do Business and Science Accelerator, Suwon, Republic of Korea (Y.C.); and Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Republic of Korea (T.-G.N.)
| | - Tae-Gyu Nam
- Departments of Anatomy and Cell Biology (Y.J.O., H.Y.K., M.H.L., W.Y.K., Y.H.Y.), Endocrinology Medicine (S.H.S.), and Rheumatology (S.Y.L.), Dong-A University College of Medicine, Busan, Republic of Korea; Gyeonggi Bio Center, Gyeonggi-do Business and Science Accelerator, Suwon, Republic of Korea (Y.C.); and Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Republic of Korea (T.-G.N.)
| | - Woo Young Kwon
- Departments of Anatomy and Cell Biology (Y.J.O., H.Y.K., M.H.L., W.Y.K., Y.H.Y.), Endocrinology Medicine (S.H.S.), and Rheumatology (S.Y.L.), Dong-A University College of Medicine, Busan, Republic of Korea; Gyeonggi Bio Center, Gyeonggi-do Business and Science Accelerator, Suwon, Republic of Korea (Y.C.); and Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Republic of Korea (T.-G.N.)
| | - Sang Yeob Lee
- Departments of Anatomy and Cell Biology (Y.J.O., H.Y.K., M.H.L., W.Y.K., Y.H.Y.), Endocrinology Medicine (S.H.S.), and Rheumatology (S.Y.L.), Dong-A University College of Medicine, Busan, Republic of Korea; Gyeonggi Bio Center, Gyeonggi-do Business and Science Accelerator, Suwon, Republic of Korea (Y.C.); and Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Republic of Korea (T.-G.N.)
| | - Young Hyun Yoo
- Departments of Anatomy and Cell Biology (Y.J.O., H.Y.K., M.H.L., W.Y.K., Y.H.Y.), Endocrinology Medicine (S.H.S.), and Rheumatology (S.Y.L.), Dong-A University College of Medicine, Busan, Republic of Korea; Gyeonggi Bio Center, Gyeonggi-do Business and Science Accelerator, Suwon, Republic of Korea (Y.C.); and Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Republic of Korea (T.-G.N.)
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10
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Wang B, Li W, Fang H, Zhou H. Hepatitis B virus infection is not associated with fatty liver disease: Evidence from a cohort study and functional analysis. Mol Med Rep 2018; 19:320-326. [PMID: 30387826 PMCID: PMC6297757 DOI: 10.3892/mmr.2018.9619] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Accepted: 10/01/2018] [Indexed: 12/11/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection has been reported to be associated with the prevalence of non-alcoholic fatty liver disease (NAFLD). However, the present study demonstrated that the incidence of fatty liver disease in HBV-infected subjects (16/152, 10.5%) was not significantly different from in non-HBV-infected subjects (292/1,714, 17%), following adjustment for age (odds ratio=0.656; 95% confidence interval=0.379–1.134; P=0.131). Hepatitis B protein X (HBx) is considered a key regulator in HBV infection and several studies have confirmed that HBx serves a pivotal role in the process of fatty liver disease. In the present study, it was demonstrated that HBx-expressing cells exhibited increased mitochondrial membrane potential, ATP generation, and endogenous mitochondrial respiration. In addition, higher levels of mitochondrial reactive oxygen species (ROS) were detected in HBx-expressing cells compared with in control cells. Increased ROS production may contribute to increased lipid droplet formation in HBx-expressing cells, whereas the removal of ROS with N-acetylcysteine may decrease the accumulation of lipid droplets in a time-dependent manner. In conclusion, the present findings indicated that HBV, and perhaps more specifically HBx, was not a protective factor against NAFLD. HBx may function as a risk factor for fatty liver disease, based on the findings of the present functional study; however, further studies are required to clarify the effects of HBx on hepatic steatosis.
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Affiliation(s)
- Bingqian Wang
- Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China
| | - Wenna Li
- Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China
| | - Hezhi Fang
- Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China
| | - Huaibin Zhou
- Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China
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11
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Scarl RT, Lawrence CM, Gordon HM, Nunemaker CS. STEAP4: its emerging role in metabolism and homeostasis of cellular iron and copper. J Endocrinol 2017; 234:R123-R134. [PMID: 28576871 PMCID: PMC6166870 DOI: 10.1530/joe-16-0594] [Citation(s) in RCA: 78] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2017] [Accepted: 06/02/2017] [Indexed: 12/28/2022]
Abstract
Preserving energy homeostasis in the presence of stressors such as proinflammatory cytokines and nutrient overload is crucial to maintaining normal cellular function. Six transmembrane epithelial antigen of the prostate 4 (STEAP4), a metalloreductase involved in iron and copper homeostasis, is thought to play a potentially important role in the cellular response to inflammatory stress. Genome-wide association studies have linked various mutations in STEAP4 with the development of metabolic disorders such as obesity, metabolic syndrome and type 2 diabetes. Several studies have shown that expression of Steap4 is modulated by inflammatory cytokines, hormones and other indicators of cellular stress and that STEAP4 may protect cells from damage, helping to maintain normal metabolic function. STEAP4 appears to be particularly relevant in metabolically oriented cells, such as adipocytes, hepatocytes and pancreatic islet cells. These cells struggle to maintain their function in iron or copper overloaded states, presumably due to increased oxidative stress, suggesting STEAP4's role in metal homeostasis is critical to the maintenance of cellular homeostasis in general, and in preventing the onset of metabolic disease. In this review, we explore genetic associations of STEAP4 with metabolic disorders, and we examine STEAP4 tissue expression, subcellular localization, regulation, structure and function as it relates to metabolic diseases. We then examine how STEAP4's role as a regulator of cellular iron and copper may relate to type 2 diabetes.
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Affiliation(s)
- Rachel T Scarl
- Diabetes InstituteHeritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, USA
- Department of Biomedical SciencesHeritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, USA
| | - C Martin Lawrence
- Department of Chemistry and BiochemistryMontana State University, Bozeman, Montana, USA
| | - Hannah M Gordon
- Diabetes InstituteHeritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, USA
- Department of Biomedical SciencesHeritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, USA
| | - Craig S Nunemaker
- Diabetes InstituteHeritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, USA
- Department of Biomedical SciencesHeritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, USA
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12
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Gordon HM, Majithia N, MacDonald PE, Fox JEM, Sharma PR, Byrne FL, Hoehn KL, Evans-Molina C, Langman L, Brayman KL, Nunemaker CS. STEAP4 expression in human islets is associated with differences in body mass index, sex, HbA1c, and inflammation. Endocrine 2017; 56:528-537. [PMID: 28405880 PMCID: PMC6166871 DOI: 10.1007/s12020-017-1297-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Accepted: 03/27/2017] [Indexed: 02/08/2023]
Abstract
OBJECTIVE STEAP4 (six-transmembrane epithelial antigen of the prostate 4) is a metalloreductase that has been shown previously to protect cells from inflammatory damage. Genetic variants in STEAP4 have been associated with numerous metabolic disorders related to obesity, including putative defects in the acute insulin response to glucose in type 2 diabetes. PURPOSE We examined whether obesity and/or type 2 diabetes altered STEAP4 expression in human pancreatic islets. METHODS Human islets were isolated from deceased donors at two medical centers and processed for quantitative polymerase chain reaction. Organ donors were selected by status as non-diabetic or having type 2 diabetes. Site 1 (Edmonton): N = 13 type 2 diabetes donors (7M, 6F), N = 20 non-diabetic donors (7M, 13F). Site 2 (Virginia): N = 6 type 2 diabetes donors (6F), N = 6 non-diabetic donors (3M, 3F). RESULTS STEAP4 showed reduced islet expression with increasing body mass index among all donors (P < 0.10) and non-diabetic donors (P < 0.05) from Site 1; STEAP4 showed reduced islet expression among type 2 diabetes donors with increasing hemoglobin A1c. Islet STEAP4 expression was also marginally higher in female donors (P < 0.10). Among type 2 diabetes donors from Site 2, islet insulin expression was reduced, STEAP4 expression was increased, and white blood cell counts were increased compared to non-diabetic donors. Islets from non-diabetic donors that were exposed overnight to 5 ng/ml IL-1β displayed increased STEAP4 expression, consistent with STEAP4 upregulation by inflammatory signaling. CONCLUSIONS These findings suggest that increased STEAP4 mRNA expression is associated with inflammatory stimuli, whereas lower STEAP4 expression is associated with obesity in human islets. Given its putative protective role, downregulation of STEAP4 by chronic obesity suggests a mechanism for reduced islet protection against cellular damage.
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Affiliation(s)
- Hannah M Gordon
- Department of Biomedical Sciences, Ohio University, Athens, OH, USA
- Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA
| | - Neil Majithia
- Department of Medicine, University of Virginia, Charlottesville, VA, USA
| | - Patrick E MacDonald
- Alberta Diabetes Institute and Department of Pharmacology, University of Alberta, Edmonton, AB, T6G 2R3, Canada
| | - Jocelyn E Manning Fox
- Alberta Diabetes Institute and Department of Pharmacology, University of Alberta, Edmonton, AB, T6G 2R3, Canada
| | - Poonam R Sharma
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA
| | - Frances L Byrne
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, 2052, Australia
| | - Kyle L Hoehn
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, 2052, Australia
| | - Carmella Evans-Molina
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
- Richard L. Roudebush VA Medical Center, Indianapolis, IN, USA
| | - Linda Langman
- Department of Surgery, University of Virginia Health System, Charlottesville, VA, USA
| | - Kenneth L Brayman
- Department of Surgery, University of Virginia Health System, Charlottesville, VA, USA
| | - Craig S Nunemaker
- Department of Biomedical Sciences, Ohio University, Athens, OH, USA.
- Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA.
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13
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Kim HY, Park SY, Lee MH, Rho JH, Oh YJ, Jung HU, Yoo SH, Jeong NY, Lee HJ, Suh S, Seo SY, Cheong J, Jeong JS, Yoo YH. Hepatic STAMP2 alleviates high fat diet-induced hepatic steatosis and insulin resistance. J Hepatol 2015; 63:477-85. [PMID: 25646886 DOI: 10.1016/j.jhep.2015.01.025] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Revised: 01/14/2015] [Accepted: 01/18/2015] [Indexed: 12/24/2022]
Abstract
BACKGROUND & AIMS Most studies on the role of STAMP2 in metabolism have used adipose tissue. Little knowledge exists concerning the role of STAMP2 in the liver, which is a metabolically central target. We hypothesized that STAMP2 is involved in non-alcoholic fatty liver disease (NAFLD) pathogenesis. METHODS We examined our hypothesis using human NAFLD patient pathology samples and a high-fat diet (HFD)-induced NAFLD mouse model. The molecular mechanism underlying hepatic STAMP2-mediated lipid imbalance was explored using an oleic acid (OA)-induced NAFLD in vitro model. RESULTS Noticeably, the expression level of STAMP2 protein was reduced in the livers obtained from NAFLD patients and HFD-induced NAFLD mice. In vivo knockdown of hepatic STAMP2 by siRNA accelerated hepatic steatosis and insulin resistance in mice fed a HFD. Conversely, the delivery of adenoviral STAMP2 (Ad-STAMP2) improved hepatic steatosis in HFD-induced NAFLD mice. The expression of lipogenic or adipogenic factors was increased in both in vitro and in vivo NAFLD models but was reversed by Ad-STAMP2. Adenoviral overexpression of STAMP2 improved insulin resistance in the HFD-induced NAFLD mice. In vivo and in vitro assays demonstrated that STAMP2 modulates insulin sensitivity and glucose metabolism and that STAMP2 counteracts OA-induced insulin resistance by modulating insulin receptor substrate-1 stability. CONCLUSIONS The present study revealed that hepatic STAMP2 plays a pivotal role in preventing HFD-induced NAFLD and that STAMP2 overexpression improves hepatic steatosis and insulin resistance in NAFLD. Our findings indicate that STAMP2 may represent a suitable target for interventions targeting NAFLD.
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Affiliation(s)
- Hye Y Kim
- Dong-A University College of Medicine and Mitochondria Hub Regulation Center, Busan 602-714, South Korea
| | - So Y Park
- Dong-A University College of Medicine and Mitochondria Hub Regulation Center, Busan 602-714, South Korea
| | - Mi H Lee
- Dong-A University College of Medicine and Mitochondria Hub Regulation Center, Busan 602-714, South Korea
| | - Jee H Rho
- Dong-A University College of Medicine and Mitochondria Hub Regulation Center, Busan 602-714, South Korea
| | - Yoo J Oh
- Dong-A University College of Medicine and Mitochondria Hub Regulation Center, Busan 602-714, South Korea
| | - Hye U Jung
- Dong-A University College of Medicine and Mitochondria Hub Regulation Center, Busan 602-714, South Korea
| | - Seung H Yoo
- Dong-A University College of Medicine and Mitochondria Hub Regulation Center, Busan 602-714, South Korea
| | - Na Y Jeong
- Dong-A University College of Medicine and Mitochondria Hub Regulation Center, Busan 602-714, South Korea
| | - Hye J Lee
- Dong-A University College of Medicine and Mitochondria Hub Regulation Center, Busan 602-714, South Korea
| | - SungHwan Suh
- Department of Endocrinology, Dong-A University College of Medicine, Busan 602-714, South Korea
| | - Su Y Seo
- Department of Microbiology, Dong-A University College of Medicine, Busan 602-714, South Korea
| | - JaeHun Cheong
- Department of Molecular Biology, College of Natural Sciences, Pusan National University, Busan 609-735, South Korea
| | - Jin S Jeong
- Department of Pathology, Dong-A University College of Medicine, Busan 602-714, South Korea
| | - Young H Yoo
- Dong-A University College of Medicine and Mitochondria Hub Regulation Center, Busan 602-714, South Korea.
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14
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Chen X, Huang Z, Zhou B, Wang H, Jia G, Liu G, Zhao H. STEAP4 and insulin resistance. Endocrine 2014; 47:372-9. [PMID: 24627165 DOI: 10.1007/s12020-014-0230-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2013] [Accepted: 02/26/2014] [Indexed: 12/31/2022]
Abstract
Obesity is a multifactorial disease that caused by the interactions between genetic susceptibility genes and environmental cues. Obesity is considered as a major risk factor of insulin resistance. STEAP4 is a novel anti-obesity gene that is significantly down-regulated in adipose tissue of obese patients. Over-expression of STEAP4 can improve glucose uptake and mitochondrial function, and increase insulin sensitivity. STEAP4 expression is regulated by a variety of inflammatory cytokines, hormones, or adipokines. In this review, we discuss function of STEAP4 in regulating insulin resistance in adipose tissue in vivo, as well as in adipocytes in vitro.
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Affiliation(s)
- Xiaoling Chen
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, 611130, Sichuan, People's Republic of China
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15
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Yoo SK, Cheong J, Kim HY. STAMPing into Mitochondria. Int J Biol Sci 2014; 10:321-6. [PMID: 24643198 PMCID: PMC3957087 DOI: 10.7150/ijbs.8456] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2013] [Accepted: 02/25/2014] [Indexed: 12/24/2022] Open
Abstract
Six transmembrane protein of prostate 2 (STAMP2) is a protein that has been extensively studied due to its association with prostate cancer. Currently, STAMP2 is well known for its critical role in metabolism and modulating inflammatory signals. Even so, the molecular mechanism of STAMP2 activity and its downstream effectors are still largely unknown. Here, we review the current knowledge of STAMP2, and suggest possible explanations for some of its less well-understood features. A few studies suggest that STAMP2 may interact with mitochondria. Considering STAMP2 functions as a potential component of mitochondrial biology may yield valuable insight into this protein.
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Affiliation(s)
- Seong Keun Yoo
- 1. Department of Molecular Biology College of Natural Sciences Pusan National University Busan 609-735, Korea; ; 2. Department of Biological Sciences College of Life Science and Bioengineering Korea Advanced Institute of Science and Technology Deajeon 305-701, Korea
| | - JaeHun Cheong
- 1. Department of Molecular Biology College of Natural Sciences Pusan National University Busan 609-735, Korea
| | - Hye Young Kim
- 1. Department of Molecular Biology College of Natural Sciences Pusan National University Busan 609-735, Korea
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16
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Xie N, Chen X, Zhang T, Liu B, Huang C. Using proteomics to identify the HBx interactome in hepatitis B virus: how can this inform the clinic? Expert Rev Proteomics 2013; 11:59-74. [PMID: 24308553 DOI: 10.1586/14789450.2014.861745] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Hepatitis B virus (HBV) is a small and enveloped DNA virus, of which chronic infection is the main risk factor of liver cirrhosis and hepatocellular carcinoma. Hepatitis B virus X protein (HBx) is a multifunctional protein encoded by HBV genome, which have significant effects on HBV replication and pathogenesis. Through directly interacting with cellular proteins, HBx is capable to promote HBV replication, regulate transcription of host genes, disrupt protein degradation, modulate signaling pathway, manipulate cell death and deregulate cell cycle. In this review, we briefly discuss the diversified effects of HBx-interactome and their potential clinical significances.
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Affiliation(s)
- Na Xie
- The State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, P.R. China
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