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Sun Y, Zhao M, Cheng L, He X, Shen S, Lv J, Zhang J, Shao Q, Yin W, Zhao F, Sun R, Lu P, Ji Y, Wang XW, Ji J. Reduction of alternative polarization of macrophages by short-term activated hepatic stellate cell-derived small extracellular vesicles. J Exp Clin Cancer Res 2025; 44:117. [PMID: 40211350 PMCID: PMC11983935 DOI: 10.1186/s13046-025-03380-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Accepted: 03/31/2025] [Indexed: 04/14/2025] Open
Abstract
BACKGROUND Activated hepatic stellate cells (HSCs) induce alternative (M2) polarization of macrophages and contribute to the progression of fibrosis and hepatocellular carcinoma (HCC). However, the effects of small extracellular vesicles released by HSCs (HSC-sEVs) during activation remain largely unknown. METHODS The aim of this study was to investigate the role of extracellular vesicles released by HSCs (HSC-sEVs) at different stages of activation in macrophage polarization. The effects of sEVs from short-term activated and long-term activated HSCs on liver macrophages was studied. Small RNA sequencing analyses were performed to obtain differential miRNAs transported by the short-term and long-term activated HSC- sEVs. The in vivo effects of short-term activated HSC-sEV-specific miRNA on liver macrophage and liver fibrosis were confirmed in a CCl4-induced liver injury mouse model. To study the tumor suppressive effects of the macrophages educated by short-term activated HSC-sEV-specific miRNA, human hepatoma cells were mixed and subcutaneously cotransplanted with miR-99a-5p mimic-pretreated macrophages. RESULTS We found that consistent with activated HSCs, long-term activated HSC-sEVs (14dHSC-sEVs) induce bone marrow-derived monocytes (MOs) toward an M2 phenotype, but short-term activated HSC-sEVs (3dHSC-sEVs) induce the resident macrophages (Kupffer cells, KCs) toward a classically activated (M1) phenotype. We identified five 3dHSC-sEV-specific miRNAs, including miR-99a-5p. In vitro and in vivo experiments support that miR-99a-5p negatively regulates alternative polarization of macrophages, decreases collagen deposition in chronic liver injury model, and suppresses the progression of hepatoma in a xenograft model partially by targeting CD93. CONCLUSION Collectively, our work reveals an unexpected proinflammatory role of 3dHSC-sEVs, preliminarily explores the underlying mechanism, and evaluates the therapeutic potential of 3dHSC-sEV-specific miR-99a-5p for liver fibrosis and tumorigenesis.
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Affiliation(s)
- Yufeng Sun
- Department of Pathology, Medical School of Nantong University, Nantong, 226001, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Nantong, 226001, China
| | - Min Zhao
- Department of Pathology, Medical School of Nantong University, Nantong, 226001, China
| | - Li Cheng
- Department of Pathology, Medical School of Nantong University, Nantong, 226001, China
| | - Xiaoqian He
- Department of Pathology, Medical School of Nantong University, Nantong, 226001, China
| | - Shiqi Shen
- Department of Pathology, Medical School of Nantong University, Nantong, 226001, China
| | - Jiaying Lv
- Department of Pathology, Medical School of Nantong University, Nantong, 226001, China
| | - Junyu Zhang
- Department of Pathology, Medical School of Nantong University, Nantong, 226001, China
| | - Qian Shao
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Nantong University, Nantong, 226001, China
| | - Wenxuan Yin
- Department of Pathology, Medical School of Nantong University, Nantong, 226001, China
| | - Fengbo Zhao
- Basic Medical Research Center, Medical School of Nantong University, Nantong, 226001, China
| | - Rui Sun
- Department of Pathology, Medical School of Nantong University, Nantong, 226001, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Nantong, 226001, China
| | - Peng Lu
- Department of Pathology, Medical School of Nantong University, Nantong, 226001, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Nantong, 226001, China
| | - Yuhua Ji
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Nantong University, Nantong, 226001, China.
- Department of Immunology and Microbiology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China.
| | - Xin Wei Wang
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, 20892, USA.
- Liver Cancer Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD, 20892, USA.
| | - Juling Ji
- Department of Pathology, Medical School of Nantong University, Nantong, 226001, China.
- Key Laboratory of Microenvironment and Translational Cancer Research, Nantong, 226001, China.
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, 226001, China.
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Sun Y, He X, Han J, Yin W, Wang H, Li J, Liu W, Kuai X, Lv J, Ji J. Activated hepatic stellate cell-derived small extracellular vesicles facilitate M2 macrophage polarization and hepatoma progression via miR-27a-3p. Front Immunol 2024; 15:1489679. [PMID: 39742261 PMCID: PMC11685157 DOI: 10.3389/fimmu.2024.1489679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Accepted: 12/03/2024] [Indexed: 01/03/2025] Open
Abstract
The progression of hepatoma is heavily influenced by the microenvironment. Tumor-associated macrophages (TAMs) are considered to play a critical role in the tumor microenvironment (TME) and increase the aggressiveness of hepatoma. The activation of hepatic stellate cells (HSCs) is involved in hepatoma progression, and accumulating evidence demonstrates a change in microRNA (miRNA) expression during HSC activation. Therefore, the potential roles of HSCs-related miRNAs in macrophage differentiation and hepatoma progression deserve to be explored. The present study aimed to investigate the effects of miRNAs carried by small extracellular vesicles (sEVs) released by activated HSCs on hepatoma progression. The results indicated that miR-27a-3p was significantly upregulated in cells and corresponding sEVs during the activation of primary rat HSCs and human HSC line-LX2 cells. Furthermore, miR-27a-3p contributed to the proliferation and migration of hepatoma cells and promoted M2 polarization of macrophage. HSC-sEVs overexpressing miR-27a-3p can directly facilitate tumor progression and modulate macrophage polarization, indirectly contributing to hepatoma progression. Finally, Sprouty2 (SPRY2) was verified to be the target gene of miR-27a-3p. In conclusion, activated HSC-derived sEVs with high levels of miR-27a-3p might induce M2 macrophage polarization and promote hepatoma progression, providing new insights into the mechanism of hepatoma progression.
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Affiliation(s)
- Yufeng Sun
- Department of Pathology, Medical School of Nantong University, Nantong, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Nantong, China
| | - Xiaoqian He
- Department of Pathology, Medical School of Nantong University, Nantong, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Nantong, China
| | - Jiayi Han
- Department of Pathology, Medical School of Nantong University, Nantong, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Nantong, China
| | - Wenxuan Yin
- Department of Pathology, Medical School of Nantong University, Nantong, China
| | - Haichen Wang
- Department of Pathology, Medical School of Nantong University, Nantong, China
| | - Jing Li
- Department of Pathology, Medical School of Nantong University, Nantong, China
| | - Weiqi Liu
- Department of Pathology, Medical School of Nantong University, Nantong, China
| | - Xingwang Kuai
- Department of Pathology, Medical School of Nantong University, Nantong, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Nantong, China
| | - Jiaying Lv
- Department of Pathology, Medical School of Nantong University, Nantong, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Nantong, China
| | - Juling Ji
- Department of Pathology, Medical School of Nantong University, Nantong, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Nantong, China
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Erman A, Hawkins LJ, Storey KB. Changes in microRNA expression related to ischemia-reperfusion injury in the kidney of the thirteen-lined ground squirrel during torpor. Biochimie 2024; 225:40-48. [PMID: 38705508 DOI: 10.1016/j.biochi.2024.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2024] [Revised: 04/18/2024] [Accepted: 05/02/2024] [Indexed: 05/07/2024]
Abstract
During the hibernation season, the thirteen-lined ground squirrel undergoes cyclical torpor and arousal periods. The decrease and restoration of metabolic rate and oxygen delivery during torpor and arousal, respectively, may cause reperfusion-ischemia injury in the kidneys. In order to maintain the structural integrity of the kidneys necessary for renal function resumption during arousal, the thirteen-lined ground squirrel has developed adaptive methods to prevent and repair kidney injury. In this present study, computational methods were used to clean and analyze sequenced kidney RNA samples. Significantly differentially expressed microRNAs and enriched gene sets were also determined. From the gene set analysis, the results showed an increase in ubiquitin-related processes and p53 signaling pathways which suggested the occurrence of kidney damage during torpor. There was also an observed increase in cell cycle processes and the anchoring junction cellular compartment which may lend to the prevention of kidney injury. From the differentially expressed microRNAs, miR-27a (log2FC = 1.639; p-value = 0.023), miR-129 (log2FC = 2.516; p-value = 0.023), miR-let-7b (log2FC = 2.360; p-value = 0.025), miR-let-7c (log2FC = 2.291; p-value = 0.037) and miR-let-7i (log2FC = 1.564; p-value = 0.039) were found to be significantly upregulated. These biochemical adaptations may allow the thirteen-lined ground squirrel to maintain kidney structure and function during hibernation.
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Affiliation(s)
- Aylin Erman
- Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, Ontario, K1S 5B6, Canada.
| | - Liam J Hawkins
- Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, Ontario, K1S 5B6, Canada
| | - Kenneth B Storey
- Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, Ontario, K1S 5B6, Canada
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Aggeletopoulou I, Tsounis EP, Triantos C. Vitamin D and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): Novel Mechanistic Insights. Int J Mol Sci 2024; 25:4901. [PMID: 38732118 PMCID: PMC11084591 DOI: 10.3390/ijms25094901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 04/23/2024] [Accepted: 04/29/2024] [Indexed: 05/13/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is an increasingly prevalent condition characterized by abnormal fat accumulation in the liver, often associated with metabolic disorders. Emerging evidence suggests a potential link between vitamin D deficiency and the development and progression of MASLD. The current review provides a concise overview of recent studies uncovering novel mechanistic insights into the interplay between vitamin D and MASLD. Several epidemiological studies have highlighted a significant association between low vitamin D levels and an increased risk of MASLD. Vitamin D, traditionally known for its role in bone health, has now been recognized as a key player in various physiological processes, including immune regulation and inflammation. Experimental studies using animal models have demonstrated that vitamin D deficiency exacerbates liver steatosis and inflammation, suggesting a potential protective role against MASLD. Mechanistically, vitamin D appears to modulate MASLD through multiple pathways. Firstly, the vitamin D receptor (VDR) is abundantly expressed in liver cells, indicating a direct regulatory role in hepatic function. Activation of the VDR has been shown to suppress hepatic lipid accumulation and inflammation, providing a mechanistic basis for the observed protective effects. Additionally, vitamin D influences insulin sensitivity, a critical factor in MASLD pathogenesis. Improved insulin sensitivity may mitigate the excessive accumulation of fat in the liver, thus attenuating MASLD progression. In parallel, vitamin D exhibits anti-inflammatory properties by inhibiting pro-inflammatory cytokines implicated in MASLD pathophysiology. Experimental evidence suggests that the immunomodulatory effects of vitamin D extend to the liver, reducing inflammation and oxidative stress, key drivers of MASLD, and the likelihood of hepatocyte injury and fibrosis. Understanding the complex interplay between vitamin D and MASLD provides a basis for exploring targeted therapeutic strategies and preventive interventions. As vitamin D deficiency is a modifiable risk factor, addressing this nutritional concern may prove beneficial in mitigating the burden of MASLD and associated metabolic disorders.
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Affiliation(s)
| | | | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece; (I.A.); (E.P.T.)
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Abdelrahman BA, El-Khatib AS, Attia YM. Insights into the role of vitamin D in targeting the culprits of non-alcoholic fatty liver disease. Life Sci 2023; 332:122124. [PMID: 37742738 DOI: 10.1016/j.lfs.2023.122124] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 09/12/2023] [Accepted: 09/21/2023] [Indexed: 09/26/2023]
Abstract
Vitamin D (VD) is a secosteroid hormone that is renowned for its crucial role in phospho-calcium homeostasis upon binding to the nuclear vitamin D receptor (VDR). Over and above, the pleiotropic immunomodulatory, anti-inflammatory, and metabolic roles VD plays in different disease settings started to surface in the past few decades. On the other hand, a growing body of evidence suggests a correlation between non-alcoholic fatty liver disease (NAFLD) and its progressive inflammatory form non-alcoholic steatohepatitis (NASH) with vitamin D deficiency (VDD) owing to the former's ingrained link with obesity and metabolic syndrome. Accordingly, a better understanding of the contribution of disrupted VDR signalling to NAFLD incidence and progression would provide further insights into its diagnosis, treatment modalities, and prognosis. This is especially significant as, hitherto, no drug for NAFLD has been approved. This review, therefore, sought to set forth the likely contribution of VDR signalling in NAFLD and how it might influence its multiple drivers.
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Affiliation(s)
- Basma A Abdelrahman
- Department of Pharmacology, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt; The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt
| | - Aiman S El-Khatib
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
| | - Yasmeen M Attia
- Department of Pharmacology, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt; The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt
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6
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Tu MJ, Yu AM. Recent Advances in Novel Recombinant RNAs for Studying Post-transcriptional Gene Regulation in Drug Metabolism and Disposition. Curr Drug Metab 2023; 24:175-189. [PMID: 37170982 PMCID: PMC10825985 DOI: 10.2174/1389200224666230425232433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 03/02/2023] [Accepted: 03/08/2023] [Indexed: 05/13/2023]
Abstract
Drug-metabolizing enzymes and transporters are major determinants of the absorption, disposition, metabolism, and excretion (ADME) of drugs, and changes in ADME gene expression or function may alter the pharmacokinetics/ pharmacodynamics (PK/PD) and further influence drug safety and therapeutic outcomes. ADME gene functions are controlled by diverse factors, such as genetic polymorphism, transcriptional regulation, and coadministered medications. MicroRNAs (miRNAs) are a superfamily of regulatory small noncoding RNAs that are transcribed from the genome to regulate target gene expression at the post-transcriptional level. The roles of miRNAs in controlling ADME gene expression have been demonstrated, and such miRNAs may consequently influence cellular drug metabolism and disposition capacity. Several types of miRNA mimics and small interfering RNA (siRNA) reagents have been developed and widely used for ADME research. In this review article, we first provide a brief introduction to the mechanistic actions of miRNAs in post-transcriptional gene regulation of drug-metabolizing enzymes, transporters, and transcription factors. After summarizing conventional small RNA production methods, we highlight the latest advances in novel recombinant RNA technologies and applications of the resultant bioengineered RNA (BioRNA) agents to ADME studies. BioRNAs produced in living cells are not only powerful tools for general biological and biomedical research but also potential therapeutic agents amenable to clinical investigations.
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Affiliation(s)
- Mei-Juan Tu
- Department of Biochemistry and Molecular Medicine, UC Davis School of Medicine, Sacramento, CA 95817, USA
| | - Ai-Ming Yu
- Department of Biochemistry and Molecular Medicine, UC Davis School of Medicine, Sacramento, CA 95817, USA
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Suriya Muthukumaran N, Velusamy P, Akino Mercy CS, Langford D, Natarajaseenivasan K, Shanmughapriya S. MicroRNAs as Regulators of Cancer Cell Energy Metabolism. J Pers Med 2022; 12:1329. [PMID: 36013278 PMCID: PMC9410355 DOI: 10.3390/jpm12081329] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 08/11/2022] [Accepted: 08/16/2022] [Indexed: 11/17/2022] Open
Abstract
To adapt to the tumor environment or to escape chemotherapy, cancer cells rapidly reprogram their metabolism. The hallmark biochemical phenotype of cancer cells is the shift in metabolic reprogramming towards aerobic glycolysis. It was thought that this metabolic shift to glycolysis alone was sufficient for cancer cells to meet their heightened energy and metabolic demands for proliferation and survival. Recent studies, however, show that cancer cells rely on glutamine, lipid, and mitochondrial metabolism for energy. Oncogenes and scavenging pathways control many of these metabolic changes, and several metabolic and tumorigenic pathways are post-transcriptionally regulated by microRNA (miRNAs). Genes that are directly or indirectly responsible for energy production in cells are either negatively or positively regulated by miRNAs. Therefore, some miRNAs play an oncogenic role by regulating the metabolic shift that occurs in cancer cells. Additionally, miRNAs can regulate mitochondrial calcium stores and energy metabolism, thus promoting cancer cell survival, cell growth, and metastasis. In the electron transport chain (ETC), miRNAs enhance the activity of apoptosis-inducing factor (AIF) and cytochrome c, and these apoptosome proteins are directed towards the ETC rather than to the apoptotic pathway. This review will highlight how miRNAs regulate the enzymes, signaling pathways, and transcription factors of cancer cell metabolism and mitochondrial calcium import/export pathways. The review will also focus on the metabolic reprogramming of cancer cells to promote survival, proliferation, growth, and metastasis with an emphasis on the therapeutic potential of miRNAs for cancer treatment.
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Affiliation(s)
| | - Prema Velusamy
- Heart and Vascular Institute, Department of Medicine, Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Dauphin, PA 17033, USA
| | - Charles Solomon Akino Mercy
- Medical Microbiology Laboratory, Department of Microbiology, Centre for Excellence in Life Sciences, Bharathidasan University, Tiruchirappalli 620 024, Tamil Nadu, India
| | - Dianne Langford
- Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Kalimuthusamy Natarajaseenivasan
- Medical Microbiology Laboratory, Department of Microbiology, Centre for Excellence in Life Sciences, Bharathidasan University, Tiruchirappalli 620 024, Tamil Nadu, India
- Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Santhanam Shanmughapriya
- Heart and Vascular Institute, Department of Medicine, Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Dauphin, PA 17033, USA
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Liver Regeneration: Changes in Oxidative Stress, Immune System, Cytokines, and Epigenetic Modifications Associated with Aging. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:9018811. [PMID: 35936214 PMCID: PMC9352489 DOI: 10.1155/2022/9018811] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 05/25/2022] [Accepted: 06/29/2022] [Indexed: 01/10/2023]
Abstract
The regenerative capacity of the liver decreases with increase in age. In recent years, studies in mice have found that the regenerative capacity of the liver is associated with changes in the immune system of the liver, cytokines in the body, aging-related epigenetic modifications in the cell, and intracellular signaling pathways. In the immune system of the aging liver, monocytes and macrophages play an important role in tissue repair. During tissue repair, monocytes and macrophages undergo a series of functional and phenotypic changes to initiate and maintain tissue repair. Studies have discovered that knocking out macrophages in the liver during the repair phase results in significant impairment of liver regeneration. Furthermore, as the body ages, the secretion and function of cytokines undergo a series of changes. For example, the levels of interleukin-6, transforming growth factor-alpha, hepatocyte growth factor, and vascular endothelial growth factor undergo changes that alter hepatocyte regulation, thereby affecting its proliferation. In addition, body aging is accompanied by cellular aging, which leads to changes in gene expression and epigenetic modifications. Additionally, this in turn causes alterations in cell function, morphology, and division and affects the regenerative capacity of the liver. As the body ages, the activity of associated functional proteins, such as CCAAT-enhancer-binding proteins, p53, and switch/sucrose nonfermentable complex, changes in the liver, leading to alterations in several signaling pathways, such as the Hippo, PI3K-Akt, mTOR, and STAT3 pathways. Therefore, in recent years, research on aging and liver regeneration has primarily focused on the immune system, signaling pathways, epigenetic changes of senescent cells, and cytokine secretion in the liver. Hence, this review details the roles of these influencing factors in liver regeneration and impact of aging-related factors.
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Ru L, Wang XM, Niu JQ. The miR-23-27-24 cluster: an emerging target in NAFLD pathogenesis. Acta Pharmacol Sin 2022; 43:1167-1179. [PMID: 34893685 PMCID: PMC9061717 DOI: 10.1038/s41401-021-00819-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 11/08/2021] [Indexed: 12/13/2022]
Abstract
The incidence of non-alcoholic fatty liver disease (NAFLD) is increasing globally, being the most widespread form of chronic liver disease in the west. NAFLD includes a variety of disease states, the mildest being non-alcoholic fatty liver that gradually progresses to non-alcoholic steatohepatitis, fibrosis, cirrhosis, and eventually hepatocellular carcinoma. Small non-coding single-stranded microRNAs (miRNAs) regulate gene expression at the miRNA or translational level. Numerous miRNAs have been shown to promote NAFLD pathogenesis and progression through increasing lipid accumulation, oxidative stress, mitochondrial damage, and inflammation. The miR-23-27-24 clusters, composed of miR-23a-27a-24-2 and miR-23b-27b-24-1, have been implicated in various biological processes as well as many diseases. Herein, we review the current knowledge on miR-27, miR-24, and miR-23 in NAFLD pathogenesis and discuss their potential significance in NAFLD diagnosis and therapy.
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Affiliation(s)
- Lin Ru
- grid.430605.40000 0004 1758 4110Department of Hepatology, The First Hospital of Jilin University, Changchun, 130021 China
| | - Xiao-mei Wang
- grid.430605.40000 0004 1758 4110Department of Hepatology, The First Hospital of Jilin University, Changchun, 130021 China ,grid.430605.40000 0004 1758 4110Key Laboratory of Zoonosis Research, Ministry of Education, The First Hospital of Jilin University, Changchun, 130021 China
| | - Jun-qi Niu
- grid.430605.40000 0004 1758 4110Department of Hepatology, The First Hospital of Jilin University, Changchun, 130021 China ,grid.430605.40000 0004 1758 4110Key Laboratory of Zoonosis Research, Ministry of Education, The First Hospital of Jilin University, Changchun, 130021 China
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Ma H, Wang X, Liu X, Wang C, Gao X, Niu J. miR-654-5p Contributes to the Activation and Proliferation of Hepatic Stellate Cells by Targeting RXRα. Front Cell Dev Biol 2022; 10:841248. [PMID: 35465330 PMCID: PMC9019757 DOI: 10.3389/fcell.2022.841248] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 03/22/2022] [Indexed: 11/13/2022] Open
Abstract
Liver fibrosis (LF) is a major disease that threatens human health. Hepatic stellate cells (HSCs) contribute directly to LF via extracellular matrix (ECM) secretion. Moreover, RXRα is an important nuclear receptor that plays a key regulatory role in HSC activation. Meanwhile, microRNAs (miRNAs) have been identified as significant regulators of LF development. In particular, miR-654-5p is involved in cellular migration and proliferation, and via bioinformatics analysis, has been identified as a potential factor that targets RXRα in humans and in mice. However, the precise relationship between miR-654-5p and RXRα in the context of LF, remains unknown and is the primary focus of the current study. To establish in vitro activated cell model human primary HSCs were cultured in vitro and LX-2 cells were stimulated with recombinant human TGF-β1. mRNA and protein levels of RXRα, miR-654-5p and fibrogenic genes were compared in quiescent and activated HSCs. Moreover, after transfected with miR-654-5p mimics, the expression changes of above related genes in LX-2 cells were estimated. Meanwhile, cell proliferation and apoptosis were detected in miR-654-5p overexpressed LX-2 cells. Simultaneously, the targeted binding between miR-654-5p and RXRα was verified in LX-2 cells. Carbon tetrachloride (CCl4)-induced mouse model with liver fibrosis was use to research the role of the miR-654-5p in vitro. Our results show that miR-654-5p expression levels increased in activated human HSCs and TGFβ-treated LX-2 cells. Moreover, miR-654-5p mimics markedly promoted LX-2 cell proliferation while inhibiting their apoptosis. Accordingly, the expression levels of RXRα are decreased in activated HSCs and LX-2 cells. Additionally, dual-luciferase reporter assay results reveal direct targeting of RXRα by miR-654-5p. Similarly, in vivo miR-654-5p overexpression aggravates LF in mice that are intraperitoneally injected with CCl4. Taken together, our findings elucidated a novel molecular mechanism with potential use for treatment of LF.
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Affiliation(s)
- Heming Ma
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
| | - Xiaomei Wang
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
| | - Xu Liu
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
| | - Chang Wang
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
| | - Xiuzhu Gao
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
- *Correspondence: Xiuzhu Gao, ; Junqi Niu,
| | - Junqi Niu
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, China
- *Correspondence: Xiuzhu Gao, ; Junqi Niu,
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Wen D, Gao Y, Ho C, Yu L, Zhang Y, Lyu G, Hu D, Li Q, Zhang Y. Focusing on Mechanoregulation Axis in Fibrosis: Sensing, Transduction and Effecting. Front Mol Biosci 2022; 9:804680. [PMID: 35359592 PMCID: PMC8963247 DOI: 10.3389/fmolb.2022.804680] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 02/09/2022] [Indexed: 11/24/2022] Open
Abstract
Fibrosis, a pathologic process featured by the excessive deposition of connective tissue components, can affect virtually every organ and has no satisfactory therapy yet. Fibrotic diseases are often associated with organ dysfunction which leads to high morbidity and mortality. Biomechanical stmuli and the corresponding cellular response havebeen identified in fibrogenesis, as the fibrotic remodeling could be seen as the incapacity to reestablish mechanical homeostasis: along with extracellular matrix accumulating, the physical property became more “stiff” and could in turn induce fibrosis. In this review, we provide a comprehensive overview of mechanoregulation in fibrosis, from initialing cellular mechanosensing to intracellular mechanotransduction and processing, and ends up in mechanoeffecting. Our contents are not limited to the cellular mechanism, but further expand to the disorders involved and current clinical trials, providing an insight into the disease and hopefully inspiring new approaches for the treatment of tissue fibrosis.
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Affiliation(s)
- Dongsheng Wen
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ya Gao
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chiakang Ho
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Li Yu
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuguang Zhang
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guozhong Lyu
- Department of Burns and Plastic Surgery, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Dahai Hu
- Burns Centre of PLA, Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Qingfeng Li
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Qingfeng Li, ; Yifan Zhang,
| | - Yifan Zhang
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Qingfeng Li, ; Yifan Zhang,
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Lin H, Mercer KE, Ou X, Mansfield K, Buchmann R, Børsheim E, Tas E. Circulating microRNAs Are Associated With Metabolic Markers in Adolescents With Hepatosteatosis. Front Endocrinol (Lausanne) 2022; 13:856973. [PMID: 35498403 PMCID: PMC9047938 DOI: 10.3389/fendo.2022.856973] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 03/14/2022] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Altered hepatic microRNA (miRNA) expression may play a role in the development of insulin resistance (IR) and non-alcoholic fatty liver disease (NAFLD). Circulating miRNAs could mirror the liver metabolism. OBJECTIVE This study aimed to assess the relationship between serum miRNA profile in children with obesity, IR, and NAFLD. METHODS Adolescents with obesity (n = 31) were stratified based on insulin resistance and NAFLD status. One-hundred seventy-nine miRNAs were determined in the serum by quantitative RT-PCR. Differentially expressed miRNAs were compared between groups, and log-transformed levels correlated with metabolic markers and intrahepatic triglyceride. RESULTS Serum miR-21-5p, -22-3p, -150-5p, and -155-5p levels were higher in children with IR and NAFLD, and their expression levels correlated with hepatic fat and serum triglyceride. In patients with NAFLD, miR-155-5p correlated with ALT (r = 0.68, p<0.01) and AST (r = 0.64, p<0.01) and miR-21-5p and -22-3p levels correlated with plasma adiponectin (r = -0.71 and r = -0.75, respectively, p<0.05) and fibroblast growth factor-21 (r = -0.73 and r = -0.89, respectively, p<0.01). miR-27-3a level was higher in children without IR and NAFLD. CONCLUSIONS Several miRNAs are differentially expressed in children with IR and NAFLD. Determining their mechanistic roles may provide newer diagnostic tools and therapeutic targets for pediatric NAFLD.
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Affiliation(s)
- Haixia Lin
- Arkansas Children’s Nutrition Center, Little Rock, AR, United States
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Kelly E. Mercer
- Arkansas Children’s Nutrition Center, Little Rock, AR, United States
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, United States
- Center for Childhood Obesity and Prevention, Arkansas Children’s Research Institute, Little Rock, AR, United States
| | - Xiawei Ou
- Arkansas Children’s Nutrition Center, Little Rock, AR, United States
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, United States
- Center for Childhood Obesity and Prevention, Arkansas Children’s Research Institute, Little Rock, AR, United States
- Department of Radiology, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Kori Mansfield
- Department of Radiology, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Robert Buchmann
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, United States
- Department of Radiology, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Elisabet Børsheim
- Arkansas Children’s Nutrition Center, Little Rock, AR, United States
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, United States
- Center for Childhood Obesity and Prevention, Arkansas Children’s Research Institute, Little Rock, AR, United States
| | - Emir Tas
- Arkansas Children’s Nutrition Center, Little Rock, AR, United States
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, United States
- Center for Childhood Obesity and Prevention, Arkansas Children’s Research Institute, Little Rock, AR, United States
- Endocrinology and Diabetes, Arkansas Children’s Hospital, Little Rock, AR, United States
- *Correspondence: Emir Tas,
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Abstract
Abstract
Non-alcoholic fatty liver disease (NAFLD) is now the most common cause of chronic liver disease, worldwide. The molecular pathogenesis of NAFLD is complex, involving numerous signalling molecules including microRNAs (miRNAs). Dysregulation of miRNA expression is associated with hepatic inflammation, fibrosis and hepatocellular carcinoma. Although miRNAs are also critical to the cellular response to vitamin D, mediating regulation of the vitamin D receptor (VDR) and vitamin D’s anticancer effects, a role for vitamin D regulated miRNAs in NAFLD pathogenesis has been relatively unexplored. Therefore, this review aimed to critically assess the evidence for a potential subset of miRNAs that are both dysregulated in NAFLD and modulated by vitamin D. Comprehensive review of 89 human studies identified 25 miRNAs found dysregulated in more than one NAFLD study. In contrast, only 17 studies, including a protocol for a trial in NAFLD, had examined miRNAs in relation to vitamin D status, response to supplementation, or vitamin D in the context of the liver. This paper summarises these data and reviews the biological roles of six miRNAs (miR-21, miR-30, miR-34, miR-122, miR-146, miR-200) found dysregulated in multiple independent NAFLD studies. While modulation of miRNAs by vitamin D has been understudied, integrating the data suggests seven vitamin D modulated miRNAs (miR-27, miR-125, miR-155, miR-192, miR-223, miR-375, miR-378) potentially relevant to NAFLD pathogenesis. Our summary tables provide a significant resource to underpin future hypothesis-driven research, and we conclude that the measurement of serum and hepatic miRNAs in response to vitamin D supplementation in larger trials is warranted.
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Chang Y, Han JA, Kang SM, Jeong SW, Ryu T, Park HS, Yoo JJ, Lee SH, Kim SG, Kim YS, Kim HS, Jin SY, Ryu S, Jang JY. Clinical impact of serum exosomal microRNA in liver fibrosis. PLoS One 2021; 16:e0255672. [PMID: 34506494 PMCID: PMC8432846 DOI: 10.1371/journal.pone.0255672] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 07/22/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND/AIM We investigated alterations in the expression of serum exosomal miRNAs with the progression of liver fibrosis and evaluated their clinical applicability as biomarkers. METHODS This study prospectively enrolled 71 patients who underwent liver biopsy at an academic hospital in Korea. Exosomes were extracted from serum samples, followed by next-generation sequencing (NGS) of miRNAs and targeted real-time quantitative polymerase chain reaction. A model was derived to discriminate advanced fibrosis based on miRNA levels and the performance of this model was evaluated. Validation of the effect of miRNA on liver fibrosis in vitro was followed. RESULTS NGS data revealed that exosomal miR-660-5p, miR-125a-5p, and miR-122 expression were changed significantly with the progression of liver fibrosis, of which miR-122 exhibited high read counts enough to be used as a biomarker. The level of exosomal miR-122 decreased as the pathologic fibrosis grade progressed and patients with biopsy-proven advanced fibrosis had significantly lower levels of exosomal miR-122 (P < 0.001) than those without advanced fibrosis. Exosomal miR-122 exhibited a fair performance in discriminating advanced fibrosis especially in combination with fibrosis-4 score and transient elastography. In a subgroup of patients with a non-viral etiology of liver disease, the performance of exosomal miR-122 as a biomarker was greatly improved. Inhibition of miR-122 expression increased the proliferation of the human hepatic stellate cell line, LX-2, and upregulated the expression of various fibrosis related proteins. CONCLUSION Exosomal miR-122 may serve as a useful non-invasive biomarker for liver fibrosis, especially in patients with non-viral etiologies of chronic liver disease.
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Affiliation(s)
- Young Chang
- Department of Internal Medicine, Institute for Digestive Research, Digestive Disease Center, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Jae-A. Han
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan, Korea
| | - Suk Min Kang
- Department of Internal Medicine, Institute for Digestive Research, Digestive Disease Center, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Soung Won Jeong
- Department of Internal Medicine, Institute for Digestive Research, Digestive Disease Center, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Tom Ryu
- Department of Internal Medicine, Institute for Digestive Research, Digestive Disease Center, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Han Seul Park
- Department of Internal Medicine, Institute for Digestive Research, Digestive Disease Center, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Jeong-Ju Yoo
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Bucheon, Korea
| | - Sae Hwan Lee
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - Sang Gyune Kim
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Bucheon, Korea
| | - Young Seok Kim
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Bucheon, Korea
| | - Hong Soo Kim
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - So Young Jin
- Department of Pathology, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Seongho Ryu
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan, Korea
| | - Jae Young Jang
- Department of Internal Medicine, Institute for Digestive Research, Digestive Disease Center, Soonchunhyang University College of Medicine, Seoul, Korea
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Bhattarai A, Likos EM, Weyman CM, Shukla GC. Regulation of cholesterol biosynthesis and lipid metabolism: A microRNA management perspective. Steroids 2021; 173:108878. [PMID: 34174291 DOI: 10.1016/j.steroids.2021.108878] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 06/07/2021] [Accepted: 06/11/2021] [Indexed: 12/14/2022]
Abstract
Cellular disruption of lipid and cholesterol metabolism results in pathological processes linked to metabolic and cardiovascular diseases. Classically, at the transcription stages, the Cholesterol levels are controlled by two cellular pathways. First, the SREBP transcription factor family controls Cholesterol biosynthesis via transcriptional regulation of critical rate-limiting cholesterogenic and lipogenic proteins. Secondly, The LXR/RXR transcription factor family controls cholesterol shuttling via transcriptional regulation of cholesterol transport proteins. In addition, the posttranscriptional control of gene expression of various enzymes and proteins of cholesterol biosynthesis pathways is mediated by small non-coding microRNAs. Regulatory noncoding miRNAs are critical regulators of biological processes, including developmental and metabolic functions. miRNAs function to fine-tune lipid and cholesterol metabolism pathways by controlling the mRNA levels and translation of critical molecules in each pathway. This review discusses the regulatory roles of miRNAs in cholesterol and lipid metabolism via direct and indirect effects on their target genes, including SREBP, LXR, HDL, LDL, and ABCA transporters. We also discuss the therapeutic implications of miRNA functions and their purported role in the potentiation of small molecule therapies.
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Affiliation(s)
- Asmita Bhattarai
- Center for Gene Regulation, Department of Biological, Geo and EVS Sciences, Cleveland State University, 2121 Euclid Avenue, Cleveland, OH 44114, USA
| | - Eviania M Likos
- Center for Gene Regulation, Department of Biological, Geo and EVS Sciences, Cleveland State University, 2121 Euclid Avenue, Cleveland, OH 44114, USA
| | - Crystal M Weyman
- Center for Gene Regulation, Department of Biological, Geo and EVS Sciences, Cleveland State University, 2121 Euclid Avenue, Cleveland, OH 44114, USA
| | - Girish C Shukla
- Center for Gene Regulation, Department of Biological, Geo and EVS Sciences, Cleveland State University, 2121 Euclid Avenue, Cleveland, OH 44114, USA
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miRNA-27a Transcription Activated by c-Fos Regulates Myocardial Ischemia-Reperfusion Injury by Targeting ATAD3a. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:2514947. [PMID: 34413925 PMCID: PMC8369174 DOI: 10.1155/2021/2514947] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 07/27/2021] [Indexed: 11/29/2022]
Abstract
MicroRNA-27a (miR-27a) has been implicated in myocardial ischemia-reperfusion injury (MIRI), but the underlying mechanism is not well understood. This study is aimed at determining the role of miR-27a in MIRI and at investigating upstream molecules that regulate miR-27a expression and its downstream target genes. miR-27a expression was significantly upregulated in myocardia exposed to ischemia/reperfusion (I/R) and cardiomyocytes exposed to hypoxia/reoxygenation (H/R). c-Fos could regulate miR-27a expression by binding to its promoter region. Moreover, overexpression of miR-27a led to a decrease in cell viability, an increase in LDH and CK-MB secretion, and an increase in apoptosis rates. In contrast, suppression of miR-27a expression resulted in the opposite effects. ATPase family AAA-domain-containing protein 3A (ATAD3a) was identified as a target of miR-27a. miR-27a regulated the translocation of apoptosis-inducing factor (AIF) from the mitochondria to the nucleus and H/R-induced apoptosis via the regulation of ATAD3a. It was found that inhibiting miR-27a in vivo by injecting a miR-27a sponge could ameliorate MIRI in an isolated rat heart model. In conclusion, our study demonstrated that c-Fos functions as an upstream regulator of miR-27a and that miR-27a regulates the translocation of AIF from the mitochondria to the nucleus by targeting ATAD3a, thereby contributing to MIRI. These findings provide new insight into the role of the c-Fos/miR-27a/ATAD3a axis in MIRI.
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17
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Shi CX, Wang Y, Jiao FZ, Chen Q, Cao P, Pei MH, Zhang LY, Guo J, Deng W, Wang LW, Gong ZJ. Epigenetic Regulation of Hepatic Stellate Cell Activation and Macrophage in Chronic Liver Inflammation. Front Physiol 2021; 12:683526. [PMID: 34276405 PMCID: PMC8281248 DOI: 10.3389/fphys.2021.683526] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 06/03/2021] [Indexed: 11/13/2022] Open
Abstract
Chronic liver inflammation is a complex pathological process under different stress conditions, and the roles of stellate cells and macrophages in chronic liver inflammation have been widely reported. Moderate liver inflammation can protect the liver from damage and facilitate the recovery of liver injury. However, an inflammatory response that is too intense can result in massive death of hepatocytes, which leads to irreversible damage to the liver parenchyma. Epigenetic regulation plays a key part in liver inflammation. This study reviews the regulation of epigenetics on stellate cells and macrophages to explore the new mechanisms of epigenetics on liver inflammation and provide new ideas for the treatment of liver disease.
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Affiliation(s)
- Chun-Xia Shi
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yao Wang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Fang-Zhou Jiao
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Qian Chen
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Pan Cao
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Mao-Hua Pei
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Lu-Yi Zhang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Jin Guo
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Wei Deng
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Lu-Wen Wang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zuo-Jiong Gong
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
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Circulating miRNA 27a and miRNA150-5p; a noninvasive approach to endometrial carcinoma. Mol Biol Rep 2021; 48:4351-4360. [PMID: 34076790 DOI: 10.1007/s11033-021-06450-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 05/27/2021] [Indexed: 01/28/2023]
Abstract
The search for novel non-invasive biomarkers such as epigenetic molecular markers is new hope for common and burdensome cancers. We aim to assess serum expression of miRNA 27a and miRNA150-5p in endometrial cancer patients. Serum was drawn for 36 un-intervened endometrial cancer patients scheduled for hysterectomy and 35 controls. miRNA 27a and miRNA150-5p were measured by real time reverse transcription polymerase chain reaction. Significant overexpression of both miRNA in patients (p < 0.001). At cutoffs 0.2872 & > 1.02, miRNA 27a showed 100% sensitivity, specificity, positive and negative predictive values. miRNA150-5p showed 88.89% sensitivity, 100% specificity, 100% positive and 78.9% negative predictive values. Areas under curve were 1.0 for miRNA 27a, 0.982 for miRNA 150 performing much better than Ca125. miRNA 27a was significantly associated with type I endometroid endometrial cancer. Conclusion: miRNA 27a and miRNA-150-5P can be suggested as promising biomarkers of endometrial cancer possibly part of a miRNA panel for management.
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HCV Proteins Modulate the Host Cell miRNA Expression Contributing to Hepatitis C Pathogenesis and Hepatocellular Carcinoma Development. Cancers (Basel) 2021; 13:cancers13102485. [PMID: 34069740 PMCID: PMC8161081 DOI: 10.3390/cancers13102485] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 05/12/2021] [Accepted: 05/17/2021] [Indexed: 12/13/2022] Open
Abstract
Simple Summary According to the last estimate by the World Health Organization (WHO), more than 71 million individuals have chronic hepatitis C worldwide. The persistence of HCV infection leads to chronic hepatitis, which can evolve into liver cirrhosis and ultimately into hepatocellular carcinoma (HCC). Although the pathogenic mechanisms are not fully understood, it is well established that an interplay between host cell factors, including microRNAs (miRNA), and viral components exist in all the phases of the viral infection and replication. Those interactions establish a complex equilibrium between host cells and HCV and participate in multiple mechanisms characterizing hepatitis C pathogenesis. The present review aims to describe the role of HCV structural and non-structural proteins in the modulation of cellular miRNA during HCV infection and pathogenesis. Abstract Hepatitis C virus (HCV) genome encodes for one long polyprotein that is processed by cellular and viral proteases to generate 10 polypeptides. The viral structural proteins include the core protein, and the envelope glycoproteins E1 and E2, present at the surface of HCV particles. Non-structural (NS) proteins consist of NS1, NS2, NS3, NS4A, NS4B, NS5a, and NS5b and have a variable function in HCV RNA replication and particle assembly. Recent findings evidenced the capacity of HCV virus to modulate host cell factors to create a favorable environment for replication. Indeed, increasing evidence has indicated that the presence of HCV is significantly associated with aberrant miRNA expression in host cells, and HCV structural and non-structural proteins may be responsible for these alterations. In this review, we summarize the recent findings on the role of HCV structural and non-structural proteins in the modulation of host cell miRNAs, with a focus on the molecular mechanisms responsible for the cell re-programming involved in viral replication, immune system escape, as well as the oncogenic process. In this regard, structural and non-structural proteins have been shown to modulate the expression of several onco-miRNAs or tumor suppressor miRNAs.
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Wu J, Nagy LE, Liangpunsakul S, Wang L. Non-coding RNA crosstalk with nuclear receptors in liver disease. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166083. [PMID: 33497819 PMCID: PMC7987766 DOI: 10.1016/j.bbadis.2021.166083] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Revised: 12/28/2020] [Accepted: 01/16/2021] [Indexed: 02/06/2023]
Abstract
The dysregulation of nuclear receptors (NRs) underlies the pathogenesis of a variety of liver disorders. Non-coding RNAs (ncRNAs) are defined as RNA molecules transcribed from DNA but not translated into proteins. MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are two types of ncRNAs that have been extensively studied for regulating gene expression during diverse cellular processes. NRs as therapeutic targets in liver disease have been exemplified by the successful application of their pharmacological ligands in clinics. MiRNA-based reagents or drugs are emerging as flagship products in clinical trials. Advancing our understanding of the crosstalk between NRs and ncRNAs is critical to the development of diagnostic and therapeutic strategies. This review summarizes recent findings on the reciprocal regulation between NRs and ncRNAs (mainly on miRNAs and lncRNAs) and their implication in liver pathophysiology, which might be informative to the translational medicine of targeting NRs and ncRNAs in liver disease.
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Affiliation(s)
- Jianguo Wu
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States of America; Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH, United States of America.
| | - Laura E Nagy
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States of America; Department of Gastroenterology and Hepatology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States of America; Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH, United States of America
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States of America; Roudebush Veterans Administration Medical Center, Indianapolis, IN, United States of America; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States of America
| | - Li Wang
- Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, CT, United States of America
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21
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Sufleţel RT, Melincovici CS, Gheban BA, Toader Z, Mihu CM. Hepatic stellate cells - from past till present: morphology, human markers, human cell lines, behavior in normal and liver pathology. ROMANIAN JOURNAL OF MORPHOLOGY AND EMBRYOLOGY 2021; 61:615-642. [PMID: 33817704 PMCID: PMC8112759 DOI: 10.47162/rjme.61.3.01] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Hepatic stellate cell (HSC), initially analyzed by von Kupffer, in 1876, revealed to be an extraordinary mesenchymal cell, essential for both hepatocellular function and lesions, being the hallmark of hepatic fibrogenesis and carcinogenesis. Apart from their implications in hepatic injury, HSCs play a vital role in liver development and regeneration, xenobiotic response, intermediate metabolism, and regulation of immune response. In this review, we discuss the current state of knowledge regarding HSCs morphology, human HSCs markers and human HSC cell lines. We also summarize the latest findings concerning their roles in normal and liver pathology, focusing on their impact in fibrogenesis, chronic viral hepatitis and liver tumors.
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Affiliation(s)
- Rada Teodora Sufleţel
- Discipline of Histology, Department of Morphological Sciences, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania;
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Hypoxia-induced miR-27 and miR-195 regulate ATP consumption, viability, and metabolism of rat cardiomyocytes by targeting PPARγ and FASN expression. Aging (Albany NY) 2021; 13:10158-10174. [PMID: 33819184 PMCID: PMC8064185 DOI: 10.18632/aging.202778] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 02/16/2021] [Indexed: 11/25/2022]
Abstract
This study examined whether hypoxia-induced microRNA (miRNA) upregulation was related to the inhibition of chondriosome aliphatic acid oxidation in myocardial cells under anoxia. We showed that anoxia induced high expression of hypoxia-inducible factor-1-alpha, muscle carnitine palmitoyltransferase I, and vascular endothelial growth factor in cardiomyocytes. Meanwhile, miR-27 and miR-195 were also upregulated in hypoxia-induced cardiomyocytes. Furthermore, hypoxia induction led to reductions in the adenosine triphosphate (ATP) consumption rate and oxidative metabolism as well as an increase in cardiomyocyte glycolysis. Metabolic reprogramming was reduced by hypoxia, as evidenced by the downregulation of sirtuin 1, forkhead box protein O1, sterol regulatory element-binding protein 1c, ATP citrate lyase, acetyl-coenzyme A carboxylase 2, adiponutrin, adipose triglyceride lipase, and glucose transporter type 4, while miR-27 and miR-195 inhibition partially recovered the expression of these transcription factors. In addition, hypoxia induction reduced cell viability and survival by triggering apoptosis; however, miR-27 and miR-195 inhibition partially increased cell viability. Moreover, miR-27 and miR-195 targeted the 3’untranslated regions of two key lipid-associated metabolic players, peroxisome proliferator-activated receptor gamma and fatty acid synthase. In conclusion, miR-27 and miR-195 are related to hypoxia-mediated ATP levels, glycolysis, oxidation, cell survival, and a cascade of transcription factors that control metabolism in cardiomyocytes.
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Liu Y, Wu H, Wang Z, Wu J, Ying S, Huang M, Li Y. Integrated expression profiles of mRNA and miRNA in a gerbil model of fatty liver fibrosis treated with exenatide. Clin Res Hepatol Gastroenterol 2021; 45:101312. [PMID: 33592427 DOI: 10.1016/j.clinre.2019.07.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 06/27/2019] [Accepted: 07/12/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND The morbidity of nonalcoholic fatty liver disease (NAFLD) has increased consistently in recent years. Exenatide could reverse liver fibrosis and lower the occurrence of fatty liver. The aim of the study was to identify and characterize mRNA and miRNA expression to elucidate the mechanism of exenatide in the gerbil model. METHODS Gerbils were fed a high-fat diet for 8 weeks to induce a fibrosis model; then, the gerbil models were treated with exenatide for 4 weeks. The total RNA extracted from the liver tissue samples was used to prepare the library and sequence on a HiSeq 2000. Bioinformatic methods were employed to analyze the sequence data to identify the mRNAs and miRNAs and to acquire the miRNA-mRNA regulatory network. RESULTS By RNA-seq, 2344 differentially expressed genes (DEGs) and 72 miRNAs were found in the model group. Compared with the model group, 591 DEGs and 19 miRNAs were found in the quercetin group, whereas 876 DEGs and 18 miRNAs were found in the treatment group. The miRNA-mRNA regulatory network was constructed in a gerbil model. Immunohistochemistry and RNA sequencing confirmed that the therapeutic effect of exenatide may be derived from extrahepatic signal transduction. The key differential genes are CYP3A, CYP4A11, ACAA1, ACSM, PHX1, MAO, FMO, UGT, ACOX2, ABAT, PIK3C and PLCG1. The key miRNAs are miR-15a, miR-27b, miR-532-3P, miR-627, miR-3596, miR-142-3P, Let-7e-5p, miR-214-5, miR-101-3p, miR-378d. New miRNAs, such as novel_127, novel_143, novel_15, novel_204 are associated with liver fibrosis, while novel_127, novel_15, and novel_54 are associated with reverse treated with exenatide. CONCLUSIONS Our research represents the first description of mRNA/miRNA profiles in a gerbil model of fatty liver fibrosis treated with exenatide, which may provide insights into the pathogenesis or treatment of the metabolic syndrome.
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Affiliation(s)
- Yuehuan Liu
- Zhejiang Academy of Medical Sciences, Hangzhou, China
| | - Hongru Wu
- Department of Gastroenterology, The first Affiliated Hospital, College of Medicine, Zhejiang University, 79, Qignchun Road, Hangzhou 310003, China
| | - Zhiyuan Wang
- Zhejiang Academy of Medical Sciences, Hangzhou, China
| | - Jiusheng Wu
- College of animal sciences, Zhejiang university, Hangzhou, China
| | - Shibo Ying
- Zhejiang Academy of Medical Sciences, Hangzhou, China
| | - Minjie Huang
- College of animal sciences, Zhejiang university, Hangzhou, China
| | - Youming Li
- Department of Gastroenterology, The first Affiliated Hospital, College of Medicine, Zhejiang University, 79, Qignchun Road, Hangzhou 310003, China.
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24
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Sun X, Kang Y, Xue S, Zou J, Xu J, Tang D, Qin H. In vivo therapeutic success of MicroRNA-155 antagomir in a mouse model of pulmonary fibrosis induced by bleomycin. Korean J Intern Med 2021; 36:S160-S169. [PMID: 32506869 PMCID: PMC8009162 DOI: 10.3904/kjim.2019.098] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Accepted: 10/07/2019] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND/AIMS MicroRNAs (miRNAs) play critical regulatory roles in the pathogenesis of pulmonary fibrosis. The aim of this study was to explore whether miRNA antagomirs could serve as potential therapeutic agents in interstitial lung diseases. METHODS A mouse model of pulmonary fibrosis was established by intratracheal injection of bleomycin (BLM). Using microarray analysis, up-regulated miRNAs were identified during the development of pulmonary fibrosis. miR-155 was chosen as the candidate miRNA. Fifteen mice were then randomized into the following three groups: BLM + antagomiR-155 group, treated with BLM plus intravenously injected with antagomiR-155; BLM group, treated with intratracheal BLM plus phosphate-buffered saline (PBS); and a control group, treated with PBS only. Lung tissues were collected for histopathological analysis, hydroxyproline measurement, and Western blotting. Enzyme-linked immunosorbent assays were used for the measurement of cytokines associated with pulmonary fibrosis. RESULTS Histological changes and hydroxyproline levels induced by BLM were significantly inhibited by antagomiR-155. The levels of interleukin 4 (IL-4) and transforming growth factor-β (TGF-β) expression were increased after BLM treatment. However, miR-155 silencing decreased the expression of IL-4, TGF-β, and interferon-γ. TGF-β-activated kinase 1/mitogen-activated protein kinase kinase kinase 7 (MAP3K7)-binding protein 2 (TAB2) of the mitogen-activated protein kinase (MAPK) signaling pathway, was activated by BLM and inhibited by in vivo silencing of miR-155 via antagomiR-155. CONCLUSION In vivo treatment with antagomiR-155 alleviated the pathological changes induced by BLM and may be a promising therapeutic strategy for pulmonary fibrosis.
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Affiliation(s)
- Xiaoyuan Sun
- Department of Respiratory, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Yu Kang
- Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Shan Xue
- Department of Respiratory, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Jing Zou
- Department of Respiratory, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Jiabo Xu
- Department of Respiratory, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Daoqiang Tang
- Department of Pathology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Hui Qin
- Department of Respiratory, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
- Correspondence to Hui Qin, M.D. Department of Respiratory, Renji Hospital, School of Medicine, Shanghai Jiaotong University, No 160, Pujian Road, Shanghai 200127, China Tel: +86-68383101 Fax: +86-2168383101 E-mail:
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Zhang HF, Zhu LL, Yang XB, Gao N, Fang Y, Wen Q, Qiao HL. Variation in the expression of cytochrome P450-related miRNAs and transcriptional factors in human livers: Correlation with cytochrome P450 gene phenotypes. Toxicol Appl Pharmacol 2020; 412:115389. [PMID: 33385404 DOI: 10.1016/j.taap.2020.115389] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 12/24/2020] [Accepted: 12/27/2020] [Indexed: 01/02/2023]
Abstract
Cytochrome P450 (CYP) gene expression exhibits large interindividual variation attributable to diverse regulatory factors including microRNAs (miRNAs) and hepatic transcription factors (TFs). We used real-time qPCR with 106 human liver samples to measure the expression and interindividual variation of seven miRNAs and four TFs that have been reported to regulate the expression of CYPs; we also identified factors that influence their expression. The results show that expression of the seven miRNAs and the four TFs exhibits a non-normal distribution and the expression variability is high (89- to 618-fold for miRNA and 12- to 85-fold for TFs). Age contributed to the interindividual variation for miR-148a, miR-27b and miR-34a, whereas cigarette smoking and alcohol consumption significantly reduced HNF4α mRNA levels. Association analysis showed significant correlations among the seven miRNAs as well as the four TFs. Furthermore, we systematically evaluated the impact of the seven miRNAs and four TFs on protein content, mRNA levels, translation efficiency and activity of 10 CYPs. The results show that numerous associations (positive and negative) are present between the seven miRNAs or the four TFs and the 10 CYP phenotypes (as indicated by mRNA, protein and activity); specifically, miR-27b, miR-34a and all four TFs played key roles in the interindividual variation of CYPs. Our results extend previous findings and suggest that miR-27b and miR-34a may be potential direct or indirect master regulators of CYP expression and thereby contribute to the interindividual variations in CYP-mediated drug metabolism.
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Affiliation(s)
- Hai-Feng Zhang
- Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Li-Li Zhu
- Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Xiao-Bei Yang
- Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Na Gao
- Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Yan Fang
- Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Qiang Wen
- Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Hai-Ling Qiao
- Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou 450052, Henan, China.
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26
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Research Trends in the Efficacy of Stem Cell Therapy for Hepatic Diseases Based on MicroRNA Profiling. Int J Mol Sci 2020; 22:ijms22010239. [PMID: 33383629 PMCID: PMC7795580 DOI: 10.3390/ijms22010239] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 12/23/2020] [Accepted: 12/25/2020] [Indexed: 02/06/2023] Open
Abstract
Liver diseases, despite the organ’s high regenerative capacity, are caused by several environmental factors and persistent injuries. Their optimal treatment is a liver transplantation. However, this option is limited by donor shortages and immune response issues. Therefore, many researchers have been interested in identifying the therapeutic potential in treating irreversible liver damage based on stem cells and developing suitable therapeutic agents. Mesenchymal stem cells (MSCs), which are representative multipotent stem cells, are known to be highly potential stem cell therapy compared to other stem cells in the clinical trial worldwide. MSCs have therapeutic potentials for several hepatic diseases such as anti-fibrosis, proliferation of hepatocytes injured, anti-inflammation, autophagic mechanism, and inactivation of hepatic stellate cells. There are much data regarding clinical treatments, however, the data for examining the efficacy of stem cell treatment and the correlation between the stem cell engraftment and the efficacy in liver diseases is limited due to the lack of monitoring system for treatment effectiveness. Therefore, this paper introduces the characteristics of microRNAs (miRNAs) and liver disease-specific miRNA profiles, and the possibility of a biomarker that miRNA can monitor stem cell treatment efficacy by comparing miRNAs changed in liver diseases following stem cell treatment. Additionally, we also discuss the miRNA profiling in liver diseases when treated with stem cell therapy and suggest the candidate miRNAs that can be used as a biomarker that can monitor treatment efficacy in liver diseases based on MSCs therapy.
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27
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Unraveling the Role of Leptin in Liver Function and Its Relationship with Liver Diseases. Int J Mol Sci 2020; 21:ijms21249368. [PMID: 33316927 PMCID: PMC7764544 DOI: 10.3390/ijms21249368] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 11/19/2020] [Accepted: 12/04/2020] [Indexed: 02/06/2023] Open
Abstract
Since its discovery twenty-five years ago, the fat-derived hormone leptin has provided a revolutionary framework for studying the physiological role of adipose tissue as an endocrine organ. Leptin exerts pleiotropic effects on many metabolic pathways and is tightly connected with the liver, the major player in systemic metabolism. As a consequence, understanding the metabolic and hormonal interplay between the liver and adipose tissue could provide us with new therapeutic targets for some chronic liver diseases, an increasing problem worldwide. In this review, we assess relevant literature regarding the main metabolic effects of leptin on the liver, by direct regulation or through the central nervous system (CNS). We draw special attention to the contribution of leptin to the non-alcoholic fatty liver disease (NAFLD) pathogenesis and its progression to more advanced stages of the disease as non-alcoholic steatohepatitis (NASH). Likewise, we describe the contribution of leptin to the liver regeneration process after partial hepatectomy, the mainstay of treatment for certain hepatic malignant tumors.
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28
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Lee DH, Park SH, Ahn J, Hong SP, Lee E, Jang YJ, Ha TY, Huh YH, Ha SY, Jeon TI, Jung CH. Mir214-3p and Hnf4a/Hnf4α reciprocally regulate Ulk1 expression and autophagy in nonalcoholic hepatic steatosis. Autophagy 2020; 17:2415-2431. [PMID: 33078654 PMCID: PMC8496708 DOI: 10.1080/15548627.2020.1827779] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Macroautophagy/autophagy, a self-degradative process, regulates metabolic homeostasis in response to various stress conditions and is a therapeutic target for nonalcoholic fatty liver disease. We found that autophagic activity was inhibited as a result of a significant reduction in the expression of autophagy-related genes such as Ulk1 in a mouse model and patients with fatty liver. This downregulation was caused by increased Mir214-3p levels and decreased Hnf4a/Hnf4α mRNA levels in hepatocytes. Mir214-3p suppressed Ulk1 expression through direct binding at a 3' untranslated region sequence. Hnf4a directly activated transcription of Ulk1. We investigated lipid accumulation and the expression of autophagy-related genes in the livers of mice treated with anti-Mir214-3p. Hepatic steatosis was alleviated, and Ulk1 mRNA levels were significantly increased by locked nucleic acid-mediated Mir214-3p silencing. Additionally, autophagosome formation and MAP1LC3/LC3-II protein levels were increased, indicating an increase in autophagic activity. Interestingly, suppression of Mir214-3p did not ameliorate fatty liver under Ulk1 suppression, suggesting that reduced Mir214-3p levels mitigate hepatic steatosis through upregulation of Ulk1. These results demonstrate that inhibition of Mir214-3p expression ameliorated fatty liver disease through increased autophagic activity by increasing the expression of Ulk1. Thus, Mir214-3p is a potential therapeutic target for nonalcoholic fatty disease.Abbreviations: AMPK: adenosine monophosphate-activated protein kinase; ATG: autophagy-related; ChIP: chromatin immunoprecipitation; CTSB: cathepsin B; CTSL: cathepsin L; CQ: chloroquine; HFD: high-fat diet; HNF4A: hepatocyte nuclear factor 4, alpha; IF: immunofluorescence; IHC: immunohistochemistry; LDs: lipid droplets; Leup: leupeptin; LFD: low-fat diet; LNA: locked nucleic acid; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; miRNA: microRNA; MTOR: mechanistic target of rapamycin kinase; NAFLD: non-alcoholic fatty liver disease; NASH: non-alcoholic steatohepatitis; PCR: polymerase chain reaction; TEM: transmission electron microscopy; TF: transcription factor; TLDA: TaqMan low-density array; ULK1: unc-51 like kinase 1; UTR: untranslated region.
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Affiliation(s)
- Da-Hye Lee
- Research Division of Food Functionality, Korea Food Research Institute, Wanju-gun, Republic of Korea.,Department of Food Biotechnology, Korea University of Science and Technology, Daejeon, Republic of Korea
| | - So-Hyun Park
- Research Division of Food Functionality, Korea Food Research Institute, Wanju-gun, Republic of Korea.,Department of Food Biotechnology, Korea University of Science and Technology, Daejeon, Republic of Korea
| | - Jiyun Ahn
- Research Division of Food Functionality, Korea Food Research Institute, Wanju-gun, Republic of Korea.,Department of Food Biotechnology, Korea University of Science and Technology, Daejeon, Republic of Korea
| | - Seung Pyo Hong
- Research Division of Food Functionality, Korea Food Research Institute, Wanju-gun, Republic of Korea
| | - Eunyoung Lee
- Research Division of Food Functionality, Korea Food Research Institute, Wanju-gun, Republic of Korea
| | - Young-Jin Jang
- Research Division of Food Functionality, Korea Food Research Institute, Wanju-gun, Republic of Korea
| | - Tae-Youl Ha
- Research Division of Food Functionality, Korea Food Research Institute, Wanju-gun, Republic of Korea.,Department of Food Biotechnology, Korea University of Science and Technology, Daejeon, Republic of Korea
| | - Yang Hoon Huh
- Center for Electron Microscopy Research, Korea Basic Science Institute, Cheongju, Republic of Korea
| | - Seung-Yeon Ha
- Department of Pathology, Gil Medical Center, Gachon University College of Medicine, Incheon, Republic of Korea
| | - Tae-Il Jeon
- Department of Animal Science, Chonnam National University, Gwangju, Republic of Korea
| | - Chang Hwa Jung
- Research Division of Food Functionality, Korea Food Research Institute, Wanju-gun, Republic of Korea.,Department of Food Biotechnology, Korea University of Science and Technology, Daejeon, Republic of Korea
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MicroRNA expression profiling reveals potential roles for microRNA in the liver during pigeon (Columba livia) development. Poult Sci 2020; 99:6378-6389. [PMID: 33248553 PMCID: PMC7705055 DOI: 10.1016/j.psj.2020.09.039] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 08/23/2020] [Accepted: 09/11/2020] [Indexed: 12/11/2022] Open
Abstract
The liver is the central organ for metabolism and influence the growth and development of the animals. To date, little is known about the microRNA (miRNA) in pigeon livers, particularly in different developmental stages. A comprehensive investigation into miRNA transcriptomes in livers across 3 pigeon developmental stages (1, 14, 28 d old) and an adult stage (2 y old) was performed by small RNA sequencing. We identified 312 known miRNA, 433 conserved miRNA, and 192 novel miRNA in pigeon livers. A set of differentially expressed (DE) miRNA in livers were screened out during pigeon development. This set of miRNA might be involved in hepatospecific phenotype and liver development. A Short Time-series Expression Miner analysis indicated significant expression variations in DE miRNA during liver development of pigeons. These DE miRNA with different expression patterns might play essential roles in response to growth factor, cell morphogenesis, and gland development, etc. Protein-protein interaction network and Molecular Complex Detection analysis identified several vital target genes (e.g., TNRC6B, FRS2, PTCH1, etc.) of DE miRNA, which is closely linked in liver development and enriched in PI3K cascade and regulation of growth. Our results expanded the repertoire of pigeon miRNA and may be of help in better understanding the mechanism of squab's rapid development from the perspective of liver development.
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30
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Liao X, Zhan W, Tian T, Yu L, Li R, Yang Q. MicroRNA-326 attenuates hepatic stellate cell activation and liver fibrosis by inhibiting TLR4 signaling. J Cell Biochem 2020; 121:3794-3803. [PMID: 31692098 DOI: 10.1002/jcb.29520] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Accepted: 10/10/2019] [Indexed: 01/24/2023]
Abstract
Hepatic fibrosis is a chronic inflammatory and reversible repair reaction of the liver under the continuous action of virus or various injuries. In this study, we aimed at identifying the role of miR-326 in the hepatic stellate cell (HSC) activation and liver fibrosis and its potential mechanism. In this study, the liver fibrosis mouse model was developed by injecting CCl4 . Liver tissue morphology was observed and the expression level of α-smooth muscle actin, collagen1α1 and miR-326 was measured. Target gene identification was performed by loss-of-function and gain-of-function. The effect of miR-326 on the expression level of the cytokines associated with the TLR4/MyD88/nuclear factor-κB (NF-κB) pathway was assessed in vitro and in vivo. We show that miR-326 was downregulated in CCl4 -induced fibrotic mice and activated HSCs. The target gene of miR-326 is TLR4. Moreover, miR-326 inhibited the activation of HSCs in vitro through TLR4/MyD88/NF-κB signaling. miR-326 attenuated hepatic fibrosis and inflammation of CCl4 -induced mice in vivo. Our results demonstrate for the first time that miR-326 inhibits HSC activation through TLR4/MyD88/NF-κB signaling. Furthermore, miR-326 plays critical roles in attenuating liver fibrosis and inflammation, suggesting the therapeutic potential of miRNAs.
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Affiliation(s)
- Xin Liao
- Department of Imaging, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
| | - Wei Zhan
- Surgery of Colorectal, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
| | - Tian Tian
- Doctoral Graduate Student of Pathophysiology, Guizhou Medical University, Guiyang, Guizhou, China
| | - Lei Yu
- Department of Pathology, Guiyang Maternal and Child Health Hospital, Guiyang, Guizhou, China
| | - Rui Li
- Department of Traditional Chinese Medicine, Guizhou Provincial People's Hospital, Guiyang, Guizhou, China
| | - Qin Yang
- Department of Pathology and Pathophysiology, Guizhou Medical University, Guiyang, Guizhou, China
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31
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Mir BA, Reyer H, Komolka K, Ponsuksili S, Kühn C, Maak S. Differentially Expressed miRNA-Gene Targets Related to Intramuscular Fat in Musculus Longissimus Dorsi of Charolais × Holstein F 2-Crossbred Bulls. Genes (Basel) 2020; 11:genes11060700. [PMID: 32630492 PMCID: PMC7348786 DOI: 10.3390/genes11060700] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 06/22/2020] [Accepted: 06/23/2020] [Indexed: 12/12/2022] Open
Abstract
Intramuscular fat (IMF) is a meat quality indicator associated with taste and juiciness. IMF deposition, influenced by genetic and non-genetic factors, occurs through a transcriptionally coordinated process of adipogenesis. MicroRNAs (miRNAs) are transcriptional regulators of vital biological processes, including lipid metabolism and adipogenesis. However, in bovines, limited data on miRNA profiling and association with divergent intramuscular fat content, regulated exclusively by genetic parameters, have been reported. Here, a microarray experiment was performed to identify and characterize the miRNA expression pattern in the Musculus longissimus dorsi of F2-cross (Charolais × German Holstein) bulls with high and low IMF. A total of 38 differentially expressed miRNAs (DE miRNAs), including 33 upregulated and 5 downregulated (corrected p-value ≤ 0.05, FC ≥ ±1.2), were reported. Among DE miRNAs, the upregulated miRNAs miR-105a/b, miR-695, miR-1193, miR-1284, miR-1287-5p, miR-3128, miR-3178, miR-3910, miR-4443, miR-4445 and miR-4745, and the downregulated miRNAs miR-877-5p, miR-4487 and miR-4706 were identified as novel fat deposition regulators. DE miRNAs were further analyzed, along with previously identified differentially expressed genes (DEGs) from the same samples and predicted target genes, using multiple bioinformatic approaches, including target prediction tools and co-expression networks, as well as Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. We identified DE miRNAs and their gene targets associated with bovine intramuscular adipogenesis, and we provide a basis for further functional investigations.
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Affiliation(s)
- Bilal Ahmad Mir
- Institute of Muscle Biology and Growth, Leibniz Institute for Farm Animal Biology (FBN), D-18196 Dummerstorf, Germany; (K.K.); (S.M.)
- Correspondence: ; Tel.: +49-38208-68885
| | - Henry Reyer
- Institute of Genome Biology, Leibniz Institute for Farm Animal Biology (FBN), D-18196 Dummerstorf, Germany; (H.R.); (S.P.); (C.K.)
| | - Katrin Komolka
- Institute of Muscle Biology and Growth, Leibniz Institute for Farm Animal Biology (FBN), D-18196 Dummerstorf, Germany; (K.K.); (S.M.)
| | - Siriluck Ponsuksili
- Institute of Genome Biology, Leibniz Institute for Farm Animal Biology (FBN), D-18196 Dummerstorf, Germany; (H.R.); (S.P.); (C.K.)
| | - Christa Kühn
- Institute of Genome Biology, Leibniz Institute for Farm Animal Biology (FBN), D-18196 Dummerstorf, Germany; (H.R.); (S.P.); (C.K.)
| | - Steffen Maak
- Institute of Muscle Biology and Growth, Leibniz Institute for Farm Animal Biology (FBN), D-18196 Dummerstorf, Germany; (K.K.); (S.M.)
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Chemello F, Grespi F, Zulian A, Cancellara P, Hebert-Chatelain E, Martini P, Bean C, Alessio E, Buson L, Bazzega M, Armani A, Sandri M, Ferrazza R, Laveder P, Guella G, Reggiani C, Romualdi C, Bernardi P, Scorrano L, Cagnin S, Lanfranchi G. Transcriptomic Analysis of Single Isolated Myofibers Identifies miR-27a-3p and miR-142-3p as Regulators of Metabolism in Skeletal Muscle. Cell Rep 2020; 26:3784-3797.e8. [PMID: 30917329 DOI: 10.1016/j.celrep.2019.02.105] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Revised: 06/29/2018] [Accepted: 02/26/2019] [Indexed: 12/27/2022] Open
Abstract
Skeletal muscle is composed of different myofiber types that preferentially use glucose or lipids for ATP production. How fuel preference is regulated in these post-mitotic cells is largely unknown, making this issue a key question in the fields of muscle and whole-body metabolism. Here, we show that microRNAs (miRNAs) play a role in defining myofiber metabolic profiles. mRNA and miRNA signatures of all myofiber types obtained at the single-cell level unveiled fiber-specific regulatory networks and identified two master miRNAs that coordinately control myofiber fuel preference and mitochondrial morphology. Our work provides a complete and integrated mouse myofiber type-specific catalog of gene and miRNA expression and establishes miR-27a-3p and miR-142-3p as regulators of lipid use in skeletal muscle.
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Affiliation(s)
- Francesco Chemello
- Department of Biology, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy; CRIBI Biotechnology Centre, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy
| | - Francesca Grespi
- Department of Biology, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy; Venetian Institute of Molecular Medicine, Via Orus 2, 35131 Padova, Italy
| | - Alessandra Zulian
- Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy
| | - Pasqua Cancellara
- Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy
| | - Etienne Hebert-Chatelain
- Department of Biology, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy; Venetian Institute of Molecular Medicine, Via Orus 2, 35131 Padova, Italy
| | - Paolo Martini
- Department of Biology, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy
| | - Camilla Bean
- Department of Biology, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy; Venetian Institute of Molecular Medicine, Via Orus 2, 35131 Padova, Italy
| | - Enrico Alessio
- Department of Biology, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy; CRIBI Biotechnology Centre, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy
| | - Lisa Buson
- Department of Biology, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy
| | - Martina Bazzega
- Department of Biology, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy
| | - Andrea Armani
- Venetian Institute of Molecular Medicine, Via Orus 2, 35131 Padova, Italy
| | - Marco Sandri
- Venetian Institute of Molecular Medicine, Via Orus 2, 35131 Padova, Italy; Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy; CIR-Myo Myology Center, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy
| | - Ruggero Ferrazza
- Department of Physics, University of Trento, Via Sommarive 14, 38123 Povo (Trento), Italy
| | - Paolo Laveder
- Department of Biology, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy
| | - Graziano Guella
- Department of Physics, University of Trento, Via Sommarive 14, 38123 Povo (Trento), Italy
| | - Carlo Reggiani
- Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy
| | - Chiara Romualdi
- Department of Biology, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy
| | - Paolo Bernardi
- Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy
| | - Luca Scorrano
- Department of Biology, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy; Venetian Institute of Molecular Medicine, Via Orus 2, 35131 Padova, Italy
| | - Stefano Cagnin
- Department of Biology, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy; CRIBI Biotechnology Centre, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy; CIR-Myo Myology Center, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy.
| | - Gerolamo Lanfranchi
- Department of Biology, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy; CRIBI Biotechnology Centre, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy; CIR-Myo Myology Center, University of Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy.
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Liang H, Wang X, Si C, Duan Y, Chen B, Liang H, Yang D. Downregulation of miR‑141 deactivates hepatic stellate cells by targeting the PTEN/AKT/mTOR pathway. Int J Mol Med 2020; 46:406-414. [PMID: 32319536 DOI: 10.3892/ijmm.2020.4578] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Accepted: 03/27/2020] [Indexed: 01/18/2023] Open
Abstract
The activation of hepatic stellate cells (HSCs) caused by stimulating factors or fibrogenic cytokines is the critical stage of liver fibrosis. Recent studies have demonstrated the influence of microRNAs (miRNAs or miRs) on HSC activation and transformation; however, the function and underlying mechanisms of miRNAs in HSC activation have not yet been completely clarified. In the present study, transforming growth factor β1 (TGF‑β1) was used to treat human HSC lines (HSC‑T6 and LX2 cells) to simulate the activation of HSCs in vivo and whether the expression of miRNAs in HSCs was affected by TGF‑β1 treatment was examined using a miRNA microarray. It was observed that miR‑141 was one of the most upregulated miRNAs during HSC activation. Functional analyses revealed that miR‑141 knockdown suppressed the viability of HSCs and inhibited the expression levels of pro‑fibrotic markers. In addition, phosphatase and tensin homolog (PTEN), a well‑known suppressor of the AKT/mammalian target of rapamycin (mTOR) pathway, was found to be directly targeted by miR‑141 in HSCs. More importantly, the knockdown of PTEN markedly reversed the suppressive effects of miR‑141 inhibition on the viability of and the expression levels of pro‑fibrotic markers during HSC activation. Finally, it was observed that the downregulation of miR‑141 blocked the TGF‑β1‑induced activation of the AKT/mTOR pathway in HSCs. On the whole, the findings of the present study indicate that miR‑141 inhibition suppresses HSC activation via the AKT/mTOR pathway by targeting PTEN, highlighting that miR‑141 may serve as a novel therapeutic target for liver fibrosis.
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Affiliation(s)
- Haijun Liang
- Department of Infectious Disease, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| | - Xinwei Wang
- Department of Infectious Disease, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| | - Changyun Si
- Department of Infectious Disease, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| | - Yuxiu Duan
- Department of Infectious Disease, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| | - Baoxin Chen
- Department of Infectious Disease, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| | - Haixia Liang
- Department of Neurology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| | - Daokun Yang
- Department of Infectious Disease, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
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Deng K, Ren C, Fan Y, Liu Z, Zhang G, Zhang Y, You P, Wang F. miR-27a is an important adipogenesis regulator associated with differential lipid accumulation between intramuscular and subcutaneous adipose tissues of sheep. Domest Anim Endocrinol 2020; 71:106393. [PMID: 31731253 DOI: 10.1016/j.domaniend.2019.106393] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2019] [Revised: 08/05/2019] [Accepted: 09/04/2019] [Indexed: 01/15/2023]
Abstract
Micro ribonucleic acids (miRNAs) are crucial regulators for various biological processes. Despite important function in the proliferation and differentiation of preadipocytes, miRNA studies are limited in regional differences in adipogenesis. Here, we show that miR-27a plays an important role in regulating differential lipid accumulation between intramuscular (IM) and subcutaneous (SC) adipose tissues in sheep. Invivo, we observed that miR-27a expression in IM adipose tissue is more abundant than in SC adipose tissue. However, the expression of Peroxisome Proliferator-Activated Receptor Gamma (PPARG) and retinoid X receptor alpha (RXR alpha) in IM adipose tissue was significantly lower than that in SC adipose tissue. In the ovine preadipocyte differentiation model, we found that the expression of miR-27a was significantly decreased in differentiated ovine adipocytes. Overexpression of miR-27a significantly downregulated the expression of PPARG and RXR alpha and suppressed the accumulation of triglyceride but promoted the proliferation of ovine preadipocytes. Whereas, inhibition of miR-27a suppressed preadipocyte proliferation but enhanced PPARG and RXR alpha expression and lipid droplet formation. In addition, dual-luciferase activity assays showed that RXR alpha was a direct target of miR-27a. Thus, miR-27a enhances ovine preadipocytes proliferation and inhibits ovine preadipocytes differentiation through regulating the expression of target RXR alpha. Collectively, our study demonstrates the functional importance of miR-27a in ovine adipogenesis and provides novel insights into exploring regional differences in adipogenesis.
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Affiliation(s)
- K Deng
- Institute of Sheep and Goat Science, Nanjing Agricultural University, Nanjing, Jiangsu, China
| | - C Ren
- Institute of Sheep and Goat Science, Nanjing Agricultural University, Nanjing, Jiangsu, China
| | - Y Fan
- Institute of Sheep and Goat Science, Nanjing Agricultural University, Nanjing, Jiangsu, China
| | - Z Liu
- Institute of Sheep and Goat Science, Nanjing Agricultural University, Nanjing, Jiangsu, China
| | - G Zhang
- Institute of Sheep and Goat Science, Nanjing Agricultural University, Nanjing, Jiangsu, China
| | - Y Zhang
- Institute of Sheep and Goat Science, Nanjing Agricultural University, Nanjing, Jiangsu, China
| | - P You
- Portal Agri-Industries Co, Ltd, Xingdian Street, Pikou District, Nanjing, Jiangsu, China
| | - F Wang
- Institute of Sheep and Goat Science, Nanjing Agricultural University, Nanjing, Jiangsu, China; National Experimental Teaching Demonstration Center of Animal Science, Nanjing Agricultural University, Nanjing, Jiangsu, China.
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Iacob DG, Rosca A, Ruta SM. Circulating microRNAs as non-invasive biomarkers for hepatitis B virus liver fibrosis. World J Gastroenterol 2020; 26:1113-1127. [PMID: 32231417 PMCID: PMC7093315 DOI: 10.3748/wjg.v26.i11.1113] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 03/04/2020] [Accepted: 03/09/2020] [Indexed: 02/06/2023] Open
Abstract
Viruses can alter the expression of host microRNAs (MiRNA s) and modulate the immune response during a persistent infection. The dysregulation of host MiRNA s by hepatitis B virus (HBV) contributes to the proinflammatory and profibrotic changes within the liver. Multiple studies have documented the differential regulation of intracellular and circulating MiRNA s during different stages of HBV infection. Circulating MiRNA s found in plasma and/or extracellular vesicles can integrate data on viral-host interactions and on the associated liver injury. Hence, the detection of circulating MiRNA s in chronic HBV hepatitis could offer a promising alternative to liver biopsy, as their expression is associated with HBV replication, the progression of liver fibrosis, and the outcome of antiviral treatment. The current review explores the available data on miRNA involvement in HBV pathogenesis with an emphasis on their potential use as biomarkers for liver fibrosis.
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Affiliation(s)
- Diana Gabriela Iacob
- Infectious Diseases Department, "Carol Davila" University of Medicine and Pharmacy, Bucharest 050474, Romania
- Bucharest Emergency University Hospital, Bucharest 050098, Romania
| | - Adelina Rosca
- Virology Department, Carol Davila University of Medicine and Pharmacy, Bucharest 050474, Romania
- Viral Emerging Diseases Department, Ștefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Simona Maria Ruta
- Virology Department, Carol Davila University of Medicine and Pharmacy, Bucharest 050474, Romania
- Viral Emerging Diseases Department, Ștefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
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Kukreti H, Amuthavalli K. MicroRNA-34a causes ceramide accumulation and effects insulin signaling pathway by targeting ceramide kinase (CERK) in aging skeletal muscle. J Cell Biochem 2020; 121:3070-3089. [PMID: 32056304 DOI: 10.1002/jcb.29312] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Accepted: 07/15/2019] [Indexed: 12/31/2022]
Abstract
Aging skeletal muscle shows perturbations in metabolic functions. MicroRNAs have been shown to play a critical role in aging and metabolic functions of skeletal muscle. MicroRNA-34a (miR-34a) is implicated in the brain and cardiac aging, however, its role in aging muscle is unclear. We analyzed levels of miR-34a, ceramide kinase (CERK) and other insulin signaling molecules in skeletal muscle from old mice. In addition to in vivo model, levels of these molecules were also analyzed in myoblast derived from insulin resistant (IR) humans and C2C12 myoblasts overexpressing mir-34a. Our results show that miR-34a is elevated in the muscles of 2-year-old mice and in the myoblasts of IR humans. Overexpression of miR-34a in C2C12 myoblasts leads to alterations in the insulin signaling pathway, which were rescued by its antagonism. Our analyses revealed that miR-34a targets CERK resulting in ceramide accumulation, activation of PP2A and the pJNK pathway in muscle and C2C12 myoblasts. Also, myostatin (Mstn) levels were increased in 2-year-old mouse muscle and Mstn treatment upregulated miR-34a in C2C12 myoblasts. In addition, miR-34a expression and ceramide levels did not increase during aging in Mstn-/- mice muscle. In summary, we, therefore, propose that Mstn levels increase in aging muscle and upregulate miR-34a, which inhibits CERK resulting in increased ceramide levels. This ceramide accumulation activates PP2A and pJNK causing hypophosphorylation of AKT and hyperphosphorylation of IRS1 (Ser307), respectively, impairing insulin signaling pathway and eventually inhibiting the sarcolemma localization of GLUT4. These changes would result in reduced glucose uptake and insulin resistance. This study is the first to explain the phenomenon of ceramide accrual and impairment of insulin signaling pathway in aging muscle through a miR-34a based mechanism. In conclusion, our results suggest that Mstn and miR-34a antagonism can help ameliorate ceramide accumulation and loss of insulin sensitivity in aging skeletal muscle.
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Affiliation(s)
- Himani Kukreti
- Department of Biochemistry, Yong Loo Lin School of Medicine (YLLSoM), National University of Singapore, Singapore
| | - Kottaiswamy Amuthavalli
- Department of Biochemistry, Yong Loo Lin School of Medicine (YLLSoM), National University of Singapore, Singapore
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Zhang Q, Wang J, Li H, Zhang Y, Chu X, Yang J, Li Y. LncRNA Gm12664-001 ameliorates nonalcoholic fatty liver through modulating miR-295-5p and CAV1 expression. Nutr Metab (Lond) 2020; 17:13. [PMID: 32042299 PMCID: PMC7001338 DOI: 10.1186/s12986-020-0430-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Accepted: 01/20/2020] [Indexed: 12/12/2022] Open
Abstract
Background Our study aims to investigate the mechanisms of lncRNA Gm12664–001 improved hepatic lipid accumulation-initiated NAFLD via regulating miR-295-5p and CAV1 in AML12 cells. Methods The animals were divided into normal control (NC) group and high fat diet (HFD) group (20 mice per group) for 8w. The steatotic liver was measured by hematoxylin eosin (HE) staining and kits. We performed systematical analyses on hepatic expression profiles of long noncoding RNAs (lncRNAs) and microRNAs in a high-fat diet (HFD)-induced steatotic animal model. The expression profile of targets was confirmed by bioinformatics analysis, luciferase assay, RT-PCR and western blot in AML12 cells. Results HFD treatment markedly observed hepatic fatty degeneration with primarily fat vacuoles, and increased TG level compared with control. According to microarray data, we found that transfection of Gm12664–001 siRNA (siRNA-118,306) obviously enhanced TG accumulation and repressed CAV1 in AML12 cells. Furthermore, the TG accumulation markedly increased by siRNA-mediated knockdown of CAV1 in AML12 cells. By bioinformatics prediction, AML12 cells were transfected of siRNA-118,306 obviously upregulated miR-295-5p. Transfection of miR-295-5p mimics significantly increased TG accumulation and obviously suppressed the target CAV1. Conclusions The results revealed that lncRNA Gm12664–001 attenuated hepatic lipid accumulation through negatively regulating miR-295-5p and enhancing CAV1 expression in AML12 cells.
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Affiliation(s)
- Qiao Zhang
- 1Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, Harbin, 150086 China.,2Department of Public Health College, Kunming Medical University, Kunming, 650550 China
| | - Jiemei Wang
- 1Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, Harbin, 150086 China
| | - Hongyin Li
- 1Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, Harbin, 150086 China
| | - Yuan Zhang
- 1Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, Harbin, 150086 China
| | - Xia Chu
- 1Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, Harbin, 150086 China
| | - Jianjun Yang
- 3School of Public Health, Ningxia Medical University, Yinchuan, 750004 China
| | - Ying Li
- 1Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, Harbin, 150086 China
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Kim JY, Kim KM, Yang JH, Cho SS, Kim SJ, Park SJ, Ahn SG, Lee GH, Yang JW, Lim SC, Kang KW, Ki SH. Induction of E6AP by microRNA-302c dysregulation inhibits TGF-β-dependent fibrogenesis in hepatic stellate cells. Sci Rep 2020. [PMID: 31949242 DOI: 10.1038/s41598-019-57322-w.] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Hepatic stellate cells (HSCs) are essential for liver fibrosis. E6 associated protein (E6AP) is one of the E3-ubiquitin-protein ligase and has been studied in proliferation and cellular stress. Currently, no information is available on the role of E6AP on transforming growth factor-β (TGF-β) signaling and hepatic fibrogenesis. This study examined whether E6AP is overexpressed in activated HSCs, and if so, its effect on hepatic fibrogenesis and the molecular mechanism. E6AP was expressed higher in HSCs than hepatocytes, and was up-regulated in activated HSCs, HSCs from the livers of carbon tetrachloride-injected mice, or TGF-β-treated LX-2 cells. The TGF-β-mediated E6AP up-regulation was not due to altered mRNA level nor protein stability. Thus, we performed microRNA (miRNA, miR) analysis and found that miR-302c was dysregulated in TGF-β-treated LX-2 cells or activated primary HSCs. We revealed that miR-302c was a modulator of E6AP. E6AP overexpression inhibited TGF-β-induced expression of plasminogen activator inhibitor-1 in LX-2 cells, albeit it was independent of Smad pathway. Additionally, E6AP inhibited TGF-β-mediated phosphorylation of mitogen-activated protein kinases. To conclude, E6AP overexpression due to decreased miR-302c in HSCs attenuated hepatic fibrogenesis through inhibition of the TGF-β-induced mitogen-activated protein kinase signaling pathway, implying that E6AP and other molecules may contribute to protection against liver fibrosis.
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Affiliation(s)
- Ji Young Kim
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea
| | - Kyu Min Kim
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea
| | - Ji Hye Yang
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea.,College of Korean Medicine, Dongshin University, Naju, Jeollanam-do, 58245, Republic of Korea
| | - Sam Seok Cho
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea
| | - Seung Jung Kim
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea
| | - Su Jung Park
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea
| | - Sang-Gun Ahn
- Department of Pathology, College of Dentistry, Chosun University, Gwangju, 61452, Republic of Korea
| | - Gum Hwa Lee
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea
| | - Jin Won Yang
- College of Pharmacy, Woosuk University, Wanju, Jeonbuk, 55338, Republic of Korea
| | - Sung Chul Lim
- College of Medicine, Chosun University, Gwangju, 61452, Republic of Korea
| | - Keon Wook Kang
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Sung Hwan Ki
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea.
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Induction of E6AP by microRNA-302c dysregulation inhibits TGF-β-dependent fibrogenesis in hepatic stellate cells. Sci Rep 2020; 10:444. [PMID: 31949242 PMCID: PMC6965100 DOI: 10.1038/s41598-019-57322-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 12/27/2019] [Indexed: 12/13/2022] Open
Abstract
Hepatic stellate cells (HSCs) are essential for liver fibrosis. E6 associated protein (E6AP) is one of the E3-ubiquitin-protein ligase and has been studied in proliferation and cellular stress. Currently, no information is available on the role of E6AP on transforming growth factor-β (TGF-β) signaling and hepatic fibrogenesis. This study examined whether E6AP is overexpressed in activated HSCs, and if so, its effect on hepatic fibrogenesis and the molecular mechanism. E6AP was expressed higher in HSCs than hepatocytes, and was up-regulated in activated HSCs, HSCs from the livers of carbon tetrachloride-injected mice, or TGF-β-treated LX-2 cells. The TGF-β-mediated E6AP up-regulation was not due to altered mRNA level nor protein stability. Thus, we performed microRNA (miRNA, miR) analysis and found that miR-302c was dysregulated in TGF-β-treated LX-2 cells or activated primary HSCs. We revealed that miR-302c was a modulator of E6AP. E6AP overexpression inhibited TGF-β-induced expression of plasminogen activator inhibitor-1 in LX-2 cells, albeit it was independent of Smad pathway. Additionally, E6AP inhibited TGF-β-mediated phosphorylation of mitogen-activated protein kinases. To conclude, E6AP overexpression due to decreased miR-302c in HSCs attenuated hepatic fibrogenesis through inhibition of the TGF-β-induced mitogen-activated protein kinase signaling pathway, implying that E6AP and other molecules may contribute to protection against liver fibrosis.
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40
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Singh SP, Barik RK. NonInvasive Biomarkers in Nonalcoholic Fatty Liver Disease: Are We There Yet? J Clin Exp Hepatol 2020; 10:88-98. [PMID: 32025168 PMCID: PMC6995889 DOI: 10.1016/j.jceh.2019.09.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2019] [Accepted: 09/15/2019] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. NAFLD encompasses a spectrum of disease ranging from simple steatosis (NAFL) to nonalcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma. However, despite the growing recognition of this important disease burden, there are significant challenges to accurately and noninvasively diagnose the various forms of NAFLD, especially to differentiate benign steatosis from the progressive NASH. This is of utmost importance because although liver biopsy is considered the current imperfect 'gold' standard for diagnosing NASH and staging fibrosis, it is an invasive procedure with significant limitations. Although, a number of noninvasive markers have been or are currently undergoing investigation, until date, no highly sensitive and specific tests are available to differentiate NASH from simple steatosis. At the moment, further investigations are needed before prediction models or blood-based biomarkers become available and acceptable for routine clinical care. There is a great need for developing inexpensive, easily accessible, highly sensitive and specific biomarkers that permit not only the identification of patients at high risk of adverse outcomes, but also the monitoring of disease progression and response after therapeutic interventions.
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Affiliation(s)
- Shivaram P. Singh
- Address for correspondence: Shivaram Prasad Singh, Professor, Dept. of Gastroenterology, S.C.B. Medical College, Cuttack, Odisha, 753007, India.
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Miguel V, Lamas S. Redox distress in organ fibrosis: The role of noncoding RNAs. OXIDATIVE STRESS 2020:779-820. [DOI: 10.1016/b978-0-12-818606-0.00037-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Fu Q, Lu Z, Fu X, Ma S, Lu X. MicroRNA 27b promotes cardiac fibrosis by targeting the FBW7/Snail pathway. Aging (Albany NY) 2019; 11:11865-11879. [PMID: 31881012 PMCID: PMC6949061 DOI: 10.18632/aging.102465] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Accepted: 11/08/2019] [Indexed: 04/09/2023]
Abstract
Our study aspires to understand the impact of miR-27b on myocardial fibrosis as well as its functional mechanism. 12 days post the ligation of coronary artery in rats, the expression of miR-27b in the peri-infarction region was elevated. Treating cultivated rat neonatal cardiac fibroblasts (CFs) with angiotensin II (AngII) also enhanced the miR-27b expression. Forced expression of miR-27b promoted the proliferation and collagen production in rat neonatal CFs, as revealed by cell counting, MTT assay, and quantitative reverse transcription-polymerase chain reaction. FBW7 was found to be the miR-27b's target since the overexpression of miR-27b reduced the transcriptional level of FBW7. The enhanced expression of FBW7 protein abrogated the effects of miR-27b in cultured CFs, while the siRNA silence of FBW7 promoted the pro-fibrosis activity of AngII. As to the mechanism, we found that the expression of FBW7 led to the degradation of Snail, which is an important regulator of cardiac epithelial-mesenchymal transitions. Importantly, inhibition of miR-27b abrogated the coronary artery ligation (CAL) induced cardiac fibrosis in vivo, suggesting that it might be a potential target for the treatment of fibrosis associated cardiac diseases.
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Affiliation(s)
- Qiang Fu
- Department of Cardiovascular Surgery, The General Hospital of Tianjin Medical University, Tianjin, China
| | - Zhihong Lu
- Department of Anatomy and Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Xiao Fu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Shitang Ma
- College of Life and Health Sciences, Anhui Science and Technology University, Chuzhou, Anhui, China
| | - Xiaochun Lu
- Department of Cardiology, The 2nd Medical Centre, PLA General Hospital, Beijing, China
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Ando Y, Yamazaki M, Yamada H, Munetsuna E, Fujii R, Mizuno G, Ichino N, Osakabe K, Sugimoto K, Ishikawa H, Ohashi K, Teradaira R, Ohta Y, Hamajima N, Hashimoto S, Suzuki K. Association of circulating miR-20a, miR-27a, and miR-126 with non-alcoholic fatty liver disease in general population. Sci Rep 2019; 9:18856. [PMID: 31827150 PMCID: PMC6906495 DOI: 10.1038/s41598-019-55076-z] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2019] [Accepted: 11/22/2019] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is closely associated with obesity, metabolic syndrome, and type II diabetes mellitus. Recently, circulating microRNAs (miRNAs) have been proposed as useful disease biomarkers. We examined whether circulating miRNAs, such as miR-20a, miR-27a, and miR-126, were useful biomarkers for NAFLD. We conducted a cross-sectional analysis of 527 subjects aged 39 years or older who had undergone a health examination in the Yakumo Study. Of the residents, 92 were diagnosed with NAFLD using a registered medical sonographer. Serum miR-20a, miR-27a and miR-126 levels were measured by quantitative real-time PCR. We then calculated the odds ratios for serum miRNA level changes according to the severity of NAFLD using normal liver status as the reference group. Serum levels of miR-20a and 27a, but not miR-126, were significantly lower in NAFLD subjects than normal subjects. Serum miR-20a and miR-27a levels were significantly lower in both male and female severe NAFLD subjects. Logistic regression analysis showed a significant relationship between low circulating miR-20a and 27a levels and severe NAFLD. Down-regulated circulating miR-20a and 27a levels were significantly associated with severe NAFLD in the general population. Circulating miR-20a and miR-27a may be useful biomarkers for severe NAFLD.
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Affiliation(s)
- Yoshitaka Ando
- Department of Biomedical and Analytical Sciences, Fujita Health University School of Medical Sciences, 1-98, Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan
| | - Mirai Yamazaki
- Department of Medical Technology, Kagawa Prefectural University of Health Sciences, 281-1, Murechohara, Takamatsu, Kagawa, 761-0123, Japan
| | - Hiroya Yamada
- Department of Hygiene, Fujita Health University School of Medicine, 1-98, Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan.
| | - Eiji Munetsuna
- Department of Biochemistry, Fujita Health University School of Medicine, 1-98, Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan
| | - Ryosuke Fujii
- Department of Preventive Medical Sciences, Fujita Health University School of Medical Sciences, 1-98, Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan
| | - Genki Mizuno
- Department of Joint Research Laboratory of Clinical Medicine, Fujita Health University Hospital, 1-98, Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan
| | - Naohiro Ichino
- Department of Clinical Physiology and Functional Imaging, Fujita Health University School of Medical Sciences, 1-98, Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan
| | - Keisuke Osakabe
- Department of Clinical Physiology and Functional Imaging, Fujita Health University School of Medical Sciences, 1-98, Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan
| | - Keiko Sugimoto
- Department of Clinical Physiology and Functional Imaging, Fujita Health University School of Medical Sciences, 1-98, Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan
| | - Hiroaki Ishikawa
- Department of Biomedical and Analytical Sciences, Fujita Health University School of Medical Sciences, 1-98, Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan
| | - Koji Ohashi
- Department of Biomedical and Analytical Sciences, Fujita Health University School of Medical Sciences, 1-98, Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan
| | - Ryoji Teradaira
- Department of Biomedical and Analytical Sciences, Fujita Health University School of Medical Sciences, 1-98, Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan
| | - Yoshiji Ohta
- Department of Chemistry, Fujita Health University School of Medicine, 1-98, Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan
| | - Nobuyuki Hamajima
- Department of Healthcare Administration, Nagoya University Graduate School of Medicine, 65, Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan
| | - Shuji Hashimoto
- Department of Hygiene, Fujita Health University School of Medicine, 1-98, Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan
| | - Koji Suzuki
- Department of Preventive Medical Sciences, Fujita Health University School of Medical Sciences, 1-98, Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan.
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Up-Regulated MicroRNA-27b Promotes Adipocyte Differentiation via Induction of Acyl-CoA Thioesterase 2 Expression. BIOMED RESEARCH INTERNATIONAL 2019; 2019:2916243. [PMID: 31930115 PMCID: PMC6942750 DOI: 10.1155/2019/2916243] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Revised: 07/22/2019] [Accepted: 08/04/2019] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is characterized by a spectrum of liver pathologies, from simple steatosis to steatohepatitis. Recent studies have increasingly noted the aberrant expression of microRNAs closely related to NAFLD pathologies. We have previously shown the presence of increased levels of microRNA-27b (miR-27b) in patients with NAFLD. In this study, we investigated the role of miR-27b in NAFLD by examining the impact of up-regulated miR-27b on the differentiation of preadipocytes into mature adipocytes. We found that miR-27b-3p remarkably enhances the adipocyte differentiation of 3T3-L1 cells associated with lipid accumulation and intracellular triglyceride contents. Furthermore, we have demonstrated not only that miR-27b-3p induces acyl-CoA thioesterase 2 (ACOT2) expression in 3T3-L1 cells, but also that the knockdown of ACOT2 suppresses lipid accumulation and adipocyte differentiation in both the presence and absence of miR-27b-3p treatment. Our data strongly suggest that the miR-27b-ACOT2 axis is an important pathway in adipocyte differentiation and may play a role in the pathogenesis of NAFLD.
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Cao A, Li X. Bilobalide protects H9c2 cell from oxygen-glucose-deprivation-caused damage through upregulation of miR-27a. ARTIFICIAL CELLS, NANOMEDICINE, AND BIOTECHNOLOGY 2019; 47:2980-2988. [PMID: 31322008 DOI: 10.1080/21691401.2019.1640708] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 05/15/2019] [Accepted: 05/15/2019] [Indexed: 01/20/2023]
Abstract
Background: Myocardial ischemia is a troublesome disease. Bilobalide possesses multiple biological functions. We researched the consequents of bilobalide in OGD-irritated H9c2 cells. Methods: OGD-stimulated H9c2 cells were treated by bilobalide, and/or transfected with miR-27a inhibitor or negative control. Use CCK-8 and flow cytometry to test cell activity and apoptosis, respectively. Luciferase activity experiment was to test targeting link between miR-27a and Tmub1. Levels of cell-cycle and apoptosis relative proteins and phosphorylation of PI3K/AKT and Wnt/β-catenin related proteins were detected through western blot. Results: OGD stimulation reduced cell activity and negatively regulated the expression of CDK4, CDK6 and CyclinD1. Cell apoptosis was increased and its related proteins were affected by OGD. Bilobalide administration reversed all the results above caused by OGD. OGD negatively regulated miR-27a while bilobalide upregulated miR-27a. miR-27a's target gene was Tmub1. The protection consequents of bilobalide were suppressed when cells were transfected with a miR-27a inhibitor that cell activity was reduced and apoptosis was raised. Attenuation in the phosphorylation level of PI3K, AKT and β-catenin by OGD was reversed by bilobalide, whereas there were opposite results after transfected with miR-27a inhibitor. Conclusion: Bilobalide relieved OGD-caused H9c2 cell damage, raising cell activity and attenuating apoptosis via upregulating miR-27a and activating of PI3K/AKT and Wnt/β-catenin signal pathway. Highlights Bilobalide alleviates OGD-induced H9c2 cell injury. Bilobalide upregulates miR-27a expression in OGD-stimulated H9c2 cells. Bilobalide alleviates cell injury by upregulation of miR-27a. Bilobalide actuates PI3K/AKT and Wnt/β-catenin pathways.
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Affiliation(s)
- Ailin Cao
- a Department of Cardiology, Affiliated Hospital of Jining Medical University , Jining , China
| | - Xiangting Li
- a Department of Cardiology, Affiliated Hospital of Jining Medical University , Jining , China
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Ren S, Chen J, Wang Q, Li X, Xu Y, Zhang X, Mu Y, Zhang H, Huang S, Liu P. MicroRNA-744/transforming growth factor β1 relationship regulates liver cirrhosis. Hepatol Int 2019; 13:814-825. [PMID: 31643031 PMCID: PMC7400990 DOI: 10.1007/s12072-019-09993-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Accepted: 09/28/2019] [Indexed: 01/18/2023]
Abstract
BACKGROUND MicroRNAs have added a new dimension to our understanding of liver cirrhosis (LC) and associated processes like the activation of hepatic stellate cells (HSCs). METHODS Serum samples were collected from 40 LC patients and 30 healthy donors. CCl4-induced LC mouse model in vivo and in vitro human HSC LX-2 and murine HSC JS-1 cells were researched. RESULTS The levels of serum microRNA (miR)-744 is inversely correlated with the severity of LC and is a reliable biomarker of LC. In CCl4-induced LC model, the abundance of miR-744 was reduced in both sera and livers compared with sham controls. Importantly, increasing miR-744 abundance with synthetic miR-744 Agomir alleviated liver fibrosis, a critical component of LC, while reducing miR-744 with Antagomir exacerbated it. To elucidate molecular mechanism underlying the suppressive role of miR-744 in LC, we observed that miR-744 and transforming growth factor β1 (TGFβ1) are inversely correlated in LC patients' sera as well as sera/livers from CCl4-induced LC mice. We demonstrated that miR-744 Agomir downregulated the expression of TGFβ1 and further confirmed that TGFβ1 mRNA was a bona fide miR-744 target in HSCs. Moreover, miR-744 Agomir reduced the degree of F-actin formation and cell proliferation while miR-744 Antagomir promoted these events, suggesting that miR-744 is a negative regulator of HSC activation. CONCLUSIONS MiR-744-led suppression in HSC activation is most likely through TGFβ1 because exogenous TGFβ1 nearly negated miR-744 Agomir's action. This study suggests that reduction of miR-744 is a reliable biomarker for LC and miR-744/TGFβ1 relationship is a key regulator of LC.
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Affiliation(s)
- Shuang Ren
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Traditional Chinese Medicine Department, First Affiliated Hospital of China Medical University, Shenyang, 201203, Liaoning, China
| | - Jiamei Chen
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Qinglan Wang
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Xuewei Li
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Ying Xu
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Xiao Zhang
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Yongping Mu
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Hua Zhang
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Shuang Huang
- Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL, 32611, USA.
| | - Ping Liu
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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Khatun M, Ray RB. Mechanisms Underlying Hepatitis C Virus-Associated Hepatic Fibrosis. Cells 2019; 8:E1249. [PMID: 31615075 PMCID: PMC6829586 DOI: 10.3390/cells8101249] [Citation(s) in RCA: 105] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 10/11/2019] [Accepted: 10/12/2019] [Indexed: 12/11/2022] Open
Abstract
Hepatitis C virus (HCV) infection often causes liver diseases, including fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Liver fibrosis is the outcome of the wound healing response to tissue damage caused by chronic HCV infection. This process is characterized by the excessive accumulation of extracellular matrix (ECM) proteins, such as collagen fibers secreted by activated hepatic stellate cells (HSCs). Activation of HSCs from the quiescent stage is mediated by different mechanisms, including pro-inflammatory cytokines and chemokines released from HCV-infected hepatocytes and liver macrophages. HCV infection modulates the expression of different microRNAs that can be transported and delivered to the HSCs via exosomes released from infected cells, also leading to the development of advanced disease pathogenesis. Although recent advancements in direct-acting antiviral (DAA) treatment can efficiently control viremia, there are very few treatment strategies available that can be effective at preventing pathogenesis in advanced liver fibrosis or cirrhosis in patients. Assessment of fibrosis is considered to be the major part of proper patient care and decision making in clinical practice. In this review, we highlighted the current knowledge of molecular mechanisms responsible for the progression of liver fibrosis in chronically HCV-infected patients, and currently available methods for evaluation of fibrosis in patients. A detailed understanding of these aspects at the molecular level may contribute to the development of new therapies targeting HCV-related liver fibrosis.
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Affiliation(s)
- Mousumi Khatun
- Department of Pathology, Saint Louis University, 1100 South Grand Boulevard, St. Louis, MO 63104, USA.
| | - Ratna B Ray
- Department of Pathology, Saint Louis University, 1100 South Grand Boulevard, St. Louis, MO 63104, USA.
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Zhang J, Cao Z, Yang G, You L, Zhang T, Zhao Y. MicroRNA-27a (miR-27a) in Solid Tumors: A Review Based on Mechanisms and Clinical Observations. Front Oncol 2019; 9:893. [PMID: 31572683 PMCID: PMC6751266 DOI: 10.3389/fonc.2019.00893] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Accepted: 08/27/2019] [Indexed: 12/11/2022] Open
Abstract
MicroRNAs (miRNAs) are a family of highly conserved, non-coding single-stranded RNAs transcribed as ~70 nucleotide precursors to an 18–22 nucleotide product (1). miRNAs can silence their homologous target genes at the post-transcriptional level, and these genes have been revealed to play an important role in tumorigenesis, invasion and metastasis (2). MicroRNA-27a (miR-27a), transcripted by miR-27a gene, has proved to implicate with many kinds of solid tumors, showing potential as a useful biomarker or drug target for clinical application. However, even though miR-27a has been reported in many cancers, the mechanism and signal pathways of miR-27 in oncogenesis, invasion, and metastasis are still obscure. Moreover, recent studies show that miR-27a pays an important role in epithelial-mesenchymal-transition, regulating tumor immune response, and chemoresistance. In this review, we summarize the current literature, demonstrate the established link between miR-27a and tumorigenesis, and focus on recently identified mechanisms. The review also aims to demonstrate the potential of miR-27a as a diagnostic and/or prognostic biomarker in solid tumors and to discuss the possibilities of targeted therapy and drug design.
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Affiliation(s)
- Jingcheng Zhang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhe Cao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Gang Yang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lei You
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Taiping Zhang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yupei Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Abstract
The aim of this study was to investigate the alterations of urinary microRNA (miRNA) expression and explore its clinical significance in patients with chronic hepatitis B (CHB).The expression levels of urinary miRNA were detected by miRNA microarray and quantitative reverse transcription polymerase chain reaction (qRT-PCR) from 106 CHB and 40 healthy controls (Ctrl) subjects. The correlation between the levels of miRNA expression and clinical characteristics were analyzed. Receiver-operator characteristic (ROC) curves were generated to determine the specificity and sensitivity of each individual miRNA. MiRNAs expression were further measured by PCR from exosomes, which were isolated from urine samples. LX2 cells were transfected with miRNA inhibitor and accumulation of cytoplasmic lipid droplets was analyzed by Oil Red O staining.miRNA expression profile analysis showed that 22 miRNAs were upregulated and 55 miRNAs were downregulated in CHB patients compared with Ctrl subjects (fold-change>1.5 and P < .05). miR-92b-3p, miR-770-5p, miR-5196-5p, and miR-7855-5p were significantly higher (P < .0001) in CHB subjects than in Ctrl subjects. ROC curve analysis showed that these four miRNAs were sensitive and specific enough to distinguish CHB and Ctrl subjects. The levels of miR-92b-3p expression were negatively correlated with total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and APOA-1. Moreover, in vitro experiments indicated that inhibition of miR-92b-3p increased lipid droplet formation in LX2 cells.Aberrant expression of miRNAs has been observed in urine of CHB patients. Our findings may provide novel insights into the pathogenesis of CHB and may assist in the diagnosis of patients with CHB.
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Affiliation(s)
- Jia-Wei Shang
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research
| | - Xiu-Li Yan
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, PR China
| | - Hui Zhang
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research
| | - Shi-Bing Su
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research
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Kiamehr M, Heiskanen L, Laufer T, Düsterloh A, Kahraman M, Käkelä R, Laaksonen R, Aalto-Setälä K. Dedifferentiation of Primary Hepatocytes is Accompanied with Reorganization of Lipid Metabolism Indicated by Altered Molecular Lipid and miRNA Profiles. Int J Mol Sci 2019; 20:ijms20122910. [PMID: 31207892 PMCID: PMC6627955 DOI: 10.3390/ijms20122910] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Revised: 06/10/2019] [Accepted: 06/11/2019] [Indexed: 02/06/2023] Open
Abstract
Aim: Primary human hepatocytes (PHHs) undergo dedifferentiation upon the two-dimensional (2D) culture, which particularly hinders their utility in long-term in vitro studies. Lipids, as a major class of biomolecules, play crucial roles in cellular energy storage, structure, and signaling. Here, for the first time, we mapped the alterations in the lipid profile of the dedifferentiating PHHs and studied the possible role of lipids in the loss of the phenotype of PHHs. Simultaneously, differentially expressed miRNAs associated with changes in the lipids and fatty acids (FAs) of the dedifferentiating PHHs were investigated. Methods: PHHs were cultured in monolayer and their phenotype was monitored morphologically, genetically, and biochemically for five days. The lipid and miRNA profile of the PHHs were analyzed by mass spectrometry and Agilent microarray, respectively. In addition, 24 key genes involved in the metabolism of lipids and FAs were investigated by qPCR. Results: The typical morphology of PHHs was lost from day 3 onward. Additionally, ALB and CYP genes were downregulated in the cultured PHHs. Lipidomics revealed a clear increase in the saturated fatty acids (SFA) and monounsaturated fatty acids (MUFA) containing lipids, but a decrease in the polyunsaturated fatty acids (PUFA) containing lipids during the dedifferentiation of PHHs. In line with this, FASN, SCD, ELOVL1, ELOVL3, and ELOVL7 were upregulated but ELOVL2 was downregulated in the dedifferentiated PHHs. Furthermore, differentially expressed miRNAs were identified, and the constantly upregulated miR-27a and miR-21, and downregulated miR-30 may have regulated the synthesis, accumulation and secretion of PHH lipids during the dedifferentiation. Conclusion: Our results showed major alterations in the molecular lipid species profiles, lipid-metabolizing enzyme expression as wells as miRNA profiles of the PHHs during their prolonged culture, which in concert could play important roles in the PHHs’ loss of phenotype. These findings promote the understanding from the dedifferentiation process and could help in developing optimal culture conditions, which better meet the needs of the PHHs and support their original phenotype.
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Affiliation(s)
- Mostafa Kiamehr
- BioMediTech, Faculty of Medicine and Health Technology, Tampere University, 33520 Tampere, Finland.
| | | | - Thomas Laufer
- Hummingbird Diagnostics GmbH, 69120 Heidelberg, Germany.
- Department of Human Genetics, Saarland University, 66421 Homburg, Germany.
| | | | - Mustafa Kahraman
- Hummingbird Diagnostics GmbH, 69120 Heidelberg, Germany.
- Clinical Bioinformatics, Saarland University, 66123 Saarbrücken, Germany.
| | - Reijo Käkelä
- Helsinki University Lipidomics Unit, Helsinki Institute for Life Science (HiLIFE) and Molecular and Integrative Biosciences Research Programme, University of Helsinki, FI-00014 Helsinki, Finland.
| | - Reijo Laaksonen
- BioMediTech, Faculty of Medicine and Health Technology, Tampere University, 33520 Tampere, Finland.
- Zora Biosciences, 02150 Espoo, Finland.
| | - Katriina Aalto-Setälä
- BioMediTech, Faculty of Medicine and Health Technology, Tampere University, 33520 Tampere, Finland.
- Heart Hospital, Tampere University Hospital, 33520 Tampere, Finland.
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