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Li LP, Chen XY, Liu HB, Zhu Y, Xie MJ, Li YJ, Luo M, Albahde M, Zhang HY, Lou JY. Oxidative stress-induced circSOD2 inhibits osteogenesis through sponging miR-29b in metabolic-associated fatty liver disease. World J Gastroenterol 2025; 31:98027. [PMID: 40061587 PMCID: PMC11886039 DOI: 10.3748/wjg.v31.i9.98027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Revised: 11/24/2024] [Accepted: 01/23/2025] [Indexed: 02/18/2025] Open
Abstract
BACKGROUND Metabolic-associated fatty liver disease (MAFLD) is characterized by lipid accumulation in hepatocytes and is closely associated with oxidative stress. Increasing clinical evidence indicates that MAFLD is linked to bone metabolic disorders, including osteoporosis. Recent studies indicate that the expression profiles of liver circular RNAs (circRNAs) are altered in MAFLD. However, the effects of these changes on bone metabolism remain poorly understood. AIM To investigate the effects and mechanism of differently expressed circRNAs secreted by the liver on osteogenic differentiation in MAFLD. METHODS RNA sequencing was performed to identify highly expressed circRNAs in the liver, validated by quantitative real-time reverse transcription polymerase chain reaction, and localized using fluorescence in situ hybridization (FISH). A mouse model induced by a high-fat diet was used to simulate MAFLD. RESULTS CircSOD2 was significantly upregulated in liver tissues and primary hepatocytes from subjects with MAFLD. CircSOD2 was induced by oxidative stress and attenuated by antioxidants in the mouse model. In addition, circSOD2 was delivered from hepatocytes to bone marrow mesenchymal stem cells (BMSCs). Furthermore, circSOD2 inhibited the osteogenic differentiation of BMSCs and in vivo bone formation by sponging miR-29b. Moreover, miR-29b inhibition reversed the stimulatory effect of circSOD2 silencing on osteogenic differentiation of BMSCs and in vivo bone formation. Mechanistically, the interaction between circSOD2 and miR-29b confirmed through a luciferase reporter assay and the co-localization in the cytoplasm evidenced by FISH indicated that circSOD2 acted as a sponge for miR-29b. CONCLUSION This study provides a novel mechanism underlying the liver-bone crosstalk, demonstrating that circSOD2 upregulation in hepatocytes, induced by oxidative stress, inhibits osteogenic differentiation of BMSCs by sponging miR-29b. These findings offer a better understanding of the relationship between MAFLD and osteoporosis.
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Affiliation(s)
- Liang-Ping Li
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
| | - Xiao-Ying Chen
- Department of Emergency Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
| | - Hong-Bo Liu
- Department of General Surgery, The People’s Hospital of Songyang, Lishui 323400, Zhejiang Province, China
| | - Yi Zhu
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
| | - Min-Jie Xie
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
| | - Yong-Jian Li
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
| | - Meng Luo
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
| | - Mugahed Albahde
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
| | - Hong-Yu Zhang
- Department of General Surgery, The People’s Hospital of Songyang, Lishui 323400, Zhejiang Province, China
| | - Jian-Ying Lou
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
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Wang X, Liu J, Yu K, Huang Z, Liu H, Li X. Association between TyG-related parameters and NAFLD risk in Japanese non-obese population. Sci Rep 2025; 15:7119. [PMID: 40016248 PMCID: PMC11868368 DOI: 10.1038/s41598-025-88478-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Accepted: 01/28/2025] [Indexed: 03/01/2025] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) constitutes a substantial proportion of cases among the non-obese population, yet it is frequently overlooked. Studies investigating the association between triglyceride-glucose (TyG)-related parameters (TyG-BMI, TyG-WC, TyG-WHtR) and NAFLD in non-obese individuals is limited. Thus, this study aims to investigate the association between TyG-related parameters and NAFLD in non-obese individuals to improve early detection and intervention strategies for NAFLD in this population. A cross-sectional analysis was conducted using data from the NAFLD database, including 11,987 participants who underwent health examinations between 2004 and 2015. Logistic regression models were employed to evaluate the relationship between TyG-related parameters and NAFLD risk, incorporating cubic spline functions and smooth curve fitting to identify potential nonlinear relationships. ROC curve analysis was conducted to assess the predictive performance of thee parameters. After controlling for confounding variables, the incidence of NAFLD in non-obese individuals increased with higher TyG-related parameters. Notably, nonlinear relationships between the TyG index and its related parameters regarding NAFLD risk were identified. The areas under the ROC curve for the TyG index and its related parameters were 0.7984, 0.8553, 0.8584, and 0.8353, respectively. Importantly, the predictive ability of the TyG index and its related parameters was stronger in the female population than in that of males. A positive and nonlinear relationship exists between the TyG-related parameters in relation to the risk of NAFLD. The TyG-related parameters exhibit predictive capabilities for NAFLD, with TyG-related parameters demonstrating greater strength than the TyG index itself.
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Affiliation(s)
- Xiuli Wang
- Department of Gastroenterology, The First People's Hospital of Chenzhou, Chenzhou, 423001, China
| | - Jie Liu
- Department of Emergency Medicine, Shenzhen New Frontier United Family Hospital, Shenzhen, 518000, China
| | - Ke Yu
- Department of Respiratory and Critical Care Medicine, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen, 518035, China
| | - Zhenhua Huang
- Department of Emergency Medicine, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen, 518035, China
| | - Hanxiong Liu
- Department of Gastroenterology, The First People's Hospital of Chenzhou, Chenzhou, 423001, China.
| | - Xiang Li
- Department of Medical Ultrasonics, Shenzhen Pingle orthopaedic hospital, Shenzhen, 518000, China.
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Babakhanzadeh E, Hoseininasab FA, Khodadadian A, Nazari M, Hajati R, Ghafouri-Fard S. Circular RNAs: novel noncoding players in male infertility. Hereditas 2024; 161:46. [PMID: 39551760 PMCID: PMC11572108 DOI: 10.1186/s41065-024-00346-8] [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: 05/07/2024] [Accepted: 11/05/2024] [Indexed: 11/19/2024] Open
Abstract
Infertility is a global problem being associated with emotional and financial burden. Recent studies have shown contribution of a group of non-coding RNAs, namely circular RNAs (circRNAs) to the etiology of some infertility conditions. CircRNA are transcribed from exons and form a circular RNA molecule, being abundant in eukaryotes. Traditionally classified as non-coding RNA, these transcripts are endogenously produced through either non-canonical back-splicing or linear splicing, typically produced from precursor messenger ribonucleic acid (pre-mRNA). While during the canonical splicing process the 3' end of the exon is joined to the 5' end of the succeeding exon to form linear mRNA, during backsplicing, the 3' end to the 5' end of the same exon is joined to make a circular molecule. circRNAs are involved in the regulation of several aspects of spermatogenesis. They appear to influence how stem germ cells grow and divide during the sperm production process. Malfunctions in circRNA activity could contribute to male infertility issues stemming from abnormalities in spermatogenesis. In the current review, we highlight the exciting potential of circRNAs as key players in the male fertility.
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Affiliation(s)
- Emad Babakhanzadeh
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Medical Genetics, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | | | - Ali Khodadadian
- Department of Medical Genetics, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Majid Nazari
- Department of Medical Genetics, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Reza Hajati
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Wu LF, Zhou ZJ, Zeng YH, Yang SL, Zhang QY. Circular RNA RRM2 alleviates metabolic dysfunction-associated steatotic liver disease by targeting miR-142-5p to increase NRG1 expression. Am J Physiol Gastrointest Liver Physiol 2024; 327:G485-G498. [PMID: 39259911 DOI: 10.1152/ajpgi.00255.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 07/08/2024] [Accepted: 07/15/2024] [Indexed: 09/13/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic liver condition worldwide, demanding further investigation into its pathogenesis. Circular RNAs (circRNAs) are emerging as pivotal regulators in MASLD processes, yet their pathological implications in MASLD remain poorly understood. This study focused on elucidating the role of circular RNA ribonucleotide reductase subunit M2 (circRRM2) in MASLD progression. In this study, we used both in vitro and in vivo MASLD models using long-chain-free fatty acid (FFA)-treated hepatocytes and high-fat diet (HFD)-induced MASLD in mice, respectively. We determined the expression patterns of circRRM2, microRNA-142-5p (miR-142-5p), and neuregulin 1 (NRG1) in livers of MASLD-afflicted mice and MASLD hepatocytes by RT-qPCR. Dual-luciferase reporter assays verified the binding relationships among circRRM2, miR-142-5p, and NRG1. We conducted further analyses of their roles in MASLD hepatocytes and modulated circRRM2, miR-142-5p, and NRG1 expression in vitro by transfection. Our findings were validated in vivo. The results demonstrated reduced levels of circRRM2 and NRG1, along with elevated miR-142-5p expression in MASLD livers and hepatocytes. Overexpression of circRRM2 downregulated lipogenesis-related genes and decreased triglycerides accumulation in livers of MASLD mice. MiR-142-5p, which interacts with circRRM2, effectively counteracted the effects of circRRM2 in MASLD hepatocytes. Furthermore, NRG1 was identified as a miR-142-5p target, and its overexpression mitigated the regulatory impact of miR-142-5p on MASLD hepatocytes. In conclusion, circRRM2, via its role as a miR-142-5p sponge, upregulating NRG1, possibly influenced triglycerides accumulation in both in vitro and in vivo MASLD models.NEW & NOTEWORTHY CircRRM2 expression was downregulated in free fatty acid (FFA)-challenged hepatocytes and high-fat diet (HFD) fed mice. Overexpressed circular RNA ribonucleotide reductase subunit M2 (circRRM2) attenuated metabolic dysfunction-associated steatotic liver disease (MASLD) development by suppressing FFA-induced triglycerides accumulation. CircRRM2 targeted microRNA-142-5p (miR-142-5p), which served as an upstream inhibitor of neuregulin 1 (NRG1) and collaboratively regulated MASLD progression.
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Affiliation(s)
- Long-Fei Wu
- Department of Preventive Medicine, Shantou University Medical College, Shantou, People's Republic of China
- Department of Cardiology, People's Hospital of Xinjin District, Chengdu, People's Republic of China
- First Affiliated Hospital of Shantou University Medical College, Shantou, People's Republic of China
| | - Zhi-Jiang Zhou
- Department of Preventive Medicine, Shantou University Medical College, Shantou, People's Republic of China
| | - Yu-Heng Zeng
- Department of Preventive Medicine, Shantou University Medical College, Shantou, People's Republic of China
| | - Sheng-Li Yang
- First Affiliated Hospital of Shantou University Medical College, Shantou, People's Republic of China
| | - Qing-Ying Zhang
- Department of Preventive Medicine, Shantou University Medical College, Shantou, People's Republic of China
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Wang Y, Tian X, Wang Z, Liu D, Zhao X, Sun X, Tu Z, Li Z, Zhao Y, Zheng S, Yao J. A novel peptide encoded by circ-SLC9A6 promotes lipid dyshomeostasis through the regulation of H4K16ac-mediated CD36 transcription in NAFLD. Clin Transl Med 2024; 14:e1801. [PMID: 39107881 PMCID: PMC11303264 DOI: 10.1002/ctm2.1801] [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: 03/18/2024] [Revised: 07/16/2024] [Accepted: 07/26/2024] [Indexed: 08/10/2024] Open
Abstract
BACKGROUND As the leading cause of end-stage liver disease, nonalcoholic fatty liver disease (NAFLD) is mainly induced by lipid dyshomeostasis. The translation of endogenous circular RNAs (circRNAs) is closely related to the progression of various diseases, but the involvement of circRNAs in NAFLD has not been determined. METHODS Combined high-throughput circRNA profiles were used to identify circRNAs with translational potential. The underlying molecular mechanisms were investigated by RNA sequencing, pull-down/MS and site-specific mutagenesis. RESULTS In this study, we focused on circ-SLC9A6, an abnormally highly expressed circRNA in human and mouse liver tissue during NAFLD development that exacerbates metabolic dyshomeostasis in hepatocytes by encoding a novel peptide called SLC9A6-126aa in vivo and in vitro. YTHDF2-mediated degradation of m6A-modified circ-SLC9A6 was found to be essential for the regulation of SLC9A6-126aa expression. We further found that the phosphorylation of SLC9A6-126aa by AKT was crucial for its cytoplasmic localization and the maintenance of physiological homeostasis, whereas high-fat stress induced substantial translocation of unphosphorylated SLC9A6-126aa to the nucleus, resulting in a vicious cycle of lipid metabolic dysfunction. Nuclear SLC9A6-126aa promotes transcriptional activation of the target gene CD36 and enhances its occupancy of the CD36 promoter locus by regulating MOF-mediated histone H4K16 acetylation. Hepatic CD36 depletion significantly ameliorated hyperactivated MAPK signalling and lipid disturbance in SLC9A6-126aa transgenic mice. Clinically, increasing levels of SLC9A6-126aa were observed during NAFLD progression and were found to be positively correlated with the CD36 and MAPK cascades. CONCLUSION This study revealed the role of circ-SLC9A6-derived SLC9A6-126aa in the epigenetic modification-mediated regulation of lipid metabolism. Our findings may provide promising therapeutic targets for NAFLD and new insights into the pathological mechanisms of metabolic diseases. HIGHLIGHTS Under normal circumstances, driven by m6A modification, YTHDF2 directly recognizes and degrades circ-SLC9A6, thereby inhibiting the translation of SLC9A6-126aa. Additionally, AKT1 phosphorylates and inhibits the nuclear translocation of SLC9A6-126aa. In NAFLD, lipid overload leads to YTHDF2 and AKT1 deficiency, ultimately increasing the expression and nuclear import of SLC9A6-126aa. Nuclear SLC9A6-126aa binds directly to the CD36 promoter and initiates CD36 transcription, which induces lipid dyshomeostasis.
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Affiliation(s)
- Yue Wang
- Department of PharmacologyDalian Medical UniversityDalianChina
| | - Xinyao Tian
- Department of SurgeryDivision of Hepatobiliary and Pancreatic SurgeryThe Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Department of SurgeryDivision of Hepatobiliary and Pancreatic SurgeryThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Zhecheng Wang
- Department of PharmacologyDalian Medical UniversityDalianChina
| | - Deshun Liu
- Department of General SurgeryThe Second Affiliated Hospital of Dalian Medical UniversityDalianChina
| | - Xuzi Zhao
- Department of General SurgeryThe Second Affiliated Hospital of Dalian Medical UniversityDalianChina
| | - Xin Sun
- Department of PharmacologyDalian Medical UniversityDalianChina
| | - Zuoyu Tu
- Department of PharmacologyDalian Medical UniversityDalianChina
| | - Zekuan Li
- Department of SurgeryDivision of Hepatobiliary and Pancreatic SurgeryThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Yan Zhao
- Department of PharmacologyDalian Medical UniversityDalianChina
| | - Shusen Zheng
- Department of SurgeryDivision of Hepatobiliary and Pancreatic SurgeryThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Department of Hepatobiliary and Pancreatic SurgeryDepartment of Liver TransplantationShulan (Hangzhou) HospitalHangzhouChina
| | - Jihong Yao
- Department of PharmacologyDalian Medical UniversityDalianChina
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Zailaie SA, Khoja BB, Siddiqui JJ, Mawardi MH, Heaphy E, Aljagthmi A, Sergi CM. Investigating the Role of Non-Coding RNA in Non-Alcoholic Fatty Liver Disease. Noncoding RNA 2024; 10:10. [PMID: 38392965 PMCID: PMC10891858 DOI: 10.3390/ncrna10010010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 01/22/2024] [Accepted: 01/27/2024] [Indexed: 02/25/2024] Open
Abstract
Non-coding RNAs (ncRNAs) are RNA molecules that do not code for protein but play key roles in regulating cellular processes. NcRNAs globally affect gene expression in diverse physiological and pathological contexts. Functionally important ncRNAs act in chromatin modifications, in mRNA stabilization and translation, and in regulation of various signaling pathways. Non-alcoholic fatty liver disease (NAFLD) is a set of conditions caused by the accumulation of triacylglycerol in the liver. Studies of ncRNA in NAFLD are limited but have demonstrated that ncRNAs play a critical role in the pathogenesis of NAFLD. In this review, we summarize NAFLD's pathogenesis and clinical features, discuss current treatment options, and review the involvement of ncRNAs as regulatory molecules in NAFLD and its progression to non-alcoholic steatohepatitis (NASH). In addition, we highlight signaling pathways dysregulated in NAFLD and review their crosstalk with ncRNAs. Having a thorough understanding of the disease process's molecular mechanisms will facilitate development of highly effective diagnostic and therapeutic treatments. Such insights can also inform preventive strategies to minimize the disease's future development.
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Affiliation(s)
- Samar A. Zailaie
- Research Center, King Faisal Specialist Hospital & Research Center-Jeddah (KFSHRC-J), Jeddah 21499, Saudi Arabia; (S.A.Z.); (B.B.K.); (E.H.); (A.A.)
| | - Basmah B. Khoja
- Research Center, King Faisal Specialist Hospital & Research Center-Jeddah (KFSHRC-J), Jeddah 21499, Saudi Arabia; (S.A.Z.); (B.B.K.); (E.H.); (A.A.)
| | - Jumana J. Siddiqui
- Biochemistry Department, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
| | - Mohammad H. Mawardi
- Medicine Department, Gastroenterology Section, King Faisal Specialist Hospital & Research Center-Jeddah (KFSHRC-J), Jeddah 21499, Saudi Arabia;
| | - Emily Heaphy
- Research Center, King Faisal Specialist Hospital & Research Center-Jeddah (KFSHRC-J), Jeddah 21499, Saudi Arabia; (S.A.Z.); (B.B.K.); (E.H.); (A.A.)
| | - Amjad Aljagthmi
- Research Center, King Faisal Specialist Hospital & Research Center-Jeddah (KFSHRC-J), Jeddah 21499, Saudi Arabia; (S.A.Z.); (B.B.K.); (E.H.); (A.A.)
| | - Consolato M. Sergi
- Children’s Hospital of Eastern Ontario (CHEO), University of Ottawa, Ottawa, ON K1H 8L1, Canada
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB T6G 2R3, Canada
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Zeng Q, Liu CH, Ampuero J, Wu D, Jiang W, Zhou L, Li H, Bai L, Romero-Gómez M, Tang H. Circular RNAs in non-alcoholic fatty liver disease: Functions and clinical significance. RNA Biol 2024; 21:1-15. [PMID: 38113132 PMCID: PMC10761141 DOI: 10.1080/15476286.2023.2290769] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/11/2023] [Indexed: 12/21/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), which affects approximately 25% of the global population, is an urgent health issue leading to various metabolic comorbidities. Circular RNAs (circRNAs), covalently closed RNA molecules, are characterized by ubiquity, diversity, stability, and conservatism. Indeed, they participate in various biological processes via distinct mechanisms that could modify the natural history of NAFLD. In this review, we briefly introduce the biogenesis, characteristics, and biological functions of circRNAs. Furthermore, we summarize circRNAs expression profiles in NAFLD by intersecting seven sequencing data sets and describe the cellular roles of circRNAs and their potential advantages as biomarkers of NAFLD. In addition, we emphatically discuss the exosomal non-coding RNA sorting mechanisms and possible functions in recipient cells. Finally, we extensively discuss the potential application of targeting disease-related circRNAs and competing endogenous RNA networks through gain-of-function and loss-of-function approaches in targeted therapy of NAFLD.
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Affiliation(s)
- Qingmin Zeng
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Chang-Hai Liu
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Javier Ampuero
- Digestive Diseases Unit, Virgen del Rocío University Hospital. SeLiver group at Institute of Biomedicine of Seville (IBIS: HUVRocío/CSIC/US). University of Seville, Seville, Spain
| | - Dongbo Wu
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Disease, West China Hospital, Sichuan University, Chengdu, China
| | - Wei Jiang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Disease, West China Hospital, Sichuan University, Chengdu, China
| | - Lingyun Zhou
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Disease, West China Hospital, Sichuan University, Chengdu, China
| | - Hong Li
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Disease, West China Hospital, Sichuan University, Chengdu, China
| | - Lang Bai
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Disease, West China Hospital, Sichuan University, Chengdu, China
| | - Manuel Romero-Gómez
- Digestive Diseases Unit, Virgen del Rocío University Hospital. SeLiver group at Institute of Biomedicine of Seville (IBIS: HUVRocío/CSIC/US). University of Seville, Seville, Spain
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Disease, West China Hospital, Sichuan University, Chengdu, China
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Chen F, Huang J, Zhao N, Jin F, Fan Q, Du E, Wei J. Dietary Morus alba L. leaf supplementation improves hepatic lipid accumulation of laying hens via downregulating CircACACA. Poult Sci 2023; 102:103042. [PMID: 37716232 PMCID: PMC10511811 DOI: 10.1016/j.psj.2023.103042] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 08/08/2023] [Accepted: 08/14/2023] [Indexed: 09/18/2023] Open
Abstract
Fatty liver hemorrhagic syndrome (FLHS) is the most common metabolic disease in laying hens. Morus alba L. (mulberry) leaf has the effect of regulating lipid metabolism. We evaluated the effects of dietary 3% mulberry leaf (MUL) supplementation in production performance, egg quality, and liver lipid deposition in laying hens. Differentially expressed genes and circRNAs in the liver were identified using whole-transcriptome sequencing. We also evaluated the effects of the MUL extract using an in vitro model of primary hepatocytes induced by free fatty acids and explored the role of key circRNAs in this process. Dietary supplementation with 3% MUL alleviated liver steatosis in laying hens, as shown by decreased fatty liver color score, relative liver weight (P < 0.01), and triglyceride levels (P < 0.05), and showed a tendency to reduce the mortality rate of laying hens (P = 0.09). In addition, mulberry leaf supplementation significantly reduced cholesterol content in egg yolk (P < 0.01). Dietary mulberry leaf supplementation downregulated the expression of genes involved in fatty acid and cholesterol biosynthesis, and upregulated the expression of fatty acid oxidation-related genes in the liver. CircACACA, which is derived from exons 2 and 3 of the acetyl-CoA carboxylase alpha (ACACA) pre-mRNA, was significantly reduced in the MUL group (P < 0.01). Upregulation of circACACA expression reversed the lipid-lowering effect of mulberry leaf extract by upregulating sterol regulatory element-binding proteins 1 c (SREBP-1c) and fatty acid synthase (FASN) (P < 0.05). Overall, mulberry leaf is an effective therapeutic strategy for FLHS in hens and can improve liver lipid metabolism by downregulating circACACA.
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Affiliation(s)
- Fang Chen
- Institute of Animal Husbandry and Veterinary Sciences, Hubei Academy of Agricultural Sciences/Hubei Key Laboratory of Animal Embryo and Molecular Breeding, Wuhan 430064, China; Key Laboratory of Prevention and Control Agents for Animal Bacteriosis, Wuhan 430064, China
| | - Jing Huang
- Institute of Animal Husbandry and Veterinary Sciences, Hubei Academy of Agricultural Sciences/Hubei Key Laboratory of Animal Embryo and Molecular Breeding, Wuhan 430064, China
| | - Na Zhao
- Institute of Animal Husbandry and Veterinary Sciences, Hubei Academy of Agricultural Sciences/Hubei Key Laboratory of Animal Embryo and Molecular Breeding, Wuhan 430064, China
| | - Feng Jin
- Institute of Animal Husbandry and Veterinary Sciences, Hubei Academy of Agricultural Sciences/Hubei Key Laboratory of Animal Embryo and Molecular Breeding, Wuhan 430064, China
| | - Qiwen Fan
- Institute of Animal Husbandry and Veterinary Sciences, Hubei Academy of Agricultural Sciences/Hubei Key Laboratory of Animal Embryo and Molecular Breeding, Wuhan 430064, China
| | - Encun Du
- Institute of Animal Husbandry and Veterinary Sciences, Hubei Academy of Agricultural Sciences/Hubei Key Laboratory of Animal Embryo and Molecular Breeding, Wuhan 430064, China
| | - Jintao Wei
- Institute of Animal Husbandry and Veterinary Sciences, Hubei Academy of Agricultural Sciences/Hubei Key Laboratory of Animal Embryo and Molecular Breeding, Wuhan 430064, China.
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Rao G, Peng X, Tian Y, Fu X, Zhang Y. Circular RNAs in hepatocellular carcinoma: biogenesis, function, and pathology. Front Genet 2023; 14:1106665. [PMID: 37485335 PMCID: PMC10361733 DOI: 10.3389/fgene.2023.1106665] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Accepted: 06/16/2023] [Indexed: 07/25/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide. Both genetic and environmental factors through a multitude of underlying molecular mechanisms participate in the pathogenesis of HCC. Recently, numerous studies have shown that circular RNAs (circRNAs), an emerging class of non-coding RNAs characterized by the presence of covalent bonds linking 3' and 5' ends, play an important role in the initiation and progression of cancers, including HCC. In this review, we outline the current status of the field of circRNAs, with an emphasis on the functions and mechanisms of circRNAs in HCC and its microenvironment. We also summarize and discuss recent advances of circRNAs as biomarkers and therapeutic targets. These efforts are anticipated to throw new insights into future perspectives about circRNAs in basic, translational and clinical research, eventually advancing the diagnosis, prevention and treatment of HCC.
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Affiliation(s)
- Guocheng Rao
- Department of Endocrinology and Metabolism, Cancer Center West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Department of Endocrinology and Metabolism, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, China
| | - Xi Peng
- Department of Endocrinology and Metabolism, Cancer Center West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Department of Endocrinology and Metabolism, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, China
| | - Yan Tian
- Department of Endocrinology and Metabolism, Cancer Center West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xianghui Fu
- Department of Endocrinology and Metabolism, Cancer Center West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Department of Endocrinology and Metabolism, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, China
| | - Yuwei Zhang
- Department of Endocrinology and Metabolism, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, China
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10
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Zhang W, Lin S, Jiao Z, An L, Xie T, Wu J, Zhang L. The Mouse CircGHR Regulates Proliferation, Differentiation and Apoptosis of Hepatocytes and Myoblasts. Genes (Basel) 2023; 14:1207. [PMID: 37372387 DOI: 10.3390/genes14061207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 05/14/2023] [Accepted: 05/29/2023] [Indexed: 06/29/2023] Open
Abstract
The anterior pituitary gland of animals secretes growth hormone (GH) to bind to the growth hormone receptor (GHR) on the liver cell membrane through the blood circulation, thereby promoting the downstream gene insulin-like growth factor-1 (IGF1) expression, which is the canonical GH-GHR-IGF1 signaling pathway. Therefore, the amount of GHR and the integrity of its structure will affect animal growth and development. In the previous study, we found that the mouse GHR gene can transcribe a circular transcript named circGHR. Our group cloned the full-length of the mouse circGHR and analyzed its spatiotemporal expression profile. In this study, we further predicted the open reading frame of circGHR with bioinformatics, subsequently constructed a Flag-tagged protein vector and preliminarily verified its coding potential with western blot. Additionally, we found that circGHR could inhibit the proliferation of NCTC469 cells and has a tendency to inhibit cell apoptosis, while for C2C12 cells, it showed a tendency to inhibit cell proliferation and promote its differentiation. Overall, these results suggested that the mouse circGHR had the potential to encode proteins and affect cell proliferation, differentiation and apoptosis.
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Affiliation(s)
- Weilu Zhang
- College of Coastal Agricultural Sciences, Guangdong Ocean University, Zhanjiang 524088, China
| | - Shudai Lin
- College of Coastal Agricultural Sciences, Guangdong Ocean University, Zhanjiang 524088, China
| | - Zhenhai Jiao
- College of Coastal Agricultural Sciences, Guangdong Ocean University, Zhanjiang 524088, China
| | - Lilong An
- College of Coastal Agricultural Sciences, Guangdong Ocean University, Zhanjiang 524088, China
| | - Tingting Xie
- College of Coastal Agricultural Sciences, Guangdong Ocean University, Zhanjiang 524088, China
| | - Jiang Wu
- Experimental Teaching Center, Guangdong Ocean University, Zhanjiang 524088, China
| | - Li Zhang
- College of Coastal Agricultural Sciences, Guangdong Ocean University, Zhanjiang 524088, China
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11
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Zhu Z, Chen Y, Qin X, Liu S, Wang J, Ren H. Multidimensional landscape of non-alcoholic fatty liver disease-related disease spectrum uncovered by big omics data: Profiling evidence and new perspectives. SMART MEDICINE 2023; 2:e20220029. [PMID: 39188279 PMCID: PMC11236021 DOI: 10.1002/smmd.20220029] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Accepted: 02/22/2023] [Indexed: 08/28/2024]
Abstract
Characterized by hepatic lipid accumulation, non-alcoholic fatty liver disease (NAFLD) is a multifactorial metabolic disorder that could promote the progression of non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC). Benefiting from recent advances in omics technologies, such as high-throughput sequencing, voluminous profiling data in HCC-integrated molecular science into clinical medicine helped clinicians with rational guidance for treatments. In this review, we conclude the majority of publicly available omics data on the NAFLD-related disease spectrum and bring up new insights to inspire next-generation therapeutics against this increasingly prevalent disease spectrum in the post-genomic era.
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Affiliation(s)
- Zhengyi Zhu
- Department of Hepatobiliary SurgeryAffiliated Drum Tower HospitalMedical SchoolNanjing UniversityNanjingChina
| | - Yuyan Chen
- Department of Hepatobiliary SurgeryAffiliated Drum Tower HospitalMedical SchoolNanjing UniversityNanjingChina
| | - Xueqian Qin
- Department of Hepatobiliary SurgeryAffiliated Drum Tower HospitalMedical SchoolNanjing UniversityNanjingChina
| | - Shujun Liu
- Department of Hepatobiliary SurgeryAffiliated Drum Tower HospitalMedical SchoolNanjing UniversityNanjingChina
| | - Jinglin Wang
- Department of Hepatobiliary SurgeryAffiliated Drum Tower HospitalMedical SchoolNanjing UniversityNanjingChina
| | - Haozhen Ren
- Department of Hepatobiliary SurgeryAffiliated Drum Tower HospitalMedical SchoolNanjing UniversityNanjingChina
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12
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Yun J, Huang X, Liu C, Shi M, Li W, Niu J, Cai C, Yang Y, Gao P, Guo X, Li B, Lu C, Cao G. Genome-wide analysis of circular RNA-mediated ceRNA regulation in porcine skeletal muscle development. BMC Genomics 2023; 24:196. [PMID: 37046223 PMCID: PMC10099641 DOI: 10.1186/s12864-023-09284-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Accepted: 03/30/2023] [Indexed: 04/14/2023] Open
Abstract
BACKGROUND As a diverse and abundant class of endogenous RNAs, circular RNAs (circRNAs) participate in various biological processes including cell proliferation and apoptosis. Nevertheless, few researchers have investigated the role of circRNAs in muscle development in cultivated pigs. RESULTS In this study, we used RNA-seq to construct circRNA expression profiles in skeletal muscle of Jinfen White pigs at the age of 1, 90, and 180 days. Among the 16,990 identified circRNAs, 584 circRNAs were differentially expressed. Moreover, the enrichment analysis of DE circRNA host genes showed that they were mainly involved in muscle contraction, muscle organ development and muscle system processes, as well as AMPK and cAMP-related signal pathways. We also constructed a circRNA-miRNA-mRNA co-expression network to find key circRNAs which many involved in the regulation of porcine skeletal muscle development through the competitive endogenous RNA (ceRNA) mechanism. It is noteworthy that circ_0018595/miR-1343/PGM1 axis may play a regulatory role in the development of porcine skeletal muscle. CONCLUSIONS This study identified the circRNAs and present the circRNA expression profile in the development of pigs, revealed that DE circRNA host genes participate in different cell fates and enriched the porcine ceRNA network. Thus, this work will become a valuable resource for further in-depth study of the regulatory mechanism of circRNA in the development of porcine skeletal muscle.
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Affiliation(s)
- Jiale Yun
- College of Animal Science, Shanxi Agricultural University, Taigu, 030801, China
| | - Xiaoyu Huang
- College of Animal Science, Shanxi Agricultural University, Taigu, 030801, China
| | - Chang Liu
- College of Animal Science, Shanxi Agricultural University, Taigu, 030801, China
| | - Mingyue Shi
- College of Animal Science, Shanxi Agricultural University, Taigu, 030801, China
| | - Wenxia Li
- College of Animal Science, Shanxi Agricultural University, Taigu, 030801, China
| | - Jin Niu
- College of Animal Science, Shanxi Agricultural University, Taigu, 030801, China
| | - Chunbo Cai
- College of Animal Science, Shanxi Agricultural University, Taigu, 030801, China
| | - Yang Yang
- College of Animal Science, Shanxi Agricultural University, Taigu, 030801, China
| | - Pengfei Gao
- College of Animal Science, Shanxi Agricultural University, Taigu, 030801, China
| | - Xiaohong Guo
- College of Animal Science, Shanxi Agricultural University, Taigu, 030801, China
| | - Bugao Li
- College of Animal Science, Shanxi Agricultural University, Taigu, 030801, China
| | - Chang Lu
- College of Animal Science, Shanxi Agricultural University, Taigu, 030801, China.
| | - Guoqing Cao
- College of Animal Science, Shanxi Agricultural University, Taigu, 030801, China.
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13
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Yuan X, Li Y, Wen S, Xu C, Wang C, He Y, Zhou L. CircLDLR acts as a sponge for miR-667-5p to regulate SIRT1 expression in non-alcoholic fatty liver disease. Lipids Health Dis 2022; 21:127. [PMID: 36443854 PMCID: PMC9706878 DOI: 10.1186/s12944-022-01740-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 11/17/2022] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND Non-alcoholic fatty liver (NAFLD) is a complex metabolic disease characterized by fatty degeneration of hepatocytes. Circular RNAs (circRNAs) have been reported to be essential for (NAFLD progression. The potential mechanism of circRNA low-density lipoprotein receptor (circLDLR) in the NAFLD was investigated in this study. METHODS Hepatocyte (Hepa1-6) cells treated with oleic acid/palmitic acid (OA/PA) were used as the in vitro NAFLD model, and C57BL/6 mice fed with high-fat diet (HFD) were used as the in vivo NAFLD model. The circLDLR, LDLR, and miR-667-5p expression were measured by quantitative real-time polymerase chain reaction (qRT-PCR), while the protein levels of Light Chain Microtubule-Associated Protein 3 (LC3) and Sequestosome-1(p62) was examined by western blot. The circLDLR location was confirmed using RNA fluorescence in situ hybridization. Oil red O staining was carried out to measure lipid deposition in cells. The secreted levels of triglyceride (TG) and total cholesterol (TC) were detected through Enzymatic. The existence of the circLDLR/miR-667-5p/sirtuin 1 (SIRT1) regulatory axis was validated by applying the dual-luciferase reporter assay. RESULTS The circLDLR expression showed a prominent down-regulation in OA/PA-treated Hepa1-6 cells, whereas the LDLR expression was up-regulated. Overexpression of circLDLR significantly attenuated lipid droplet accumulation in NAFLD models in vitro/vivo, reduced TG, TC, and p62 levels, and increased LC3-II levels and the amount of the green fluorescent protein (GFP)-LC3 puncta in cells. CircLDLR and SIRT1 are common targets of miR-667-5p to inhibit the TG and TC and promote the autophagy pathway. SIRT1 knockdown reversed the effects of circLDLR overexpression. CONCLUSIONS CircLDLR alleviated the development of NAFLD by inducing autophagic flux while modulating the miR-667-5p/SIRT1 axis reversed its effects, suggesting that targeting circLDLR/miR-667-5p/SIRT1 axis may be a promising therapeutic strategy for NAFLD.
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Affiliation(s)
- Xinlu Yuan
- Department of Endocrinology and Metabolic Diseases, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Road, Pudong, Shanghai, 201399, China.
| | - Yanyan Li
- Department of Endocrinology and Metabolic Diseases, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Road, Pudong, Shanghai, 201399, China
| | - Song Wen
- Department of Endocrinology and Metabolic Diseases, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Road, Pudong, Shanghai, 201399, China
| | - Chenglin Xu
- Department of Endocrinology and Metabolic Diseases, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Road, Pudong, Shanghai, 201399, China
| | - Congcong Wang
- Department of Endocrinology and Metabolic Diseases, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Road, Pudong, Shanghai, 201399, China
| | - Yanju He
- Department of Endocrinology and Metabolic Diseases, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Road, Pudong, Shanghai, 201399, China
| | - Ligang Zhou
- Department of Endocrinology and Metabolic Diseases, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Road, Pudong, Shanghai, 201399, China.
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He Z, Bin Y, Chen G, Li Q, Fan W, Ma Y, Yi J, Luo X, Tan Z, Li J. Identification of MAP3K4 as a novel regulation factor of hepatic lipid metabolism in non-alcoholic fatty liver disease. J Transl Med 2022; 20:529. [PMID: 36376950 PMCID: PMC9664664 DOI: 10.1186/s12967-022-03734-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 10/30/2022] [Indexed: 11/16/2022] Open
Abstract
Background Non-alcoholic fatty liver disease (NAFLD) is a metabolic disorder with abnormal lipid metabolism. The present study was to identify regulatory genes related to lipid droplets (LDs) abnormal accumulation in NAFLD. Methods transcriptomic analysis and bioinformatics analysis (GEO database) were used to identify potential genes in abnormal lipid metabolism of NAFLD. A candidate gene MAP3K4 expression were detected by immunohistochemistry staining in NAFLD and controls. RNA interference and immunoblotting were used to verify the roles of MAP3K4 in the formation of hepatic LDs. Results A total of 134 candidate genes were screened, including 44 up-regulated genes and 90 down-regulated genes. 29 genes in the protein–protein interaction (PPI) were selected as hub genes, including MAP3K4. The expression levels of MAP3K4 were positively correlated with NAFLD activity score (r = 0.702, p = 0.002). Furthermore, we found a positive correlation of MAP3K4 expression with serum total cholesterol (r = 0.564, p = 0.023), uric acid levels (r = 0.520, p = 0.039), and body mass index (r = 0.574, p = 0.020). Downregulation of MAP3K4 decreased LDs accumulation in HepG2 cells and reduced the expression of CGI-58 and Plin-2 by imbibition of JNK and group IVA cytosolic phospholipase A2 (cPLA2) activation. Conclusion The study revealed a number of regulatory genes related to hepatic lipid metabolism of NAFLD, and demonstrated that MAP3K4 played a pivotal role in the hepatic lipogenesis of NAFLD. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-022-03734-8.
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Yepmo M, Potier JB, Pinget M, Grabarz A, Bouzakri K, Dumond Bourie A. Discussing the role of circular RNA in the pathogenesis of non-alcoholic fatty liver disease and its complications. Front Endocrinol (Lausanne) 2022; 13:1035159. [PMID: 36407314 PMCID: PMC9667057 DOI: 10.3389/fendo.2022.1035159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 10/17/2022] [Indexed: 01/24/2023] Open
Abstract
Circular RNAs (circRNAs) are class of non-coding RNA, which are characterized by a covalently closed loop structure. Functionally they can act on cellular physiology, notably by sponging microRNAs (miR), regulating gene expression or interacting with binding protein. To date, circRNAs might represent an interesting, underexploited avenue for new target discovery for therapeutic applications, especially in the liver. The first characteristic of non-alcoholic fatty liver disease (NAFLD) is hepatic cholesterol accumulation, followed by its advanced form of the affection, nonalcoholic steatohepatitis (NASH), due to the occurrence of lobular inflammation, irreversible fibrosis, and in some cases hepatocellular carcinoma (HCC). Therefore, studies have investigated the importance of the dysregulation of circRNAs in the onset of metabolic disorders. In this review, we summarize the potential role of circRNAs in the development of metabolic diseases associated with the liver such as NAFLD or NASH, and their potential to become therapeutic strategies for these pathologies.
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Affiliation(s)
- Melissa Yepmo
- Centre européen d’étude du Diabète, Unité Mixte de Recherche de l’Université de Strasbourg « Diabète et Thérapeutique », Strasbourg, France
| | - Jean-Baptiste Potier
- Centre européen d’étude du Diabète, Unité Mixte de Recherche de l’Université de Strasbourg « Diabète et Thérapeutique », Strasbourg, France
- ILONOV, Strasbourg, France
| | - Michel Pinget
- Centre européen d’étude du Diabète, Unité Mixte de Recherche de l’Université de Strasbourg « Diabète et Thérapeutique », Strasbourg, France
| | | | - Karim Bouzakri
- Centre européen d’étude du Diabète, Unité Mixte de Recherche de l’Université de Strasbourg « Diabète et Thérapeutique », Strasbourg, France
- ILONOV, Strasbourg, France
| | - Aurore Dumond Bourie
- Centre européen d’étude du Diabète, Unité Mixte de Recherche de l’Université de Strasbourg « Diabète et Thérapeutique », Strasbourg, France
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Zhu X, Xia M, Gao X. Update on genetics and epigenetics in metabolic associated fatty liver disease. Ther Adv Endocrinol Metab 2022; 13:20420188221132138. [PMID: 36325500 PMCID: PMC9619279 DOI: 10.1177/20420188221132138] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 09/25/2022] [Indexed: 11/06/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is becoming the most frequent chronic liver disease worldwide. Metabolic (dysfunction) associated fatty liver disease (MAFLD) is suggested to replace the nomenclature of NAFLD. For individuals with metabolic dysfunction, multiple NAFLD-related factors also contribute to the development and progression of MAFLD including genetics and epigenetics. The application of genome-wide association study (GWAS) and exome-wide association study (EWAS) uncovers single-nucleotide polymorphisms (SNPs) in MAFLD. In addition to the classic SNPs in PNPLA3, TM6SF2, and GCKR, some new SNPs have been found recently to contribute to the pathogenesis of liver steatosis. Epigenetic factors involving DNA methylation, histone modifications, non-coding RNAs regulations, and RNA methylation also play a critical role in MAFLD. DNA methylation is the most reported epigenetic modification. Developing a non-invasion biomarker to distinguish metabolic steatohepatitis (MASH) or liver fibrosis is ongoing. In this review, we summarized and discussed the latest progress in genetic and epigenetic factors of NAFLD/MAFLD, in order to provide potential clues for MAFLD treatment.
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Affiliation(s)
- Xiaopeng Zhu
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan Institute for Metabolic Diseases, Fudan University, Shanghai, China
| | - Mingfeng Xia
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan Institute for Metabolic Diseases, Fudan University, 180 Fenglin Rd, Shanghai 200032, China
| | - Xin Gao
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan Institute for Metabolic Diseases, Fudan University, Shanghai, China
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17
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Noncoding RNAs Associated with PPARs in Etiology of MAFLD as a Novel Approach for Therapeutics Targets. PPAR Res 2022; 2022:6161694. [PMID: 36164476 PMCID: PMC9509273 DOI: 10.1155/2022/6161694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 07/25/2022] [Accepted: 08/27/2022] [Indexed: 11/18/2022] Open
Abstract
Background. Metabolic associated fatty liver disease (MAFLD) is a complex disease that results from the accumulation of fat in the liver. MAFLD is directly associated with obesity, insulin resistance, diabetes, and metabolic syndrome. PPARγ ligands, including pioglitazone, are also used in the management of this disease. Noncoding RNAs play a critical role in various diseases such as diabetes, obesity, and liver diseases including MAFLD. However, there is no adequate knowledge about the translation of using these ncRNAs to the clinics, particularly in MAFLD conditions. The aim of this study was to identify ncRNAs in the etiology of MAFLD as a novel approach to the therapeutic targets. Methods. We collected human and mouse MAFLD gene expression datasets available in GEO. We performed pathway enrichment analysis of total mRNAs based on KEGG repository data to screen the most potential pathways in the liver of MAFLD human subjects and mice model, and analyzed pathway interconnections via ClueGO. Finally, we screened disease causality of the MAFLD ncRNAs, which were associated with PPARs, and then discussed the role of revealed ncRNAs in PPAR signaling and MAFLD. Results. We found 127 ncRNAs in MAFLD which 25 out of them were strongly validated before for regulation of PPARs. With a polypharmacology approach, we screened 51 ncRNAs which were causal to a subset of diseases related to MAFLD. Conclusion. This study revealed a subset of ncRNAs that could help in more clear and guided designation of preclinical and clinical studies to verify the therapeutic application of the revealed ncRNAs by manipulating the PPARs molecular mechanism in MAFLD.
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Liu B, Tian Y, He J, Gu Q, Jin B, Shen H, Li W, Shi L, Yu H, Shan G, Cai X. The potential of mecciRNA in hepatic stellate cell to regulate progression of nonalcoholic hepatitis. J Transl Med 2022; 20:393. [PMID: 36058953 PMCID: PMC9441041 DOI: 10.1186/s12967-022-03595-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 08/14/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Nonalcoholic steatohepatitis (NASH) occupies a substantial proportion of chronic liver disease worldwide, of which pathogenesis needs further research. Recent studies have demonstrated the significant roles of circular RNAs (circRNAs) in NASH, while the function of a novel type of circRNAs, namely mitochondria-encoded circRNAs (mecciRNAs), remains elusive. Therefore, we aimed to investigate their potential to regulate the progression of NASH in this study. METHODS GSE134146 was used to screen for differentially expressed mecciRNAs in NASH, while GSE46300 was used to identify NASH-related genes. To establish the mecciRNA-miRNA-mRNA networks, circMINE and miRNet databases were used for predicting downstream targets. Then, consensus clustering analysis was used to determine immune subtypes of NASH. Finally, we successfully validated our findings in vitro (LPS-treated hepatic stellate cells [HSCs]) and in vivo (MCD-diet mice) NASH models. RESULTS We confirmed that circRNomics balance is disrupted in HSCs of NASH, while two mecciRNAs (hsa_circ_0089761 and hsa_circ_0089763) could function as competing for endogenous RNAs (ceRNAs) to regulate fibrosis-related signals. Furthermore, we constructed two ceRNA networks based on mecciRNAs for the first time. Cell and animal NASH models validated our findings that c-MYC and SMAD2/3 were upregulated in HSCs, while THBS1 and p-STAT3 were upregulated in hepatocytes. Moreover, we identified 21 core genes by overlapping the differentially expressed genes (NASH vs. Normal) with mecciRNA-targeted genes. According to their expression profiles, NASH patients could be divided in 2 different clusters, in which proinflammatory signals (TNF and IL-17 pathways) are significantly activated in Cluster 1. CONCLUSION We successfully established two novel mecciRNA-miRNA-mRNA networks in HSCs and hepatocytes, which were further confirmed by in vitro and in vivo models. Meanwhile, the novel immunotyping model revealed the heterogeneity of NASH, thereby might guiding treatment options. Altogether, our study brought a distinct perspective on the relationship between mecciRNAs and NASH.
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Affiliation(s)
- Boqiang Liu
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China.,Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Zhejiang University, Hangzhou, 310016, China.,Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Hangzhou, 310016, China.,Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Hangzhou, 310016, China.,Zhejiang University Cancer Center, Zhejiang University, Hangzhou, 310030, China
| | - Yuanshi Tian
- Department of Diagnostic Ultrasound & Echocardiography, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China
| | - Jing He
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China.,Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Zhejiang University, Hangzhou, 310016, China.,Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Hangzhou, 310016, China.,Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Hangzhou, 310016, China.,Zhejiang University Cancer Center, Zhejiang University, Hangzhou, 310030, China
| | - Qiuxia Gu
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China.,Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Zhejiang University, Hangzhou, 310016, China.,Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Hangzhou, 310016, China.,Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Hangzhou, 310016, China.,Zhejiang University Cancer Center, Zhejiang University, Hangzhou, 310030, China
| | - Binghan Jin
- Department of Endocrinology, The Children's Hospital, School of Medicine, National Clinical Research Center for Child Health, Zhejiang University, Hangzhou, 310053, China
| | - Hao Shen
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China.,Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Zhejiang University, Hangzhou, 310016, China.,Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Hangzhou, 310016, China.,Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Hangzhou, 310016, China.,Zhejiang University Cancer Center, Zhejiang University, Hangzhou, 310030, China
| | - Weiqi Li
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China.,Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Zhejiang University, Hangzhou, 310016, China.,Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Hangzhou, 310016, China.,Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Hangzhou, 310016, China.,Zhejiang University Cancer Center, Zhejiang University, Hangzhou, 310030, China
| | - Liang Shi
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China.,Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Zhejiang University, Hangzhou, 310016, China.,Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Hangzhou, 310016, China.,Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Hangzhou, 310016, China.,Zhejiang University Cancer Center, Zhejiang University, Hangzhou, 310030, China
| | - Hong Yu
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China.,Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Zhejiang University, Hangzhou, 310016, China.,Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Hangzhou, 310016, China.,Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Hangzhou, 310016, China.,Zhejiang University Cancer Center, Zhejiang University, Hangzhou, 310030, China
| | - Ge Shan
- Zhejiang University Cancer Center, Zhejiang University, Hangzhou, 310030, China. .,Department of Pulmonary and Critical Care Medicine, Regional Medical Center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China. .,Department of Clinical Laboratory, First Affiliated Hospital of the USTC, Chinese Academy of Sciences (CAS) Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China (UTSC), Hefei, 230027, China.
| | - Xiujun Cai
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China. .,Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Zhejiang University, Hangzhou, 310016, China. .,Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Hangzhou, 310016, China. .,Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Hangzhou, 310016, China. .,Zhejiang University Cancer Center, Zhejiang University, Hangzhou, 310030, China.
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Li Y, Cen CQ, Liu B, Zhou L, Huang XM, Liu GY. Overexpression of circ PTK2 suppresses the progression of nonalcoholic fatty liver disease via the miR-200c/SIK2/PI3K/Akt axis. Kaohsiung J Med Sci 2022; 38:869-878. [PMID: 35791807 DOI: 10.1002/kjm2.12568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 03/01/2022] [Accepted: 05/25/2022] [Indexed: 11/11/2022] Open
Abstract
Excessive hepatic lipid accumulation is involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). A previous study showed that the circular RNA (circRNA) PTK2 was significantly downregulated in NAFLD mice. However, the detailed function of circ PTK2 in NAFLD remains unclear. A high-fat diet (HFD) was used to establish a mouse model of NAFLD, and free fatty acid (FFA) treatment was used to establish an in vitro model of NAFLD. Oil red O staining was used to evaluate lipid accumulation. The pathological changes in mice were observed by HE staining. Western blotting and RT-qPCR were applied to assess protein and mRNA levels, respectively. A dual luciferase reporter assay and RIP were used to explore the relationship among circ PTK2, miR-200c and SIK2. Circ PTK2 and SIK2 were downregulated and miR-200c was upregulated in NAFLD. Upregulation of circ PTK2 reversed lipid accumulation in FFA-treated HepG2 cells. Moreover, circ PTK2 bound to miR-200c, and SIK2 was identified as the direct target of miR-200c. Moreover, the miR-200c inhibitor-induced decrease in lipid accumulation was reversed by SIK2 knockdown. Furthermore, the impact of circ PTK2 overexpression on PI3K/Akt signaling was partially reversed by SIK2 silencing. Circ PTK2 overexpression alleviates NAFLD development via the miR-200c/SIK2/PI3K/Akt axis. Thus, our work might provide new methods for NAFLD treatment.
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Affiliation(s)
- Yong Li
- Department of Emergency, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Chao-Qun Cen
- Department of Emergency, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Bo Liu
- Department of Orthopedics, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Lu Zhou
- Department of Dermatology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xiang-Miao Huang
- Department of Emergency, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Geng-Yan Liu
- Department of Orthopedics, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
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Chen Y, Lu S, Ye Z, Cai X, Wu S, Li P, Du B. New compound probiotic beverage protects against antibiotic-associated diarrhea in mice by modulating the microbiota. Future Microbiol 2022; 17:943-956. [PMID: 35694881 DOI: 10.2217/fmb-2021-0240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Probiotics and their products are the classic way to treat and prevent gastrointestinal diseases. In this study, the authors designed new combinations and doses of probiotic beverages for antibiotic-associated diarrhea. Group S1 was different from the other groups, including Lactobacillus rhamnosus HN001, Lactobacillus acidophilus NCFM and Bifidobacterium lactis BI-07. Its inulin content was higher than those of the other groups. Mice were induced with a 16-day administration of triple antibiotics in advance for 2 weeks prior to antibiotic treatment. In the experiment, the treatment group returned to normal more quickly than the placebo group. In group S1, the relative abundance of the phylum Firmicutes and genus Lactobacillus increased, and the structure of the microbiota was the closest to normal among all groups. In conclusion, the combinations of probiotic beverages effectively caused structural recovery of the gut and fecal microbiota against antibiotic-associated diarrhea, and the S1 formula showed the best efficacy.
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Affiliation(s)
- Yang Chen
- College of Food Science, South China Agricultural University, Guangzhou, Guangdong, 510640, China
| | - Siming Lu
- College of Food Science, South China Agricultural University, Guangzhou, Guangdong, 510640, China
| | - Zhiwei Ye
- College of Food Science, South China Agricultural University, Guangzhou, Guangdong, 510640, China
| | - Xin Cai
- College of Food Science, South China Agricultural University, Guangzhou, Guangdong, 510640, China
| | - Shanshan Wu
- College of Food Science, South China Agricultural University, Guangzhou, Guangdong, 510640, China
| | - Pan Li
- College of Food Science, South China Agricultural University, Guangzhou, Guangdong, 510640, China
| | - Bing Du
- College of Food Science, South China Agricultural University, Guangzhou, Guangdong, 510640, China
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Li J, Qi J, Tang Y, Liu H, Zhou K, Dai Z, Yuan L, Sun C. A nanodrug system overexpressed circRNA_0001805 alleviates nonalcoholic fatty liver disease via miR-106a-5p/miR-320a and ABCA1/CPT1 axis. J Nanobiotechnology 2021; 19:363. [PMID: 34789275 PMCID: PMC8596892 DOI: 10.1186/s12951-021-01108-8] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 10/30/2021] [Indexed: 12/22/2022] Open
Abstract
Our study aimed to explore the function of circRNA_0001805 in the pathogenesis of NAFLD and the underlying mechanism. A nanodrug system (GA-RM/GZ/PL) was constructed to overexpress circRNA_0001805 specifically in hepatocytes for the treatment of NAFLD. Fat droplet accumulation in cultured cells and mouse hepatic tissues was detected using Oil Red O or H&E staining. The relative expression of circRNAs, genes associated with lipogenesis was quantified by qRT-PCR. Interactions between circRNA_0001805 and miR-106a-5p/miR-320a, between miR-106a-5p/miR-320a and ABCA1/CPT1 were confirmed by dual-luciferase reporter assay. A novel metalorganic framework nanocarrier (GZ) was prepared from glycyrrhizic acid and zinc ions (Zn2+), and this nanocarrier was loaded with the circRNA_0001805 plasmid to construct a nanocore (GZ/PL). Then, this GZ/PL was coated with a galactose-modified RBC membrane (GA-RM) to generate GA-RM/GZ/PL. CircRNA_0001805 expression was downregulated in FFA-challenged primary hepatocytes, HFD-fed mice and NAFLD patients. Overexpressed circRNA_0001805 attenuated NAFLD development by suppressing lipid metabolism disorder and inflammation. CircRNA_0001805 targeted miR-106a-5p/miR-320a, which served as an upstream inhibitor of ABCA1/CPT1 and collaboratively regulated NAFLD progression. GA-RM/GZ/PL targeted hepatocytes, overexpressed circRNA_0001805, released glycyrrhizic acid to reduce the accumulation of lipids in the liver and played a synergistic role against NAFLD-induced lipid metabolism disorder. ![]()
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Affiliation(s)
- Jian Li
- Department of Blood Transfusion, Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China
| | - Jing Qi
- Department of Emergency, Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, People's Republic of China
| | - Yishu Tang
- Department of Emergency, Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, People's Republic of China
| | - Huaizheng Liu
- Department of Emergency, Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, People's Republic of China
| | - Kefu Zhou
- Department of Emergency, Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, People's Republic of China
| | - Zheren Dai
- Department of Emergency, Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, People's Republic of China
| | - Lehong Yuan
- Department of Emergency, Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, People's Republic of China
| | - Chuanzheng Sun
- Department of Emergency, Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, People's Republic of China.
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22
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Circular RNA as An Epigenetic Regulator in Chronic Liver Diseases. Cells 2021; 10:cells10081945. [PMID: 34440714 PMCID: PMC8392363 DOI: 10.3390/cells10081945] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 07/19/2021] [Accepted: 07/28/2021] [Indexed: 02/05/2023] Open
Abstract
Circular RNA (circRNA) is a type of non-coding RNA characterized by a covalently closed continuous loop. CircRNA is generated by pre-mRNA through back-splicing and is probably cleared up by extracellular vesicles. CircRNAs play a pivotal role in the epigenetic regulation of gene expression at transcriptional and post-transcriptional levels. Recently, circRNAs have been demonstrated to be involved in the regulation of liver homeostasis and diseases. However, the epigenetic role and underlying mechanisms of circRNAs in chronic liver diseases remain unclear. This review discussed the role of circRNAs in non-neoplastic chronic liver diseases, including alcoholic liver disease (ALD), metabolic-associated fatty liver disease (MAFLD), viral hepatitis, liver injury and regeneration, liver cirrhosis, and autoimmune liver disease. The review also highlighted that further efforts are urgently needed to develop circRNAs as novel diagnostics and therapeutics for chronic liver diseases.
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