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Wang W, Gao X, Niu W, Yin J, He K. Targeting Metabolism: Innovative Therapies for MASLD Unveiled. Int J Mol Sci 2025; 26:4077. [PMID: 40362316 PMCID: PMC12071536 DOI: 10.3390/ijms26094077] [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: 02/22/2025] [Revised: 04/01/2025] [Accepted: 04/23/2025] [Indexed: 05/15/2025] Open
Abstract
The recent introduction of the term metabolic-dysfunction-associated steatotic liver disease (MASLD) has highlighted the critical role of metabolism in the disease's pathophysiology. This innovative nomenclature signifies a shift from the previous designation of non-alcoholic fatty liver disease (NAFLD), emphasizing the condition's progressive nature. Simultaneously, MASLD has become one of the most prevalent liver diseases worldwide, highlighting the urgent need for research to elucidate its etiology and develop effective treatment strategies. This review examines and delineates the revised definition of MASLD, exploring its epidemiology and the pathological changes occurring at various stages of the disease. Additionally, it identifies metabolically relevant targets within MASLD and provides a summary of the latest metabolically targeted drugs under development, including those in clinical and some preclinical stages. The review finishes with a look ahead to the future of targeted therapy for MASLD, with the goal of summarizing and providing fresh ideas and insights.
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Affiliation(s)
- Weixin Wang
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China; (W.W.); (W.N.)
| | - Xin Gao
- School of Public Health, Jilin University, Changchun 130021, China;
| | - Wentong Niu
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China; (W.W.); (W.N.)
| | - Jinping Yin
- NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun 130041, China;
| | - Kan He
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China; (W.W.); (W.N.)
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Carpi S, Daniele S, de Almeida JFM, Gabbia D. Recent Advances in miRNA-Based Therapy for MASLD/MASH and MASH-Associated HCC. Int J Mol Sci 2024; 25:12229. [PMID: 39596297 PMCID: PMC11595301 DOI: 10.3390/ijms252212229] [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: 10/03/2024] [Revised: 11/08/2024] [Accepted: 11/11/2024] [Indexed: 11/28/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is a growing health concern worldwide, affecting more than 1 billion adults. It may progress to metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis, and ultimately hepatocellular carcinoma (HCC). Emerging evidence has demonstrated the role in this transition of microRNAs (miRNAs), which regulate the expression of genes associated with lipid metabolism, inflammation, fibrosis, and cell proliferation. Specific miRNAs have been identified to exacerbate or mitigate fibrotic and carcinogenic processes in hepatic cells. The modulation of these miRNAs through synthetic mimics or inhibitors represents a promising therapeutic strategy. Preclinical models have demonstrated that miRNA-based therapies can attenuate liver inflammation, reduce fibrosis, and inhibit tumorigenesis, thus delaying or preventing the onset of HCC. However, challenges such as delivery mechanisms, off-target effects, and long-term safety remain to be addressed. This review, focusing on recently published preclinical and clinical studies, explores the pharmacological potential of miRNA-based interventions to prevent MASLD/MASH and progression toward HCC.
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Affiliation(s)
- Sara Carpi
- Department of Health Sciences, University ‘Magna Græcia’ of Catanzaro, 88100 Catanzaro, Italy
- NEST (National Enterprise for nanoScience and nanoTechnology), Istituto Nanoscienze-CNR and Scuola Normale Superiore, 41125 Modena, Italy
| | - Simona Daniele
- Department of Pharmacy, University of Pisa, 56126 Pisa, Italy; (S.D.); (J.F.M.d.A.)
| | | | - Daniela Gabbia
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy
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3
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Cooper RD, Shaffer HB. Managing invasive hybrids with pond hydroperiod manipulation in an endangered salamander system. CONSERVATION BIOLOGY : THE JOURNAL OF THE SOCIETY FOR CONSERVATION BIOLOGY 2024; 38:e14167. [PMID: 37551773 DOI: 10.1111/cobi.14167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 07/07/2023] [Accepted: 07/31/2023] [Indexed: 08/09/2023]
Abstract
When invasive and endangered native taxa hybridize, the resulting admixture introduces novel conservation challenges. Across a large region of central California, a hybrid swarm consisting of admixed endangered California tiger salamanders (CTS) (Ambystoma californiense) and introduced barred tiger salamanders (BTS) (Ambystoma mavortium) has replaced native populations, threatening the genetic integrity of CTS and the vernal pool systems they inhabit. We employed a large-scale, genomically informed field experiment to test whether shortening breeding pond hydroperiod would favor native CTS genotypes. We constructed 14 large, seminatural ponds to evaluate the effect of hydroperiod duration on larval survival and mass at metamorphosis. We tracked changes in non-native allele frequencies with a 5237-gene exon capture array and employed a combination of custom Bayesian and generalized linear models to quantify the effect of pond duration on salamander fitness. Earlier work on this system showed hybrid superiority under many conditions and suggested that hybrids are favored in human-modified ponds with artificially long hydroperiods. Consistent with these earlier studies, we found overwhelming evidence for hybrid superiority. Very short hydroperiods substantially reduced the mass (1.1-1.5 fold) and survival probability (10-13 fold) of both native and hybrid larvae, confirming that hydroperiod likely exerts a strong selective pressure in the wild. We identified 86 genes, representing 1.8% of 4723 screened loci, that significantly responded to this hydroperiod-driven selection. In contrast to earlier work, under our more natural experimental conditions, native CTS survival and size at metamorphosis were always less than hybrids, suggesting that hydroperiod management alone will not shift selection to favor native larval genotypes. However, shortening pond hydroperiod may limit productivity of hybrid ponds, complementing other strategies to remove hybrids while maintaining vernal pool ecosystems. This study confirms and expands on previous work that highlights the importance of hydroperiod management to control invasive aquatic species.
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Affiliation(s)
- Robert D Cooper
- Department of Ecology and Evolutionary Biology, University of California, Los Angeles, Los Angeles, California, USA
- La Kretz Center for California Conservation Science, Institute of the Environment and Sustainability, University of California, Los Angeles, Los Angeles, California, USA
| | - H Bradley Shaffer
- Department of Ecology and Evolutionary Biology, University of California, Los Angeles, Los Angeles, California, USA
- La Kretz Center for California Conservation Science, Institute of the Environment and Sustainability, University of California, Los Angeles, Los Angeles, California, USA
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Ma M, Cao R, Tian Y, Fu X. Ubiquitination and Metabolic Disease. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1466:47-79. [PMID: 39546135 DOI: 10.1007/978-981-97-7288-9_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2024]
Abstract
The increasing incidence of metabolic diseases, including obesity, type 2 diabetes mellitus (T2DM), and non-alcoholic fatty liver disease (NAFLD), in the past decade is a serious concern worldwide. Disruption of cellular protein homeostasis has been considered as a crucial contributor to the pathogenesis of metabolic diseases. To maintain protein homeostasis, cells have evolved multiple dynamic and self-regulating quality control processes to adapt new environmental conditions and prevent prolonged damage. Among them, the ubiquitin proteasome system (UPS), the primary proteolytic pathway for degradation of aberrant proteins via ubiquitination, has an essential role in maintaining cellular homeostasis in response to intracellular stress. Correspondingly, accumulating evidences have shown that dysregulation of ubiquitination can aggravate various metabolic derangements in many tissues, including the liver, skeletal muscle, pancreas, and adipose tissue, and is involved in the initiation and progression of diverse metabolic diseases. In this part, we will summarize the role of ubiquitination in the pathogenesis of metabolic diseases, including obesity, T2DM and NAFLD, and discuss its potential as a therapeutic target.
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Affiliation(s)
- Meilin Ma
- Division of Endocrinology and Metabolism, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, China
| | - Rong Cao
- Division of Endocrinology and Metabolism, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, China
| | - Yan Tian
- Division of Endocrinology and Metabolism, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, China
| | - Xianghui Fu
- State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
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Rusu I, Pirlog R, Chiroi P, Nutu A, Puia VR, Fetti AC, Rusu DR, Berindan-Neagoe I, Al Hajjar N. The Implications of Noncoding RNAs in the Evolution and Progression of Nonalcoholic Fatty Liver Disease (NAFLD)-Related HCC. Int J Mol Sci 2022; 23:12370. [PMID: 36293225 PMCID: PMC9603983 DOI: 10.3390/ijms232012370] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 10/12/2022] [Accepted: 10/13/2022] [Indexed: 11/07/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver pathology worldwide. Meanwhile, liver cancer represents the sixth most common malignancy, with hepatocellular carcinoma (HCC) as the primary, most prevalent subtype. Due to the rising incidence of metabolic disorders, NAFLD has become one of the main contributing factors to HCC development. However, although NAFLD might account for about a fourth of HCC cases, there is currently a significant gap in HCC surveillance protocols regarding noncirrhotic NAFLD patients, so the majority of NAFLD-related HCC cases were diagnosed in late stages when survival chances are minimal. However, in the past decade, the focus in cancer genomics has shifted towards the noncoding part of the genome, especially on the microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), which have proved to be involved in the regulation of several malignant processes. This review aims to summarize the current knowledge regarding some of the main dysregulated, noncoding RNAs (ncRNAs) and their implications for NAFLD and HCC development. A central focus of the review is on miRNA and lncRNAs that can influence the progression of NAFLD towards HCC and how they can be used as potential screening tools and future therapeutic targets.
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Affiliation(s)
- Ioana Rusu
- Department of Pathology, Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
- 3rd Department of General Surgery, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400186 Cluj-Napoca, Romania
| | - Radu Pirlog
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
| | - Paul Chiroi
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
| | - Andreea Nutu
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
| | - Vlad Radu Puia
- 3rd Department of General Surgery, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400186 Cluj-Napoca, Romania
- Department of Surgery, Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
| | - Alin Cornel Fetti
- 3rd Department of General Surgery, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400186 Cluj-Napoca, Romania
- Department of Surgery, Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
| | - Daniel Radu Rusu
- Department of Pathology, Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
| | - Ioana Berindan-Neagoe
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
| | - Nadim Al Hajjar
- 3rd Department of General Surgery, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400186 Cluj-Napoca, Romania
- Department of Surgery, Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
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Bonek K, Kuca Warnawin E, Kornatka A, Plebańczyk M, Burakowski T, Maśliński W, Wisłowska M, Głuszko P, Ciechomska M. Circulating miRNA Correlates with Lipid Profile and Disease Activity in Psoriatic Arthritis, Rheumatoid Arthritis, and Ankylosing Spondylitis Patients. Biomedicines 2022; 10:biomedicines10040893. [PMID: 35453643 PMCID: PMC9024741 DOI: 10.3390/biomedicines10040893] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 04/04/2022] [Accepted: 04/06/2022] [Indexed: 02/04/2023] Open
Abstract
This study aimed to investigate the associations of microRNA (miRs) signatures with cytokines, serum lipids, and disease activity in patients with psoriatic arthritis (PsA), ankylosing spondylitis (AS), and rheumatoid arthritis (RA). In total, 65 patients (PsA n = 25, AS n = 25, RA n = 15) and 25 healthy controls (HC) were enrolled into the study. The expression of miR-223-5p, miR-92b-3p, miR-485-3p, miR-10b-5p, let-7d-5p, miR-26a-2-3p, miR-146b-3p, and cytokines levels were measured in sera. DIANA-mirPath analysis was used to predict pathways targeted by the dysregulated miRs. Disease activity scores were calculated. Lipid profile, uric acid, glucose level, and C-reactive protein (CRP) concentrations were determined in the blood. Based on lipid profiles, the PsA group had hypertriglyceridaemia, and RA patients revealed mixed dyslipidaemia, while in AS, no specific changes were found. miR expression analysis revealed upregulation of miR-26a-2-3p and miR-10b-5p in PsA, miR-485-3p in AS, and let-7d-5p in RA. Several correlations between disease activity indexes, metabolites levels, and expression of miRs were observed in PsA, RA, and AS patients. Finally, in ROC analysis, miR-26a-2-3p/miR-485-3p, and let-7d-5p/miR-146b-3p tandems revealed high sensitivity and specificity in distinguishing between PsA, AS, and RA. Our study illustrates the superiority of miR expressions in distinguishing between RA, PsA, and AS. In PsA, a unique regulatory pathway exists through miR-26a-2-3p, miR-223-5p, miR-10b-5p, and miR-92b-3p that converges proatherogenic metabolism and disease activity.
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Affiliation(s)
- Krzysztof Bonek
- Department of Rheumatology, National Institute of Geriatrics, Rheumatology and Rehabilitation, 02-637 Warsaw, Poland; (M.W.); (P.G.)
- Correspondence: (K.B.); (M.C.)
| | - Ewa Kuca Warnawin
- Department of Pathophysiology and Immunology, National Institute of Geriatrics, Rheumatology and Rehabilitation, 02-637 Warsaw, Poland; (E.K.W.); (A.K.); (M.P.); (T.B.); (W.M.)
| | - Anna Kornatka
- Department of Pathophysiology and Immunology, National Institute of Geriatrics, Rheumatology and Rehabilitation, 02-637 Warsaw, Poland; (E.K.W.); (A.K.); (M.P.); (T.B.); (W.M.)
| | - Magdalena Plebańczyk
- Department of Pathophysiology and Immunology, National Institute of Geriatrics, Rheumatology and Rehabilitation, 02-637 Warsaw, Poland; (E.K.W.); (A.K.); (M.P.); (T.B.); (W.M.)
| | - Tomasz Burakowski
- Department of Pathophysiology and Immunology, National Institute of Geriatrics, Rheumatology and Rehabilitation, 02-637 Warsaw, Poland; (E.K.W.); (A.K.); (M.P.); (T.B.); (W.M.)
| | - Włodzimierz Maśliński
- Department of Pathophysiology and Immunology, National Institute of Geriatrics, Rheumatology and Rehabilitation, 02-637 Warsaw, Poland; (E.K.W.); (A.K.); (M.P.); (T.B.); (W.M.)
| | - Małgorzata Wisłowska
- Department of Rheumatology, National Institute of Geriatrics, Rheumatology and Rehabilitation, 02-637 Warsaw, Poland; (M.W.); (P.G.)
| | - Piotr Głuszko
- Department of Rheumatology, National Institute of Geriatrics, Rheumatology and Rehabilitation, 02-637 Warsaw, Poland; (M.W.); (P.G.)
| | - Marzena Ciechomska
- Department of Pathophysiology and Immunology, National Institute of Geriatrics, Rheumatology and Rehabilitation, 02-637 Warsaw, Poland; (E.K.W.); (A.K.); (M.P.); (T.B.); (W.M.)
- Correspondence: (K.B.); (M.C.)
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7
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Jiang Y, Xi Y, Li Y, Zuo Z, Zeng C, Fan J, Zhang D, Tao H, Guo Y. Ethanol promoting the upregulation of C-X-C Motif Chemokine Ligand 1（CXCL1） and C-X-C Motif Chemokine Ligand 6（CXCL6） in models of early alcoholic liver disease. Bioengineered 2022; 13:4688-4701. [PMID: 35156518 PMCID: PMC8973977 DOI: 10.1080/21655979.2022.2030557] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Alcoholic liver disease (ALD) denotes a series of liver diseases caused by ethanol. Recently, immune-related genes (IRGs) play increasingly crucial role in diseases. However, it’s unclear the role of IRGs in ALD. Bioinformatic analysis was used to discern the core immune-related differential genes (IRDGs) in the present study. Subsequently, Cell Counting Kit-8 say, oil red O staining, and triglyceride detection were employed to explore optimal experimental conditions of establishing hepatocellular models of early ALD. Ultimately, real-time reverse transcription-PCR and immunohistochemistry/immunocytochemistry methods were adopted to verify the expressions of mRNA and proteins of core IRDGs, respectively. C-X-C Motif Chemokine Ligand 1 (Cxcl1) and Cxcl6 were regarded as core IRDGs via integrated bioinformatics analysis. Besides, Lieber Decarli Ethanol feeding and 200 mM and 300 mM ethanol stimulating L02 cells for 36 h can both successfully hepatocellular model. In ethanol groups, the levels of CXCL1 and CXCL6 mRNA were significantly upregulated than pair-fed groups (P < 0.0001). Also, immunohistochemistry revealed that positive particles of CXCL1 and CXCL6 in mice model of early ALD were obviously more than control groups (P < 0.0001). Besides, in L02 hepatocytes stimulated by ethanol, CXCL1 and CXCL6 mRNA were over-expressed, compared with normal L02 cells (P < 0.0001). Meanwhile, immunocytochemistry indicated that CXCL1 and CXCL6 proteins in hepatocellular model of early ALD were higher than normal L02 hepatocytes stimulus (P < 0.0001). Ethanol promoted the upregulation of Cxcl1 and Cxcl6 mRNA and proteins in models of early ALD, denoting their potentiality of acting as biomarkers of ALD.
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Affiliation(s)
- Yao Jiang
- Clinical Laboratory, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Yuge Xi
- Clinical Laboratory, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Yiqin Li
- Clinical Laboratory, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Zhihua Zuo
- Department of Clinical Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Chuyi Zeng
- Department of Clinical Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Jia Fan
- Clinical Laboratory, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Dan Zhang
- Clinical Laboratory, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Hualin Tao
- Department of Clinical Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yongcan Guo
- Clinical Laboratory, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
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8
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Bardhi E, McDaniels J, Rousselle T, Maluf DG, Mas VR. Nucleic acid biomarkers to assess graft injury after liver transplantation. JHEP REPORTS : INNOVATION IN HEPATOLOGY 2022; 4:100439. [PMID: 35243279 PMCID: PMC8856989 DOI: 10.1016/j.jhepr.2022.100439] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 12/13/2021] [Accepted: 12/20/2021] [Indexed: 02/07/2023]
Abstract
Many risk factors and complications impact the success of liver transplantation, such as ischaemia-reperfusion injury, acute rejection, and primary graft dysfunction. Molecular biomarkers have the potential to accurately diagnose, predict, and monitor injury progression or organ failure. There is a critical opportunity for reliable and non-invasive biomarkers to reduce the organ shortage by enabling i) the assessment of donor organ quality, ii) the monitoring of short- and long-term graft function, and iii) the prediction of acute and chronic disease development. To date, no established molecular biomarkers have been used to guide clinical decision-making in transplantation. In this review, we outline the recent advances in cell-free nucleic acid biomarkers for monitoring graft injury in liver transplant recipients. Prior work in this area can be divided into two categories: biomarker discovery and validation studies. Circulating nucleic acids (CNAs) can be found in the extracellular environment pertaining to different biological fluids such as bile, blood, urine, and perfusate. CNAs that are packaged into extracellular vesicles may facilitate intercellular and interorgan communication. Thus, decoding their biological function, cellular origins and molecular composition is imperative for diagnosing causes of graft injury, guiding immunosuppression and improving overall patient survival. Herein, we discuss the most promising molecular biomarkers, their state of development, and the critical aspects of study design in biomarker research for early detection of post-transplant liver injury. Future advances in biomarker studies are expected to personalise post-transplant therapy, leading to improved patient care and outcomes.
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9
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Non-alcoholic fatty liver disease as a medical and social problem. КЛИНИЧЕСКАЯ ПРАКТИКА 2021. [DOI: 10.17816/clinpract83782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
The article considers the non-alcoholic fatty liver disease as an important medical and social problem. This problem include such questions as metabolic syndrome, essential lipoproteinemia, insulinoresistance. It is possible to consider non-alcoholic steatohepatitis as predictor of liver fibrosis and chirrosis. The questions of diagnosis and treatment are discussed.
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10
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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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11
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Jin W, Zhao Y, Zhai B, Li Y, Fan S, Yuan P, Sun G, Jiang R, Wang Y, Liu X, Tian Y, Kang X, Li G. Characteristics and expression profiles of circRNAs during abdominal adipose tissue development in Chinese Gushi chickens. PLoS One 2021; 16:e0249288. [PMID: 33857153 PMCID: PMC8049301 DOI: 10.1371/journal.pone.0249288] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Accepted: 03/15/2021] [Indexed: 12/14/2022] Open
Abstract
Circular RNAs (circRNAs) play important roles in adipogenesis. However, studies on circRNA expression profiles associated with the development of abdominal adipose tissue are lacking in chickens. In this study, 12 cDNA libraries were constructed from the abdominal adipose tissue of Chinese domestic Gushi chickens at 6, 14, 22, and 30 weeks. A total of 1,766 circRNAs were identified by Illumina HiSeq 2500 sequencing. These circRNAs were primarily distributed on chr1 through chr10 and sex chromosomes, and 84.95% of the circRNAs were from gene exons. Bioinformatic analysis showed that each circRNA has 35 miRNA binding sites on average, and 62.71% have internal ribosome entry site (IRES) elements. Meanwhile, these circRNAs were primarily concentrated in TPM < 0.1 and TPM > 60, and their numbers accounted for 18.90% and 80.51%, respectively, exhibiting specific expression patterns in chicken abdominal adipose tissue. In addition, 275 differentially expressed (DE) circRNAs were identified by comparison analysis. Functional enrichment analysis showed that the parental genes of DE circRNAs were primarily involved in biological processes and pathways related to lipid metabolism, such as regulation of fat cell differentiation, fatty acid homeostasis, and triglyceride homeostasis, as well as fatty acid biosynthesis, fatty acid metabolism, and glycerolipid metabolism. Furthermore, ceRNA regulatory networks related to abdominal adipose development were constructed. The results of this study indicated that circRNAs can regulate lipid metabolism, adipocyte proliferation and differentiation, and cell junctions during abdominal adipose tissue development in chickens through complex ceRNA networks between circRNAs, miRNAs, genes, and pathways. The results of this study may help to expand the number of known circRNAs in abdominal adipose tissue and provide a valuable resource for further research on the function of circRNAs in chicken abdominal adipose tissue.
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Affiliation(s)
- Wenjiao Jin
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, Henan Province, P.R. China
| | - Yinli Zhao
- College of Biological Engineering, Henan University of Technology, Zhengzhou, Henan Province, P.R. China
| | - Bin Zhai
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, Henan Province, P.R. China
| | - Yuanfang Li
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, Henan Province, P.R. China
| | - Shengxin Fan
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, Henan Province, P.R. China
| | - Pengtao Yuan
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, Henan Province, P.R. China
| | - Guirong Sun
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, Henan Province, P.R. China
| | - Ruirui Jiang
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, Henan Province, P.R. China
| | - Yanbin Wang
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, Henan Province, P.R. China
| | - Xiaojun Liu
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, Henan Province, P.R. China
| | - Yadong Tian
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, Henan Province, P.R. China
| | - Xiangtao Kang
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, Henan Province, P.R. China
| | - Guoxi Li
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, Henan Province, P.R. China
- * E-mail:
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12
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Sundrani DP, Karkhanis AR, Joshi SR. Peroxisome Proliferator-Activated Receptors (PPAR), fatty acids and microRNAs: Implications in women delivering low birth weight babies. Syst Biol Reprod Med 2021; 67:24-41. [PMID: 33719831 DOI: 10.1080/19396368.2020.1858994] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Low birth weight (LBW) babies are associated with neonatal morbidity and mortality and are at increased risk for noncommunicable diseases (NCDs) in later life. However, the molecular determinants of LBW are not well understood. Placental insufficiency/dysfunction is the most frequent etiology for fetal growth restriction resulting in LBW and placental epigenetic processes are suggested to be important regulators of pregnancy outcome. Early life exposures like altered maternal nutrition may have long-lasting effects on the health of the offspring via epigenetic mechanisms like DNA methylation and microRNA (miRNA) regulation. miRNAs have been recognized as major regulators of gene expression and are known to play an important role in placental development. Angiogenesis in the placenta is known to be regulated by transcription factor peroxisome proliferator-activated receptor (PPAR) which is activated by ligands such as long-chain-polyunsaturated fatty acids (LCPUFA). In vitro studies in different cell types indicate that fatty acids can influence epigenetic mechanisms like miRNA regulation. We hypothesize that maternal fatty acid status may influence the miRNA regulation of PPAR genes in the placenta in women delivering LBW babies. This review provides an overview of miRNAs and their regulation of PPAR gene in the placenta of women delivering LBW babies.Abbreviations: AA - Arachidonic Acid; Ago2 - Argonaute2; ALA - Alpha-Linolenic Acid; ANGPTL4 - Angiopoietin-Like Protein 4; C14MC - Chromosome 14 miRNA Cluster; C19MC - Chromosome 19 miRNA Cluster; CLA - Conjugated Linoleic Acid; CSE - Cystathionine γ-Lyase; DHA - Docosahexaenoic Acid; EFA - Essential Fatty Acids; E2F3 - E2F transcription factor 3; EPA - Eicosapentaenoic Acid; FGFR1 - Fibroblast Growth Factor Receptor 1; GDM - Gestational Diabetes Mellitus; hADMSCs - Human Adipose Tissue-Derived Mesenchymal Stem Cells; hBMSCs - Human Bone Marrow Mesenchymal Stem Cells; HBV - Hepatitis B Virus; HCC - Hepatocellular Carcinoma; HCPT - Hydroxycamptothecin; HFD - High-Fat Diet; Hmads - Human Multipotent Adipose-Derived Stem; HSCS - Human Hepatic Stellate Cells; IUGR - Intrauterine Growth Restriction; LA - Linoleic Acid; LBW - Low Birth Weight; LCPUFA - Long-Chain Polyunsaturated Fatty Acids; MEK1 - Mitogen-Activated Protein Kinase 1; MiRNA - MicroRNA; mTOR - Mammalian Target of Rapamycin; NCDs - NonCommunicable Diseases; OA - Oleic Acid; PASMC - Pulmonary Artery Smooth Muscle Cell; PLAG1 - Pleiomorphic Adenoma Gene 1; PPAR - Peroxisome Proliferator-Activated Receptor; PPARα - PPAR alpha; PPARγ - PPAR gamma; PPARδ - PPAR delta; pre-miRNA - precursor miRNA; RISC - RNA-Induced Silencing Complex; ROS - Reactive Oxygen Species; SAT - Subcutaneous Adipose Tissue; WHO - World Health Organization.
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Affiliation(s)
- Deepali P Sundrani
- Mother and Child Health, Interactive Research School for Health Affairs (IRSHA), Bharati Vidyapeeth (Deemed to be University), Pune, India
| | - Aishwarya R Karkhanis
- Mother and Child Health, Interactive Research School for Health Affairs (IRSHA), Bharati Vidyapeeth (Deemed to be University), Pune, India
| | - Sadhana R Joshi
- Mother and Child Health, Interactive Research School for Health Affairs (IRSHA), Bharati Vidyapeeth (Deemed to be University), Pune, India
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13
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Seidemann L, Krüger A, Kegel-Hübner V, Seehofer D, Damm G. Influence of Genistein on Hepatic Lipid Metabolism in an In Vitro Model of Hepatic Steatosis. Molecules 2021; 26:molecules26041156. [PMID: 33671486 PMCID: PMC7926972 DOI: 10.3390/molecules26041156] [Citation(s) in RCA: 18] [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: 01/06/2021] [Revised: 02/15/2021] [Accepted: 02/16/2021] [Indexed: 12/18/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is among the leading causes of end-stage liver disease. The impaired hepatic lipid metabolism in NAFLD is exhibited by dysregulated PPARα and SREBP-1c signaling pathways, which are central transcription factors associated with lipid degradation and de novo lipogenesis. Despite the growing prevalence of this disease, current pharmacological treatment options are unsatisfactory. Genistein, a soy isoflavone, has beneficial effects on lipid metabolism and may be a candidate for NAFLD treatment. In an in vitro model of hepatic steatosis, primary human hepatocytes (PHHs) were incubated with free fatty acids (FFAs) and different doses of genistein. Lipid accumulation and the cytotoxic effects of FFAs and genistein treatment were evaluated by colorimetric and enzymatic assays. Changes in lipid homeostasis were examined by RT-qPCR and Western blot analyses. PPARα protein expression was induced in steatotic PHHs, accompanied by an increase in CPT1L and ACSL1 mRNA. Genistein treatment increased PPARα protein expression only in control PHHs, while CPTL1 and ACSL1 were unchanged and PPARα mRNA was reduced. In steatotic PHHs, genistein reversed the increase in activated SREBP-1c protein. The model realistically reflected the molecular changes in hepatic steatosis. Genistein suppressed the activation of SREBP-1c in steatotic hepatocytes, but the genistein-mediated effects on PPARα were abolished by high hepatic lipid levels.
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Affiliation(s)
- Lena Seidemann
- Department of Hepatobiliary Surgery and Visceral Transplantation, University Hospital, Leipzig University, 04103 Leipzig, Germany; (L.S.); (V.K.-H.); (D.S.)
- Saxonian Incubator for Clinical Translation (SIKT), Leipzig University, 04103 Leipzig, Germany
| | - Anne Krüger
- Department of General, Visceral and Transplantation Surgery, Charité University Medicine Berlin, 13353 Berlin, Germany;
| | - Victoria Kegel-Hübner
- Department of Hepatobiliary Surgery and Visceral Transplantation, University Hospital, Leipzig University, 04103 Leipzig, Germany; (L.S.); (V.K.-H.); (D.S.)
| | - Daniel Seehofer
- Department of Hepatobiliary Surgery and Visceral Transplantation, University Hospital, Leipzig University, 04103 Leipzig, Germany; (L.S.); (V.K.-H.); (D.S.)
- Department of General, Visceral and Transplantation Surgery, Charité University Medicine Berlin, 13353 Berlin, Germany;
| | - Georg Damm
- Department of Hepatobiliary Surgery and Visceral Transplantation, University Hospital, Leipzig University, 04103 Leipzig, Germany; (L.S.); (V.K.-H.); (D.S.)
- Saxonian Incubator for Clinical Translation (SIKT), Leipzig University, 04103 Leipzig, Germany
- Department of General, Visceral and Transplantation Surgery, Charité University Medicine Berlin, 13353 Berlin, Germany;
- Correspondence: ; Tel.: +49-341-9739656
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14
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Physicochemical Properties and Effects of Honeys on Key Biomarkers of Oxidative Stress and Cholesterol Homeostasis in HepG2 Cells. Nutrients 2021; 13:nu13010151. [PMID: 33466262 PMCID: PMC7824776 DOI: 10.3390/nu13010151] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 12/03/2020] [Accepted: 12/18/2020] [Indexed: 12/21/2022] Open
Abstract
Manuka honey and newly developed honeys (arjuna, guggul, jiaogulan and olive) were examined for their physicochemical, biochemical properties and effects on oxidative stress and cholesterol homeostasis in fatty acid-induced HepG2 cells. The honeys exhibited standard moisture content (<20%), electrical conductivity (<0.8 mS/cm), acidic pH, and monosaccharides (>60%), except olive honey (<60% total monosaccharides). They all expressed non-Newtonian behavior and 05 typical regions of the FTIR spectra as those of natural ones. Guggul and arjuna, manuka honeys showed the highest phenolic contents, correlating with their significant antioxidant activities. Arjuna, guggul and manuka honeys demonstrated the agreement of total cholesterol reduction and the transcriptional levels of AMPK, SREBP2, HCMGR, LDLR, LXRα. Jiaogulan honey showed the least antioxidant content and activity, but it was the most cytotoxic. Both jiaogulan and olive honeys modulated the tested gene in the pattern that should lead to a lower TC content, but this reduction did not occur after 24 h. All 2% concentrations of tested honeys elicited a clearer effect on NQO1 gene expression. In conclusion, the new honeys complied with international norms for natural honeys and we provide partial evidence for the protective effects of manuka, arjuna and guggul honeys amongst the tested ones on key biomarkers of oxidative stress and cholesterol homeostasis, pending further studies to better understand their modes of action.
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Ramos LF, Silva CM, Pansa CC, Moraes KCM. Non-alcoholic fatty liver disease: molecular and cellular interplays of the lipid metabolism in a steatotic liver. Expert Rev Gastroenterol Hepatol 2021; 15:25-40. [PMID: 32892668 DOI: 10.1080/17474124.2020.1820321] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Non-alcoholic fatty liver disease (NAFLD) affects ~25% of world population and cases have increased in recent decades. These anomalies have several etiologies; however, obesity and metabolic dysfunctions are the most relevant causes. Despite being considered a public health problem, no effective therapeutic approach to treat NAFLD is available. For that, a deep understanding of metabolic routes that support hepatic diseases is needed. AREAS COVERED This review covers aspects of the onset of NAFLD. Thereby, biochemistry routes as well as cellular and metabolic effects of the gut microbiota in body's homeostasis and epigenetics are contextualized. EXPERT OPINION Recently, the development of biological sciences has generated innovative knowledge, bringing new insights and perspectives to clarify the systems biology of liver diseases. A detailed comprehension of epigenetics mechanisms will offer possibilities to develop new therapeutic and diagnostic strategies for NAFLD. Different epigenetic processes have been reported that are modulated by the environment such as gut microbiota, suggesting strong interplays between cellular behavior and pathology. Thus, a more complete description of such mechanisms in hepatic diseases will help to clarify how to control the establishment of fatty liver, and precisely describe molecular interplays that potentially control NAFLD.
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Affiliation(s)
- Letícia F Ramos
- Molecular Biology Laboratory, Departamento de Biologia Geral e Aplicada, Universidade Estadual Paulista "Júlio de Mesquita Filho" - Campus Rio Claro, Instituto de Biociências , Rio Claro, Brazil
| | - Caio M Silva
- Molecular Biology Laboratory, Departamento de Biologia Geral e Aplicada, Universidade Estadual Paulista "Júlio de Mesquita Filho" - Campus Rio Claro, Instituto de Biociências , Rio Claro, Brazil
| | - Camila C Pansa
- Molecular Biology Laboratory, Departamento de Biologia Geral e Aplicada, Universidade Estadual Paulista "Júlio de Mesquita Filho" - Campus Rio Claro, Instituto de Biociências , Rio Claro, Brazil
| | - Karen C M Moraes
- Molecular Biology Laboratory, Departamento de Biologia Geral e Aplicada, Universidade Estadual Paulista "Júlio de Mesquita Filho" - Campus Rio Claro, Instituto de Biociências , Rio Claro, Brazil
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Yang J, Tao D, Ma W, Liu S, Liao Y, Shu L, Zhang S, Li C, Du N, Shi Z. Sijunzi, Lizhong, and Fuzilizhong Decoction Alleviate Nonalcoholic Fatty Liver Disease through Activation of PPAR Pathway. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2020; 2020:6363748. [PMID: 33178320 PMCID: PMC7648686 DOI: 10.1155/2020/6363748] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 09/23/2020] [Accepted: 10/16/2020] [Indexed: 01/30/2023]
Abstract
OBJECTIVE Sijunzi, Lizhong, and Fuzilizhong decoction were traditional Chinese classic formulations, which are widely used in clinical treatment, and the underlying mechanism is unclear. In this study, we aim to investigate the molecular mechanisms underlying the protective effects of Sijunzi, Lizhong, and Fuzilizhong on nonalcoholic fatty liver disease (NAFLD). METHODS Male Wistar rats were fed a high-fat diet for four weeks to induce NAFLD and were thereafter administered Sijunzi (8 g/kg/d), Lizhong (10 g/kg/d), or Fuzilizhong (10 g/kg/d) by gavage for four weeks. Hepatic damage, lipid accumulation, inflammation, autophagy, and peroxisome proliferator-activated receptor-α signaling were evaluated. RESULTS The high-fat diet-fed rats showed typical symptoms of NAFLD, including elevated levels of hepatic damage indicators, increased hepatic lipid deposition and fibrosis, severe liver inflammation, and prominent autophagy. Upon administration of Sijunzi, Lizhong, and Fuzilizhong, liver health was improved remarkably, along with ameliorated symptoms of NAFLD. In addition, NAFLD-suppressed peroxisome proliferator-activated receptor-α signaling was reactivated after treatment with the three types of decoctions. CONCLUSIONS The results collectively signify the effective therapeutic and protective functions of Sijunzi, Lizhong, and Fuzilizhong against NAFLD and demonstrate the potential of Chinese herbal medication in mitigating the symptoms of liver diseases. Novelty of the Work. Traditional Chinese herbal medicine has been used for centuries to treat various diseases, but the molecular mechanisms of individual ingredients have rarely been studied. The novelty of our work lies in elucidating the specific signaling pathways involved in the control of NAFLD using three common Chinese herbal decoctions. We suggest that natural herbal formulations can be effective therapeutic agents to combat against NAFLD.
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Affiliation(s)
- Jiayao Yang
- Department of Gastroenterology, Wuhan Integrated TCM and Western Medicine Hospital, Wuhan, China
| | - Dongqing Tao
- Department of Endocrinology, The Third People's Hospital of Hubei Province, Wuhan, China
| | - Wei Ma
- Department of Center Laboratory, Wuhan Integrated TCM and Western Medicine Hospital, Wuhan, China
| | - Song Liu
- Department of Gastroenterology, Wuhan Integrated TCM and Western Medicine Hospital, Wuhan, China
| | - Yan Liao
- Department of Gastroenterology, Wuhan Integrated TCM and Western Medicine Hospital, Wuhan, China
| | - Lei Shu
- Department of Gastroenterology, Wuhan Integrated TCM and Western Medicine Hospital, Wuhan, China
| | - Shu Zhang
- Department of Gastroenterology, Wuhan Integrated TCM and Western Medicine Hospital, Wuhan, China
| | - Chenyu Li
- Hubei University of Traditional Chinese Medicine, Wuhan, China
| | - Nianlong Du
- Department of Gastroenterology, Wuhan Integrated TCM and Western Medicine Hospital, Wuhan, China
| | - Zhaohong Shi
- Department of Gastroenterology, Wuhan Integrated TCM and Western Medicine Hospital, Wuhan, China
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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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Wang G, Guo G, Tian X, Hu S, Du K, Zhang Q, Mao J, Jia X, Chen S, Wang J, Lai S. Screening and identification of MicroRNAs expressed in perirenal adipose tissue during rabbit growth. Lipids Health Dis 2020; 19:35. [PMID: 32145738 PMCID: PMC7060515 DOI: 10.1186/s12944-020-01219-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2019] [Accepted: 03/03/2020] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND MicroRNAs (miRNAs) regulate adipose tissue development, which are closely related to subcutaneous and intramuscular fat deposition and adipocyte differentiation. As an important economic and agricultural animal, rabbits have low adipose tissue deposition and are an ideal model to study adipose regulation. However, the miRNAs related to fat deposition during the growth and development of rabbits are poorly defined. METHODS In this study, miRNA-sequencing and bioinformatics analyses were used to profile the miRNAs in rabbit perirenal adipose tissue at 35, 85 and 120 days post-birth. Differentially expressed (DE) miRNAs between different stages were identified by DEseq in R. Target genes of DE miRNAs were predicted by TargetScan and miRanda. To explore the functions of identified miRNAs, Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed. RESULTS Approximately 1.6 GB of data was obtained by miRNA-seq. A total of 987 miRNAs (780 known and 207 newly predicted) and 174 DE miRNAs were identified. The miRNAs ranged from 18 nt to 26 nt. GO enrichment and KEGG pathway analyses revealed that the target genes of the DE miRNAs were mainly involved in zinc ion binding, regulation of cell growth, MAPK signaling pathway, and other adipose hypertrophy-related pathways. Six DE miRNAs were randomly selected, and their expression profiles were validated by q-PCR. CONCLUSIONS This is the first report of the miRNA profiles of adipose tissue during different growth stages of rabbits. Our data provide a theoretical reference for subsequent studies on rabbit genetics, breeding and the regulatory mechanisms of adipose development.
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Affiliation(s)
- Guoze Wang
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, 211# Huimin Road, Wenjiang, 611130, Sichuan, China
- Guizhou Medical University, Guiyang, 550025, China
| | - Guo Guo
- Guizhou Medical University, Guiyang, 550025, China
| | - Xueting Tian
- College of Pharmacy and Biological Engineering, Chengdu University, Chengdu, 610106, China
| | - Shenqiang Hu
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, 211# Huimin Road, Wenjiang, 611130, Sichuan, China
| | - Kun Du
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, 211# Huimin Road, Wenjiang, 611130, Sichuan, China
| | | | - Jingxin Mao
- Southwest University, Chongqing, 400715, China
| | - Xianbo Jia
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, 211# Huimin Road, Wenjiang, 611130, Sichuan, China
| | - Shiyi Chen
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, 211# Huimin Road, Wenjiang, 611130, Sichuan, China
| | - Jie Wang
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, 211# Huimin Road, Wenjiang, 611130, Sichuan, China
| | - Songjia Lai
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, 211# Huimin Road, Wenjiang, 611130, Sichuan, China.
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Melatonin Orchestrates Lipid Homeostasis through the Hepatointestinal Circadian Clock and Microbiota during Constant Light Exposure. Cells 2020; 9:cells9020489. [PMID: 32093272 PMCID: PMC7072737 DOI: 10.3390/cells9020489] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Revised: 02/17/2020] [Accepted: 02/17/2020] [Indexed: 02/07/2023] Open
Abstract
Misalignment between natural light rhythm and modern life activities induces disruption of the circadian rhythm. It is mainly evident that light at night (LAN) interferes with the human endocrine system and contributes to the increasing rates of obesity and lipid metabolic disease. Maintaining hepatointestinal circadian homeostasis is vital for improving lipid homeostasis. Melatonin is a chronobiotic substance that plays a main role in stabilizing bodily rhythm and has shown beneficial effects in protecting against obesity. Based on the dual effect of circadian rhythm regulation and antiobesity, we tested the effect of melatonin in mice under constant light exposure. Exposure to 24-h constant light (LL) increased weight and insulin resistance compared with those of the control group (12-h light–12-h dark cycle, LD), and simultaneous supplementation in the melatonin group (LLM) ameliorated this phenotype. Constant light exposure disturbed the expression pattern of a series of transcripts, including lipid metabolism, circadian regulation and nuclear receptors in the liver. Melatonin also showed beneficial effects in improving lipid metabolism and circadian rhythm homeostasis. Furthermore, the LL group had increased absorption and digestion of lipids in the intestine as evidenced by the elevated influx of lipids in the duodenum and decrease in the efflux of lipids in the jejunum. More interestingly, melatonin ameliorated the gut microbiota dysbiosis and improved lipid efflux from the intestine. Thus, these findings offer a novel clue regarding the obesity-promoting effect attributed to LAN and suggest a possibility for obesity therapy by melatonin in which melatonin could ameliorate rhythm disorder and intestinal dysbiosis.
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Viktorovna SE, Alekseevich NY, Yakovlevich PV, Michailovich MI. Association of Arterial Hypertension with Hepatobiliary Pathology: The Occurrence of Comorbidity and Features of Metabolic Processes. Curr Hypertens Rev 2020; 16:138-147. [PMID: 31368876 PMCID: PMC7499357 DOI: 10.2174/1573402115666190801104227] [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] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 07/11/2019] [Accepted: 07/19/2019] [Indexed: 11/22/2022]
Abstract
Comorbidity of hypertension and hepatobiliary pathology has negative medical and social consequences, including an increase in the indicators of hospital admissions, disability and mortality. OBJECTIVE The aim was to study the occurrence of hypertension combined with hepatobiliary diseases depending on social status, gender and age in 2003-2017 and their influence on indicators of metabolic processes in patients with a therapeutic profile. METHODS A cross-sectional study using the inpatients' medical record database of the clinic of Federal Research Centre for Basic and Translational Medicine (Novosibirsk, Russia), which collects demographics, diagnoses (using ICD-10 codes), procedures and examinations of all inpatients from 2003-2017 was conducted. The incidence of comorbidity of hypertension and hepatobiliary pathology depending on age, gender and social status, based on the analysis of 13496 medical records was examined. A comparative analysis of biochemical parameters characterizing the main types of metabolism (lipid, protein, carbohydrate and purine) was carried out in 3 groups of patients: with hypertension; with hepatobiliary pathology, and with a combined pathology. RESULTS During the years 2003-2005, there was the greatest frequency of this comorbidity in workers, in women, in the age group 60 years and older. In 2009-2017, the highest incidence was observed in the male administrative staff. In patients with this comorbidity, more pronounced changes in carbohydrate, protein, lipid and purine metabolism were found in comparison with groups of patients with isolated diseases. CONCLUSION The results highlight the need to improve the system of prevention and treatment of comorbidity taking into account sex, age, occupation and features of metabolism.
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Affiliation(s)
- Sevostyanova E. Viktorovna
- Department of Medical and Environmental Studies, Federal Research Center for Basic and Translational Medicine, Timakova str.2, Novosibirsk, 630117, Russian Federation
| | - Nikolaev Y. Alekseevich
- Department of Medical and Environmental Studies, Federal Research Center for Basic and Translational Medicine, Timakova str.2, Novosibirsk, 630117, Russian Federation
| | - Polyakov V. Yakovlevich
- Department of Medical and Environmental Studies, Federal Research Center for Basic and Translational Medicine, Timakova str.2, Novosibirsk, 630117, Russian Federation
| | - Mitrofanov I. Michailovich
- Department of Medical and Environmental Studies, Federal Research Center for Basic and Translational Medicine, Timakova str.2, Novosibirsk, 630117, Russian Federation
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Koushki M, Zare M, Shabani M, Teimouri M, Hosseini H, Babaei Khorzoughi R, Meshkani R. Resveratrol Reduces Lipid Accumulation through Upregulating the Expression of MicroRNAs Regulating Fatty Acid Bet Oxidation in Liver Cells: Evidence from In-vivo and In-vitro Studies. IRANIAN JOURNAL OF PHARMACEUTICAL RESEARCH : IJPR 2020; 19:333-340. [PMID: 33224240 PMCID: PMC7667538 DOI: 10.22037/ijpr.2019.111745.13332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
MicroRNAs have been shown to regulate lipogenesis in liver. The aim of the present study was to investigate whether the effects of resveratrol (RSV) on lipogenesis are associated with the changes in the expression of two miRNAs (miR-107 and miR-10b) that regulate lipogenic pathways. 30 wild type C57BL/6j male mice were randomly fed three diets: a standard chow diet (ND), a high fat diet (HFD, 60% fat) and the high fat diet supplemented with 0.4% RSV (HFD-RSV) for 16 weeks. HepG2 cells were treated with high glucose (33 mM) and RSV (20 µM) for 24 h. The expression of the genes and miRNAs were measured by real-time PCR. Triglyceride level was increased in the liver of mice and HepG2 cells. In both animal and In-vitro experiments, triglyceride level was significantly decreased in groups treated with RSV. The expression of the miR-107 and miR-10b was significantly upregulated in the liver of HFD mice, whereas HFD-RSV group demonstrated a significant lower expression of both miRNAs compared to HFD group. In addition, RSV treatment significantly upregulated the expression of CPT-1a and PPARα genes in the liver of HFD mice. Moreover, treatment with RSV could reduce the expression of miR-107 and miR-10b and increase the expression of CPT-1a and PPARα in HG-treated HepG2 cells. These evidence, as a whole, suggest that RSV could exert its anti-lipogenic effect partially through alterations in the expression of miR-107 and miR-10b in liver cells.
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Affiliation(s)
- Mehdi Koushki
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| | - Mina Zare
- Recombinant Protein Laboratory, Department of Biochemistry, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Maryam Shabani
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| | - Maryam Teimouri
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| | - Hossein Hosseini
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| | - Reyhaneh Babaei Khorzoughi
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| | - Reza Meshkani
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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22
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Zhang L, Wu K, Bo T, Zhou L, Gao L, Zhou X, Chen W. Integrated microRNA and proteome analysis reveal a regulatory module in hepatic lipid metabolism disorders in mice with subclinical hypothyroidism. Exp Ther Med 2019; 19:897-906. [PMID: 32010250 PMCID: PMC6966133 DOI: 10.3892/etm.2019.8281] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Accepted: 11/11/2019] [Indexed: 12/12/2022] Open
Abstract
Subclinical hypothyroidism (SCH) is becoming a global health problem due to its increasing prevalence and potential adverse effects, including cardiovascular diseases and nonalcoholic fatty liver disease (NAFLD). However, the association between SCH and NAFLD remains controversial. MicroRNAs (miRNAs/miRs) have been reported to be implicated in lipid metabolism disorders; however, how miRNAs regulate hepatic lipid metabolism in SCH mice remains unknown. The present study investigated miRNA alterations and proteome profiles in an SCH mouse model, which was generated by methimazole administration in mice for 16 weeks. Next, the profiles of 17 miRNAs that are critical to hepatic lipid metabolism and the proteome were investigated using reverse transcription-quantitative polymerase chain reaction and iTRAQ labeling in the liver specimens of SCH (n=9) and control (n=7) mice. Putative target prediction of miRNAs was also conducted using TargetScan and miRanda. Compared with the control mice, SCH mice had 8 miRNAs and 36 proteins with significantly different expression in the liver tissues. Furthermore, a regulatory module containing 3 miRNAs (miR-34a-5p, miR-24-3p and miR-130a-3p) and 4 proteins (thioredoxin, selenium-binding protein 2, elongation factor 1β and prosaposin) was identified. Overall, integrated analysis of miRNAs and the proteome highlighted a regulatory module between miRNAs and proteins, which, to a certain extent, may contribute to a better understanding of hepatic lipid metabolism disorders in SCH mice.
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Affiliation(s)
- Liya Zhang
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China.,Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Shandong Academy of Clinical Medicine, Jinan, Shandong 250021, P.R. China.,Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, Shandong 250021, P.R. China
| | - Kunpeng Wu
- Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, Shandong 250021, P.R. China.,Department of Hematology, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Tao Bo
- Scientific Center, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Lingyan Zhou
- Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, Shandong 250021, P.R. China.,Department of Endocrinology and Metabolism, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Ling Gao
- Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Shandong Academy of Clinical Medicine, Jinan, Shandong 250021, P.R. China.,Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, Shandong 250021, P.R. China.,Scientific Center, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Xiaoming Zhou
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China.,Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Shandong Academy of Clinical Medicine, Jinan, Shandong 250021, P.R. China.,Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, Shandong 250021, P.R. China
| | - Wenbin Chen
- Scientific Center, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
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23
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Xie J, Fang H, Liao S, Guo T, Yin P, Liu Y, Tian L, Niu J. Study on Schizochytrium sp. improving the growth performance and non-specific immunity of golden pompano (Trachinotus ovatus) while not affecting the antioxidant capacity. FISH & SHELLFISH IMMUNOLOGY 2019; 95:617-623. [PMID: 31622676 DOI: 10.1016/j.fsi.2019.10.028] [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: 05/22/2019] [Revised: 09/13/2019] [Accepted: 10/11/2019] [Indexed: 06/10/2023]
Abstract
A feeding experiment was conducted to determine the effects of Schizochytrium sp. on growth performance, antioxidant capacity and non-specific immunity in golden pompano (Trachinotus ovatus).Two diets were formulated with or without Schizochytrium sp. supplemented (D1:0% and D2: 3%) to feed fish for 8 weeks. Results showed that growth performance, feed intake and survival rate increased significantly with Schizochytrium sp. supplemented (P < 0.05). Feed coefficient rate (FCR) of golden pompano fed the diet supplemented with Schizochytrium sp. was significantly lower than that of fish fed the control diet (P < 0.05). No significant differences were found in antioxidant capacity both in transcriptional level, including nclear factor erythroid-2-related factor-2 (Nrf2), Kelch-like-ECH-associated protein (keap1), catalase (CAT), glutathione peroxidase (GSH-PX) and heme oxygenase 1 (HO-1) and enzyme activity, such as total antioxidant capacity (T-AOC), malondialdehyde (MDA) and superoxide dismutase (SOD) (P > 0.05). Gut amylase and lipase were significantly higher in dietary Schizochytrium sp. supplemented treatment than that in control group (P < 0.05). The relative peroxisome proliferator-activated receptor-α (PPARα) expression level in liver was significantly higher in Schizochytrium sp supplemented treatment than that in control one (P < 0.05). The mRNA expression of myeloid differentiation factor 88 (MyD88), IL-1R-associated kinases 4 (IRAK4), interferon regulating Factor 3 (IRF3), interferon regulating Factor 3(IRF7) and heat shock protein 70 (HSP70) were significantly lower in Schizochytrium sp. supplemented treatment than that in control one (P < 0.05). In Schizochytrium sp. supplemented diet, golden pompano had significantly longer villi length than that in control diet (P < 0.05); muscle thickness in Schizochytrium sp. supplemented diet was thicker than that in control one (P < 0.05) and there were more goblet cells in Schizochytrium sp. treatment (P < 0.05). After the rearing trial, an air exposure trial was conducted. Results showed that the air-exposure mortality (AEM) and mRNA expression level of Nrf2, keap1, CAT, GSH-PX and HO-1 showed no significant difference (P > 0.05). These results indicated that dietary Schizochytrium sp. improved the growth performance and non-specific immunity of golden pompano while made no difference to antioxidant capacity.
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Affiliation(s)
- Jiajun Xie
- State Key Laboratory of Biocontrol, Institute of Aquatic Economic Animal and Guangdong Province Key Laboratory for Aquatic Economic Animals, School of Life Science, Sun Yat-sen University, Guangzhou, 510275, PR China
| | - Haohang Fang
- State Key Laboratory of Biocontrol, Institute of Aquatic Economic Animal and Guangdong Province Key Laboratory for Aquatic Economic Animals, School of Life Science, Sun Yat-sen University, Guangzhou, 510275, PR China
| | - Shiyu Liao
- State Key Laboratory of Biocontrol, Institute of Aquatic Economic Animal and Guangdong Province Key Laboratory for Aquatic Economic Animals, School of Life Science, Sun Yat-sen University, Guangzhou, 510275, PR China
| | - Tianyu Guo
- State Key Laboratory of Biocontrol, Institute of Aquatic Economic Animal and Guangdong Province Key Laboratory for Aquatic Economic Animals, School of Life Science, Sun Yat-sen University, Guangzhou, 510275, PR China
| | - Peng Yin
- State Key Laboratory of Biocontrol, Institute of Aquatic Economic Animal and Guangdong Province Key Laboratory for Aquatic Economic Animals, School of Life Science, Sun Yat-sen University, Guangzhou, 510275, PR China
| | - Yongjian Liu
- State Key Laboratory of Biocontrol, Institute of Aquatic Economic Animal and Guangdong Province Key Laboratory for Aquatic Economic Animals, School of Life Science, Sun Yat-sen University, Guangzhou, 510275, PR China
| | - Lixia Tian
- State Key Laboratory of Biocontrol, Institute of Aquatic Economic Animal and Guangdong Province Key Laboratory for Aquatic Economic Animals, School of Life Science, Sun Yat-sen University, Guangzhou, 510275, PR China
| | - Jin Niu
- State Key Laboratory of Biocontrol, Institute of Aquatic Economic Animal and Guangdong Province Key Laboratory for Aquatic Economic Animals, School of Life Science, Sun Yat-sen University, Guangzhou, 510275, PR China.
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24
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Huang J, Wang S, Feng X, Liu X, Zhao J, Zheng Q, Wei X, Ma Y. miRNA transcriptome comparison between muscle and adipose tissues indicates potential miRNAs associated with intramuscular fat in Chinese swamp buffalo. Genome 2019; 62:729-738. [PMID: 31398299 DOI: 10.1139/gen-2018-0178] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The amount of intramuscular fat (IMF) affects the tenderness and juiciness of beef and is an important indicator of beef quality. A few miRNAs involved in IMF deposition have been identified in other livestock. However, in the buffalo, the association between miRNA and IMF has not been reported and the miRNA expression profile remains poorly understood. In this study, small RNA sequencing was performed to characterize the miRNA expression pattern in muscle and adipose tissues using the Illumina platform. A total of 108 differentially expressed (DE) miRNAs were identified, including 98 known miRNAs and 10 novel miRNAs. A qRT-PCR experiment confirmed the quality of the DE analysis. Eight DE miRNAs showed high expression in adipose tissue and a considerable expression level in muscle tissue. Functional enrichment indicated that bta-miR-148a, bta-miR-143, bta-miR-10b, bta-let-7i, bta-let-7f, bta-let-7b, bta-miR-30a-5p, and bta-miR-100 were significantly associated with adipogenesis, suggesting these as candidate regulators for IMF deposition in buffalo. However, further functional validation is required. This is the first characterization of the miRNA expression profile in the muscle and adipose tissues of buffalo. These results provide information for the identification of miRNAs with potential effects on IMF deposition in buffalo.
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Affiliation(s)
- Jieping Huang
- College of Life Sciences, Xinyang Normal University, Xinyang, Henan, 464000, China
| | - Shuzhe Wang
- College of Life Sciences, Xinyang Normal University, Xinyang, Henan, 464000, China
| | - Xue Feng
- College of Life Sciences, Xinyang Normal University, Xinyang, Henan, 464000, China
| | - Xiaoyan Liu
- College of Life Sciences, Xinyang Normal University, Xinyang, Henan, 464000, China
| | - Jinhui Zhao
- College of Life Sciences, Xinyang Normal University, Xinyang, Henan, 464000, China
| | - Qiuzhi Zheng
- College of Life Sciences, Xinyang Normal University, Xinyang, Henan, 464000, China
| | - Xuefeng Wei
- College of Life Sciences, Xinyang Normal University, Xinyang, Henan, 464000, China
| | - Yun Ma
- College of Life Sciences, Xinyang Normal University, Xinyang, Henan, 464000, China.,School of Agriculture, Ningxia University, Yinchuan, Ningxia, 750021, China
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25
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Seiri P, Abi A, Soukhtanloo M. PPAR-γ: Its ligand and its regulation by microRNAs. J Cell Biochem 2019; 120:10893-10908. [PMID: 30770587 DOI: 10.1002/jcb.28419] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Accepted: 12/04/2018] [Indexed: 01/24/2023]
Abstract
Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear receptor superfamily. PPARs are categorized into three subtypes, PPARα, β/δ, and γ, encoded by different genes, expressed in diverse tissues and participate in various biological functions and can be activated by their metabolic derivatives in the body or dietary fatty acids. The PPAR-γ also takes parts in the regulation of energy balance, lipoprotein metabolism, insulin sensitivity, oxidative stress, and inflammatory signaling. It has been implicated in the pathology of numerous diseases including obesity, diabetes, atherosclerosis, and cancers. Among various cellular and molecular targets that are able to regulate PPAR-γ and its underlying pathways, microRNAs (miRNAs) appeared as important regulators. Given that the deregulation of these molecules via targeting PPAR-γ could affect initiation and progression of various diseases, identification of miRNAs that affects PPAR-γ could contribute to the better understanding of roles of PPAR-γ in various biological and pathological conditions. Here, we have summarized the function and various ligands of PPAR-γ and have highlighted various miRNAs involved in the regulation of PPAR-γ.
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Affiliation(s)
- Parvaneh Seiri
- Department of Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Abbas Abi
- Department of Biotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Soukhtanloo
- Department of Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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26
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Desgagné V, Guérin R, Guay SP, Boyer M, Hutchins E, Picard S, Maréchal A, Corbin F, Keuren-Jensen KV, Arsenault BJ, Bouchard L. Human high-density lipoprotein microtranscriptome is unique and suggests an extended role in lipid metabolism. Epigenomics 2019; 11:917-934. [PMID: 31144512 DOI: 10.2217/epi-2018-0161] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Aim: To comprehensively characterize the high-density lipoproteins (HDLs) microtranscriptome and to assess whether it is distinct from that of plasma and different between women and men. Methods: RNA was extracted from ultracentrifugation-purified HDLs and plasma from 17 healthy women and men couples, and libraries were sequenced on a HiSeq2500 platform. Results: On average, 310 ± 64 and 355 ± 31 miRNAs were detected (≥1 read per million) in HDLs and plasma, respectively. A total of 62 and 134 miRNAs were over-represented (e.g., miR-150-5p; fold change = 7.52; padj = 5.41 × 10-111) and under-represented (e.g., miR-22-3p; fold change = -5.28; padj = 2.11 × 10-154) in HDLs compared with plasma. These miRNAs were enriched in lipid metabolism and cellular processes-related pathways. Conclusion: HDLs exhibit a sex-independent miRNA profile distinct from that of plasma. These miRNAs may contribute to the HDLs' physiology.
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Affiliation(s)
- Véronique Desgagné
- Department of Biochemistry, Université de Sherbrooke, Sherbrooke, Québec, J1H 5N4, Canada.,ECOGENE-21 Biocluster, CIUSSS du Saguenay-Lac-St-Jean - Hôpital de Chicoutimi, Saguenay, Québec, G7H 5H6, Canada
| | - Renée Guérin
- Department of Biochemistry, Université de Sherbrooke, Sherbrooke, Québec, J1H 5N4, Canada.,Department of Laboratory Medicine, CIUSSS du Saguenay-Lac-St-Jean - Hôpital de Chicoutimi, Saguenay, Québec, G7H 5H6, Canada
| | - Simon-Pierre Guay
- Department of Biochemistry, Université de Sherbrooke, Sherbrooke, Québec, J1H 5N4, Canada.,ECOGENE-21 Biocluster, CIUSSS du Saguenay-Lac-St-Jean - Hôpital de Chicoutimi, Saguenay, Québec, G7H 5H6, Canada.,Department of Medicine, Programme de formation médicale à Saguenay (PFMS), Université de Sherbrooke, Sherbrooke, Québec, G7H 2B1, Canada.,Department of Medical Genetics, MUHC, McGill University, Montreal, Québec, H4A 3J1, Canada
| | - Marjorie Boyer
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (IUCPQ), Québec City, Québec, G1V 4G5, Canada.,Department of medicine, Faculty of Medicine, Université Laval, Québec City, Québec, G1V 0A6, Canada
| | - Elizabeth Hutchins
- Neurogenomics Division, Translational Genomics Research Institute (TGen), Phoenix, Arizona, 85004, USA
| | - Samuel Picard
- Department of Biology, Université de Sherbrooke, Sherbrooke, Québec, J1K 2R1, Canada
| | - Alexandre Maréchal
- Department of Biology, Université de Sherbrooke, Sherbrooke, Québec, J1K 2R1, Canada
| | - François Corbin
- Department of Biochemistry, Université de Sherbrooke, Sherbrooke, Québec, J1H 5N4, Canada
| | - Kendall Van Keuren-Jensen
- Neurogenomics Division, Translational Genomics Research Institute (TGen), Phoenix, Arizona, 85004, USA
| | - Benoit J Arsenault
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (IUCPQ), Québec City, Québec, G1V 4G5, Canada.,Department of medicine, Faculty of Medicine, Université Laval, Québec City, Québec, G1V 0A6, Canada
| | - Luigi Bouchard
- Department of Biochemistry, Université de Sherbrooke, Sherbrooke, Québec, J1H 5N4, Canada.,ECOGENE-21 Biocluster, CIUSSS du Saguenay-Lac-St-Jean - Hôpital de Chicoutimi, Saguenay, Québec, G7H 5H6, Canada.,Department of Laboratory Medicine, CIUSSS du Saguenay-Lac-St-Jean - Hôpital de Chicoutimi, Saguenay, Québec, G7H 5H6, Canada
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27
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Yu J, Peng J, Luan Z, Zheng F, Su W. MicroRNAs as a Novel Tool in the Diagnosis of Liver Lipid Dysregulation and Fatty Liver Disease. Molecules 2019; 24:molecules24020230. [PMID: 30634538 PMCID: PMC6358728 DOI: 10.3390/molecules24020230] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2018] [Revised: 12/23/2018] [Accepted: 12/24/2018] [Indexed: 02/07/2023] Open
Abstract
In recent years, metabolic disorder, especially fatty liver disease, has been considered a major challenge to global health. The attention of researchers focused on expanding knowledge of the regulation mechanism behind these diseases and towards the new diagnostics tools and treatments. The pathophysiology of the fatty liver disease is undoubtedly complex. Abnormal hepatic lipid accumulation is a major symptom of most metabolic diseases. Therefore, the identification of novel regulation factors of lipid metabolism is important and meaningful. As a new diagnostic tool, the function of microRNAs during fatty liver disease has recently come into notice in biological research. Accumulating evidence supports the influence of miRNAs in lipid metabolism. In this review, we discuss the potential role of miRNAs in liver lipid metabolism and the pathogenesis of fatty liver disease.
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Affiliation(s)
- Jingwei Yu
- Shenzhen University Medical Center, Shenzhen University Health Science Center, Shenzhen 518060, China.
- Department of Biology, Guangdong Pharmaceutical University, Guangzhou 510006, China.
| | - Jun Peng
- Shenzhen University Medical Center, Shenzhen University Health Science Center, Shenzhen 518060, China.
| | - Zhilin Luan
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, Liaoning 116044, China.
| | - Feng Zheng
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, Liaoning 116044, China.
| | - Wen Su
- Shenzhen University Medical Center, Shenzhen University Health Science Center, Shenzhen 518060, China.
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28
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Jia N, Lin X, Ma S, Ge S, Mu S, Yang C, Shi S, Gao L, Xu J, Bo T, Zhao J. Amelioration of hepatic steatosis is associated with modulation of gut microbiota and suppression of hepatic miR-34a in Gynostemma pentaphylla (Thunb.) Makino treated mice. Nutr Metab (Lond) 2018; 15:86. [PMID: 30555521 PMCID: PMC6282400 DOI: 10.1186/s12986-018-0323-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Accepted: 11/26/2018] [Indexed: 02/07/2023] Open
Abstract
Background Non-alcoholic fatty liver disease (NAFLD) is a chronic and progressive liver disease with an increased risk of morbidity and mortality. However, so far no specific pharmacotherapy has been approved. Gynostemma pentaphylla (Thunb.) Makino (GP) is a traditional Chinese medicine that is widely used against hyperlipemia as well as hyperglycemia. This study aims to evaluate the effect of GP on NAFLD and explore the possible mechanism. Methods High-fat-diet induced NAFLD mice model were orally administrated with GP at dose of 11.7 g/kg or equivalent volume of distilled water once a day for 16 weeks. Body weight, food intake and energy expenditure were assessed to evaluate the general condition of mice. The triglycerides, total cholesterol content in the liver and liver histopathology, serum lipid profile and serum insulin level, fecal microbiome, hepatic microRNAs and relative target genes were analyzed. Results Mice in GP treatment group displayed improved hepatic triglycerides content with lower lipid droplet in hepatocyte and NAFLD activity score. Besides, GP treatment altered the composition of gut microbiota and the relative abundance of some of the key components that are implicated in metabolic disorders, especially phylum Firmicutes (Eubacterium, Blautia, Clostridium and Lactobacillus). Several hepatic microRNAs were downregulated by GP treatment such as miR-130a, miR-34a, miR-29a, miR-199a, among which the expression miR-34a was altered by more than four-fold compared to that of HFD group (3:14). The correlation analysis showed that miR-34a was strongly related to the change of gut microbiota especially phylum Firmicutes (R = 0.796). Additionally, the target genes of miR-34a (HNF4α, PPARα and PPARα) were restored by GP both in mRNA and protein levels. Conclusion Our results suggested that GP modulated the gut microbiota and suppressed hepatic miR-34a, which was associated with the amelioration of hepatic steatosis.
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Affiliation(s)
- Ning Jia
- 1Shandong University of Traditional Chinese Medicine, Jinan, 250355 China.,2Department of Endocrinology, Shandong Provincial Hospital affiliated to Shandong University, Jinan, 250021 China.,Shandong Provincial Key Laboratory of Institute of Endocrinology and Lipid Metabolism, Jinan, 250021 China.,Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, 250021 China
| | - Xiaoyan Lin
- 6Department of Pathology, Shandong Provincial Hospital affiliated to Shandong University, 324, Jing 5 Rd, Jinan, 250021 China
| | - Shizhan Ma
- 2Department of Endocrinology, Shandong Provincial Hospital affiliated to Shandong University, Jinan, 250021 China.,Shandong Provincial Key Laboratory of Institute of Endocrinology and Lipid Metabolism, Jinan, 250021 China.,Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, 250021 China
| | - Shujian Ge
- 7Department of Scientific Research, Shandong Provincial Hospital affiliated to Shandong University, 324, Jing 5 Rd, Jinan, 250021 China
| | - Shumin Mu
- 8Department of Endocrinology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014 China
| | - Chongbo Yang
- 2Department of Endocrinology, Shandong Provincial Hospital affiliated to Shandong University, Jinan, 250021 China.,Shandong Provincial Key Laboratory of Institute of Endocrinology and Lipid Metabolism, Jinan, 250021 China.,Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, 250021 China
| | - Shulong Shi
- 1Shandong University of Traditional Chinese Medicine, Jinan, 250355 China.,2Department of Endocrinology, Shandong Provincial Hospital affiliated to Shandong University, Jinan, 250021 China.,Shandong Provincial Key Laboratory of Institute of Endocrinology and Lipid Metabolism, Jinan, 250021 China.,Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, 250021 China
| | - Ling Gao
- Shandong Provincial Key Laboratory of Institute of Endocrinology and Lipid Metabolism, Jinan, 250021 China.,Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, 250021 China.,5Scientific Center, Shandong Provincial Hospital affiliated to Shandong University, 324, Jing 5 Rd, Jinan, 250021 China
| | - Jin Xu
- 2Department of Endocrinology, Shandong Provincial Hospital affiliated to Shandong University, Jinan, 250021 China.,Shandong Provincial Key Laboratory of Institute of Endocrinology and Lipid Metabolism, Jinan, 250021 China.,Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, 250021 China
| | - Tao Bo
- 5Scientific Center, Shandong Provincial Hospital affiliated to Shandong University, 324, Jing 5 Rd, Jinan, 250021 China
| | - Jiajun Zhao
- 1Shandong University of Traditional Chinese Medicine, Jinan, 250355 China.,2Department of Endocrinology, Shandong Provincial Hospital affiliated to Shandong University, Jinan, 250021 China.,Shandong Provincial Key Laboratory of Institute of Endocrinology and Lipid Metabolism, Jinan, 250021 China.,Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, 250021 China
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29
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Torres JL, Novo-Veleiro I, Manzanedo L, Alvela-Suárez L, Macías R, Laso FJ, Marcos M. Role of microRNAs in alcohol-induced liver disorders and non-alcoholic fatty liver disease. World J Gastroenterol 2018; 24:4104-4118. [PMID: 30271077 PMCID: PMC6158486 DOI: 10.3748/wjg.v24.i36.4104] [Citation(s) in RCA: 90] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Revised: 06/25/2018] [Accepted: 06/27/2018] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that regulate multiple physiological and pathological functions through the modulation of gene expression at the post-transcriptional level. Accumulating evidence has established a role for miRNAs in the development and pathogenesis of liver disease. Specifically, a large number of studies have assessed the role of miRNAs in alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD), two diseases that share common underlying mechanisms and pathological characteristics. The purpose of the current review is to summarize and update the body of literature investigating the role of miRNAs in liver disease. In addition, the potential use of miRNAs as biomarkers and/or therapeutic targets is discussed. Among all miRNAs analyzed, miR-34a, miR-122 and miR-155 are most involved in the pathogenesis of NAFLD. Of note, these three miRNAs have also been implicated in ALD, reinforcing a common disease mechanism between these two entities and the pleiotropic effects of specific miRNAs. Currently, no single miRNA or panel of miRNAs has been identified for the detection of, or staging of ALD or NAFLD. While promising results have been shown in murine models, no therapeutic based-miRNA agents have been developed for use in humans with liver disease.
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Affiliation(s)
- Jorge-Luis Torres
- Department of Internal Medicine, University Hospital of Salamanca, Institute of Biomedical Research of Salamanca-IBSAL, Salamanca 37007, Spain
- Spanish Working Group on Alcohol and Alcoholism, Spanish Society of Internal Medicine, Madrid 28016, Spain
| | - Ignacio Novo-Veleiro
- Department of Internal Medicine, University Hospital of Santiago de Compostela, A Coruña 15706, Spain
- Spanish Working Group on Alcohol and Alcoholism, Spanish Society of Internal Medicine, Madrid 28016, Spain
| | - Laura Manzanedo
- Department of Internal Medicine, University Hospital of Salamanca, Institute of Biomedical Research of Salamanca-IBSAL, Salamanca 37007, Spain
| | - Lucía Alvela-Suárez
- Department of Internal Medicine, HM Rosaleda Hospital, Santiago de Compostela, A Coruña 15701, Spain
| | - Ronald Macías
- Department of Internal Medicine, University Hospital of Salamanca, Institute of Biomedical Research of Salamanca-IBSAL, Salamanca 37007, Spain
| | - Francisco-Javier Laso
- Department of Internal Medicine, University Hospital of Salamanca, Institute of Biomedical Research of Salamanca-IBSAL, Salamanca 37007, Spain
- Department of Medicine, Faculty of Medicine, University of Salamanca, Salamanca 37007, Spain
- Spanish Working Group on Alcohol and Alcoholism, Spanish Society of Internal Medicine, Madrid 28016, Spain
| | - Miguel Marcos
- Department of Internal Medicine, University Hospital of Salamanca, Institute of Biomedical Research of Salamanca-IBSAL, Salamanca 37007, Spain
- Department of Medicine, Faculty of Medicine, University of Salamanca, Salamanca 37007, Spain
- Spanish Working Group on Alcohol and Alcoholism, Spanish Society of Internal Medicine, Madrid 28016, Spain
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Iravani F, Hosseini N, Mojarrad M. Role of MicroRNAs in Pathophysiology of Non-alcoholic Fatty Liver Disease and Non-alcoholic Steatohepatitis. Middle East J Dig Dis 2018; 10:213-219. [PMID: 31049168 PMCID: PMC6488503 DOI: 10.15171/mejdd.2018.113] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Accepted: 07/14/2018] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder worldwide. It
includes wide range of diseases from different subtypes of simple steatosis to non-alcoholic steatohepatitis
(NASH), which may be complicated by liver fibrosis, cirrhosis, or hepatocellular carcinoma.
Of the epigenetic factors that play a key role in the progression of it, is microRNAs (miRNAs).
MiRNAs are short non-coding RNAs of 22-23 nucleotides in length, which regulate a large
number of genes that have a critical role in regulation of lipid and cholesterol biosynthesis in
hepatocytes. MiRNAs can be used as a very powerful biomarker to diagnosis and follow-up any
disorder, such as NAFLD and NASH with a high specificity and sensitivity. The aim of this study
was to review the role of different miRNAs in the pathophysiology of NASH and NAFLD
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Affiliation(s)
- Farzaneh Iravani
- MSc of human genetics, Department of Medical Genetics, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Neda Hosseini
- MSc of Molecular and Cellular biology, Medical Genetics Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Mojarrad
- Assistant Professor of Medical Genetics, Medical Genetics Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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Adams BD, Arem H, Hubal MJ, Cartmel B, Li F, Harrigan M, Sanft T, Cheng CJ, Pusztai L, Irwin ML. Exercise and weight loss interventions and miRNA expression in women with breast cancer. Breast Cancer Res Treat 2018; 170:55-67. [PMID: 29511965 PMCID: PMC6444907 DOI: 10.1007/s10549-018-4738-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Accepted: 02/26/2018] [Indexed: 02/06/2023]
Abstract
PURPOSE Obesity and weight gain are associated with comorbidities including a higher risk of tumor recurrence and cancer-related deaths among breast cancer (BC) survivors; however, the underlying mechanisms linking obesity and cancer are poorly understood. Given the lack of clinically validated BC biomarkers, obesity and weight-loss studies utilize serum biomarkers as the intermediary outcomes of tumor recurrence. Studies have indicated microRNAs (miRNA)s are reliable biomarkers for cancer. We hypothesized that miRNA expression correlates with obesity and weight loss amongst BC survivors. This would yield insight into the biological pathways by which this association occurs, enabling more precise development of therapeutics. PATIENTS AND METHODS We correlated baseline body mass index (BMI) with serum miRNA expression in 121 BC survivors enrolled in the Hormones and Physical Exercise (HOPE) trial. We then analyzed expression of the 35 most abundant miRNAs from HOPE in a six-month randomized controlled weight-loss trial (Lifestyle, Exercise, and Nutrition; LEAN) in 100 BC survivors. Ingenuity pathway analysis (IPA) software was used to identify biological pathway targets of the BMI-associated and intervention-responsive miRNAs using predictive biomarkers. RESULTS Pearson correlations in HOPE identified eight miRNAs associated with BMI, including miR-191-5p (r = - 0.22, p = 0.016) and miR-122-5p (r = 0.25, p = 0.0048). In the LEAN validation study, levels of miR-191-5p significantly increased during the six-month intervention (p = 0.082). Ingenuity Pathway Analysis identified "Estrogen-mediated S-phase entry" (HOPE p = 0.003; LEAN p < 0.001) and "Molecular mechanisms of cancer" (HOPE p = 0.02; LEAN p < 0.001) as the top canonical pathways that significantly correlated with BMI-associated and intervention-responsive miRNAs and contain obesity and cancer-relevant genes including the E2F family of transcription factors and CCND1, which have been implicated in sporadic BC. CONCLUSION While the association between obesity and BC recurrence and mortality has been demonstrated in the literature, mechanisms underlying the link between weight gain and cancer are unclear. Using two independent clinical trials, we identified novel miRNAs associative to BMI and weight loss that contribute to the development of cancer. Predictive modeling of miRNA targets identified multiple canonical pathways associated with cancer, highlighting potential mechanisms explaining the link between BMI and increased cancer risk.
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Affiliation(s)
- Brian D Adams
- The RNA Institute, University at Albany State University of New York, Albany, NY, 12222, USA
- Investigative Medicine Program, Yale University Medical School, New Haven, CT, 06520, USA
- Department of RNA Sciences, The Brain Institute of America, Groton, CT, 06340, USA
| | - Hannah Arem
- Department of Epidemiology and Biostatistics, Milken Institute of Public Health George Washington University, Washington, DC, 20052, USA
| | - Monica J Hubal
- Department of Exercise and Nutrition Sciences, Milken Institute of Public Health George Washington University, Washington, DC, 20052, USA
| | | | - Fangyong Li
- Yale Center for Analytical Sciences, Yale School of Public Health, New Haven, CT, 06510, USA
| | | | - Tara Sanft
- Yale Medical Oncology, Smilow Cancer Center at Yale New Haven Hospital, New Haven, CT, 06511, USA
| | - Christopher J Cheng
- Division of Nucleic Acid Technology, Alexion Pharmaceuticals, Cheshire, CT, 06410, USA
| | - Lajos Pusztai
- Yale Medical Oncology, Smilow Cancer Center at Yale New Haven Hospital, New Haven, CT, 06511, USA
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Fu S, Zhao Y, Li Y, Li G, Chen Y, Li Z, Sun G, Li H, Kang X, Yan F. Characterization of miRNA transcriptome profiles related to breast muscle development and intramuscular fat deposition in chickens. J Cell Biochem 2018; 119:7063-7079. [PMID: 29737555 DOI: 10.1002/jcb.27024] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2018] [Accepted: 04/06/2018] [Indexed: 12/31/2022]
Abstract
Studies of the miRNA expression profiles associated with the postnatal late development of skeletal muscle and IMF deposition are lacking in chicken. Here, we evaluated the patterns of muscle fiber growth and IMF deposition in breast muscle in the Chinese domestic breed called Gushi chicken, where we constructed four small RNA libraries from breast muscle tissues at 6, 14, 22, and 30 weeks. A total of 388 known miRNAs and 31 novel miRNAs were identified based on four small RNA libraries. Comparative analysis identified 92 significant differentially expressed (SDE) miRNAs based on six combinations. KEGG pathway analysis for the SDE miRNAs showed that metabolic pathways such as glycolysis and biosynthesis of amino acids were significantly enriched before 22 weeks, and pathways such as biosynthesis of unsaturated fatty acids and fatty acid elongation were significantly enriched after 22 weeks. This trend was consistent with the patterns of breast muscle fiber growth and IMF deposition in Gushi chickens. We also constructed miRNA-mRNA interaction networks related to breast muscle development and IMF deposition. The results showed that miRNAs such as gga-miR-1a-3p, and gga-miR-133a-5p may play important roles in breast muscle development, and miRNAs such as gga-miR-103-3p, and gga-miR-138-2-3p may have key roles in IMF deposition. This study determined the dynamic miRNA transcriptome in breast muscle tissue for the first time in Gushi chickens. The results provide a valuable resource for investigating the post-transcriptional regulation mechanisms during postnatal late development of breast muscle and IMF deposition and for evaluating the muscular disease.
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Affiliation(s)
- Shouyi Fu
- College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zheng Zhou, Henan Province, P. R. China
| | - Yinli Zhao
- College of Biological Engineering, Henan University of Technology, Zheng Zhou, Henan Province, P. R. China
| | - Yuanfang Li
- College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zheng Zhou, Henan Province, P. R. China
| | - Guoxi Li
- College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zheng Zhou, Henan Province, P. R. China
| | - Yi Chen
- College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zheng Zhou, Henan Province, P. R. China
| | - Zhuanjian Li
- College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zheng Zhou, Henan Province, P. R. China
| | - Guirong Sun
- College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zheng Zhou, Henan Province, P. R. China
| | - Hong Li
- College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zheng Zhou, Henan Province, P. R. China
| | - Xiangtao Kang
- College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zheng Zhou, Henan Province, P. R. China
| | - Fengbin Yan
- College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zheng Zhou, Henan Province, P. R. China
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Lei L, Zhou C, Yang X, Li L. Down-regulation of microRNA-375 regulates adipokines and inhibits inflammatory cytokines by targeting AdipoR2 in non-alcoholic fatty liver disease. Clin Exp Pharmacol Physiol 2018; 45:819-831. [PMID: 29569260 DOI: 10.1111/1440-1681.12940] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2017] [Revised: 03/14/2018] [Accepted: 03/15/2018] [Indexed: 12/16/2022]
Affiliation(s)
- Lei Lei
- Department of Gastroenterology and Hepatology; Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital; Chengdu China
| | - Chao Zhou
- Department of Gastroenterology and Hepatology; Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital; Chengdu China
| | - Xue Yang
- Department of Gastroenterology and Hepatology; Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital; Chengdu China
| | - Liangping Li
- Department of Gastroenterology and Hepatology; Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital; Chengdu China
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Lai CY, Lin CY, Hsu CC, Yeh KY, Her GM. Liver-directed microRNA-7a depletion induces nonalcoholic fatty liver disease by stabilizing YY1-mediated lipogenic pathways in zebrafish. Biochim Biophys Acta Mol Cell Biol Lipids 2018; 1863:844-856. [PMID: 29678641 DOI: 10.1016/j.bbalip.2018.04.009] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2017] [Revised: 03/16/2018] [Accepted: 04/15/2018] [Indexed: 01/12/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has been associated with the function and changes in expression levels of microRNAs (miRs). MiR-7 has been proven to play an important role in many cellular processes; however, its functions in the context of liver lipogenesis remain unknown. We applied the microRNA-sponge (miR-SP) technology and generated transgenic miR-7a-SP models (hC7aSP and bC7aSP), which disrupted the activities of hepatic miR-7a and induced the early onset of NAFLD and nonalcoholic steatohepatitis (NASH) in zebrafish. We identified a novel miR-7a target, YY1, and demonstrated novel miR-7a functions to regulate zebrafish hepatic lipid metabolism by controlling YY1 stabilization through the regulation of the expression of lipogenic signaling pathways. Correspondingly, liver specific miR-7a depletion functionally promoted lipid accumulation in hC7ASP livers. NASH hC7aSP increased the expression of inflammatory genes (il-1b, il-6, tnf-α, ifn-γ, nfkb2, and NF-kB) and endoplasmic reticulum stress markers (atf6, ern2, ire1, perk, hspa5 and ddit3). Molecular analysis revealed that miR-7a-SP can stabilize YY1 expression and contribute to the accumulation of hepatic triglycerides by reducing the CHOP-10 expression in the hC7aSP and then inducing the transactivation of C/EBP-α and PPAR-γ expression. PPAR-γ antagonists and miR-7a mimic treatment ameliorate hC7aSP NASH phenotypes. CONCLUSION Our results suggest that miR-7a-SP acts as a lipid enhancer by directly increasing YY1 stability to disrupt CHOP-10-dependent suppression of lipogenic pathways, resulting in increased lipid accumulation. MiR-7a expression improves liver steatosis and steatohepatitis in hC7aSPs, which suggests a novel strategy for the prevention and early treatment of NASH in humans.
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Affiliation(s)
- Chi-Yu Lai
- Department of Bioscience and Biotechnology, National Taiwan Ocean University, 2, Pei Ning Road, Keelung 202, Taiwan
| | - Chiu-Ya Lin
- Department of Bioscience and Biotechnology, National Taiwan Ocean University, 2, Pei Ning Road, Keelung 202, Taiwan
| | - Chia-Chun Hsu
- Department of Radiology, Buddhist Tzu Chi General Hospital, Taichung Branch, No. 66 Fēngxìng Road Section 1, Taichung 427, Taiwan; School of Medicine, Tzu Chi University, No. 701, Sec. 3, Jhongyang Road, Hualien 97004, Taiwan
| | - Kun-Yun Yeh
- Division of Hemato-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, 222 Maijin Road, Keelung 204, Taiwan.
| | - Guor Mour Her
- Department of Bioscience and Biotechnology, National Taiwan Ocean University, 2, Pei Ning Road, Keelung 202, Taiwan; Institute of Biopharmaceutical Sciences, National Yang Ming University, TNo. 155, Sec. 2, Linong Street, Taipei 112, Taiwan.
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Duan X, Meng Q, Wang C, Liu Z, Sun H, Huo X, Sun P, Ma X, Peng J, Liu K. Effects of calycosin against high-fat diet-induced nonalcoholic fatty liver disease in mice. J Gastroenterol Hepatol 2018; 33:533-542. [PMID: 28699662 DOI: 10.1111/jgh.13884] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Revised: 07/03/2017] [Accepted: 07/10/2017] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIM Nonalcoholic fatty liver disease (NAFLD) has become a major health concern worldwide. The present study was designed to investigate the effects of calycosin against high-fat diet (HFD)-induced NAFLD in mice. METHODS C57BL/6 J male mice were fed with HFD to induce NAFLD model and treated with or without calycosin for 12 weeks. The levels of ALT, AST, insulin, and adiponectin were measured using biochemical methods. Hemotoxylin and eosin staining and Oil Red O staining were used to determine the liver histopathology changes and measure the degree of lipid accumulation respectively. Glucose tolerance tests and insulin tolerance tests were performed followed by quantitative insulin sensitivity check index determination. Western blot and quantitative real-time polymerase chain reaction were used to explore the potential mechanism involved in the beneficial effects of calycosin. RESULTS Calycosin effectively decreased the levels of ALT and AST, increased the levels of adiponectin and insulin. Hemotoxylin and eosin staining indicated calycosin treatment remarkably improved liver injury. Oil Red O staining indicated calycosin treatment remarkably improved lipid accumulation. Quantitative insulin sensitivity check index in HFD fed mice was significantly lower than in the standard chow fed mice. Further, calycosin suppressed phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, sterol-regulatory element binding protein 1c, and FASN involved in gluconeogenesis and triglyceride synthesis. Calycosin increased glycogen synthase kinase 3 beta, glucose transporter 4, and phosphorylated insulin receptor substrates 1 and 2 expressions involved in glucose metabolism. The aforementioned beneficial effects of calycosin against HFD-induced NAFLD may be attributed to farnesoid X receptor activation. CONCLUSION Calycosin could produce the favorable effects against HFD-induced NAFLD in mice.
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Affiliation(s)
- Xingping Duan
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China
- Department of Pharmacy, Maternal and Child Health Care Hospital of Zigong, Zigong, Sichuan, China
| | - Qiang Meng
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China
- Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, China
| | - Changyuan Wang
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China
- Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, China
| | - Zhihao Liu
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China
- Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, China
| | - Huijun Sun
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China
- Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, China
| | - Xiaokui Huo
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China
- Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, China
| | - Pengyuan Sun
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China
- Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, China
| | - Xiaodong Ma
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China
| | - Jinyong Peng
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China
- Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, China
| | - Kexin Liu
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China
- Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, China
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Transcriptome analysis of mRNA and microRNAs in intramuscular fat tissues of castrated and intact male Chinese Qinchuan cattle. PLoS One 2017; 12:e0185961. [PMID: 29073274 PMCID: PMC5657623 DOI: 10.1371/journal.pone.0185961] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Accepted: 09/24/2017] [Indexed: 11/19/2022] Open
Abstract
Intramuscular fat (IMF) is known to enhance beef palatability and can be markedly increased by castration. However, there is little understanding of the molecular mechanism underlying the IMF deposition after castration of beef cattle. We hypothesize that genetic regulators function differently in IMF from bulls and steers. Therefore, after detecting serum testosterone and lipid parameter, as well as the contents of IMF at 6, 12, 18 and 24 months, we have investigated differentially expressed (DE) microRNAs (miRNAs) and mRNAs in IMF of bulls and steers at 24 months of age in Qinchuan cattle using next-generation sequencing, and then explored the possible biopathways regulating IMF deposition. Serum testosterone levels were significantly decreased in steers, whereas IMF content, serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TGs) were markedly increased in steers. Comparing the results of steers and bulls, 580 upregulated genes and 1,120 downregulated genes in IMF tissues were identified as DE genes correlated with IMF deposition. The upregulated genes were mainly associated with lipid metabolism, lipogenesis and fatty acid transportation signalling pathways, and the downregulated genes were correlated with immune response and intracellular signal transduction. Concurrently, the DE miRNAs—important players in adipose tissue accumulation induced by castration—were also examined in IMF tissues; 52 DE miRNAs were identified. The expression profiles of selected genes and miRNAs were also confirmed by quantitative real-time PCR (qRT-PCR) assays. Using integrated analysis, we constructed the microRNA-target regulatory network which was supported by target validation using the dual luciferase reporter system. Moreover, Ingenuity Pathway Analysis (IPA) software was used to construct a molecular interaction network that could be involved in regulating IMF after castration. The detected molecular network is closely associated with lipid metabolism and adipocyte differentiation, which is supported by functional identification results of bta-let-7i on bovine preadipocytes. These results provided valuable insights into the molecular mechanisms of the IMF phenotype differences between steers and bulls.
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Rajamoorthi A, Arias N, Basta J, Lee RG, Baldán Á. Amelioration of diet-induced steatohepatitis in mice following combined therapy with ASO-Fsp27 and fenofibrate. J Lipid Res 2017; 58:2127-2138. [PMID: 28874443 PMCID: PMC5665668 DOI: 10.1194/jlr.m077941] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Revised: 08/18/2017] [Indexed: 12/16/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease. NAFLD progresses from benign steatosis to steatohepatitis (NASH) to cirrhosis and is linked to hepatocellular carcinoma. No targeted treatment is currently approved for NAFLD/NASH. We previously showed that fat-specific protein 27 (FSP27), a lipid droplet-associated protein that controls triglyceride turnover in the hepatocyte, is required for fasting- and diet-induced triglyceride accumulation in the liver. However, silencing Fsp27 with antisense oligonucleotides (ASOs) did not improve hepatosteatosis in genetic nor nutritional mouse models of obesity. Herein, we tested the therapeutic potential of ASO-Fsp27 when used in combination with the PPARα agonist fenofibrate. C57BL/6 mice were fed a high-trans-fat, high-cholesterol, high-fructose diet for eight weeks to establish NASH, then kept on diet for six additional weeks while dosed with ASOs and fenofibrate, alone or in combination. Data show that ASO-Fsp27 and fenofibrate synergize to promote resistance to diet-induced obesity and hypertriglyceridemia and to reverse hepatic steatosis, inflammation, oxidative stress, and fibrosis. This multifactorial improvement of liver disease noted when combining both drugs suggests that a course of treatment that includes both reduced FSP27 activity and activation of PPARα could provide therapeutic benefit to patients with NAFLD/NASH.
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Affiliation(s)
- Ananthi Rajamoorthi
- Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University, Saint Louis, MO
| | - Noemí Arias
- Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University, Saint Louis, MO
| | - Jeannine Basta
- Department of Internal Medicine, Saint Louis University, Saint Louis, MO
| | - Richard G Lee
- Cardiovascular Group, Antisense Drug Discovery, Ionis Pharmaceuticals, Carlsbad, CA
| | - Ángel Baldán
- Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University, Saint Louis, MO .,Center for Cardiovascular Research, Saint Louis University, Saint Louis, MO.,Liver Center, Saint Louis University, Saint Louis, MO
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Feng C, Li D, Jiang L, Liu X, Li Q, Geng C, Sun X, Yang G, Yao X, Chen M. Citreoviridin induces triglyceride accumulation in hepatocytes through inhibiting PPAR-α in vivo and in vitro. Chem Biol Interact 2017. [PMID: 28645467 DOI: 10.1016/j.cbi.2017.06.021] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Citreoviridin (CIT) is a mycotoxin produced by Penicillum citreonigrum, Aspergillus terreus and Eupenicillium ochrosalmoneum. CIT occurs naturally in moldy rice and corn. CIT is associated with the development of atherosclerosis in the general population. Alteration in hepatic lipid metabolism is a pathogenic factor in atherosclerosis. However the effect and the underlying mechanism of CIT on hepatic lipid metabolism are largely unknown. In this study, we reported that CIT induced triglyceride accumulation in mice liver and human liver HepG2 cells as shown in oil red O staining. CIT (0.1 mg/kg-0.3 mg/kg) for 6 weeks elevated liver triglyceride contents in mice. CIT inhibited the transactivation activity of peroxisome proliferator-activated receptor-α (PPAR-α) in hepatocyte in vivo and in vitro, as shown by the reduced mRNA levels of PPAR-α target genes which play key roles in lipid metabolism in various aspects. PPAR-α agonist fenofibrate attenuated CIT-induced triglyceride accumulation in HepG2 cells. Furthermore, CIT increased serum total cholesterol/high-density lipoprotein cholesterol ratio, a strong risk factor for cardiovascular disease. In summary, we reported that CIT induced PPAR-α-dependent hepatic triglyceride accumulation and dyslipidemia. Our data will provide new mechanistic insights into CIT-induced lipid alterations.
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Affiliation(s)
- Chang Feng
- Department of Preventive Medicine, Dalian Medical University, Dalian, China
| | - Dandan Li
- Department of Preventive Medicine, Dalian Medical University, Dalian, China
| | - Liping Jiang
- Liaoning Anti-Degenerative Diseases Natural Products Engineering Research Center, Dalian Medical University, Dalian, China
| | - Xiaofang Liu
- Department of Preventive Medicine, Dalian Medical University, Dalian, China
| | - Qiujuan Li
- Department of Preventive Medicine, Dalian Medical University, Dalian, China
| | - Chengyan Geng
- Department of Preventive Medicine, Dalian Medical University, Dalian, China
| | - Xiance Sun
- Department of Preventive Medicine, Dalian Medical University, Dalian, China; Liaoning Anti-Degenerative Diseases Natural Products Engineering Research Center, Dalian Medical University, Dalian, China
| | - Guang Yang
- Department of Preventive Medicine, Dalian Medical University, Dalian, China
| | - Xiaofeng Yao
- Department of Preventive Medicine, Dalian Medical University, Dalian, China; Department of Medicine, University of California San Diego, La Jolla, United States.
| | - Min Chen
- Department of Preventive Medicine, Dalian Medical University, Dalian, China.
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Kucher AN, Nazarenko MS, Markov AV, Koroleva IA, Barbarash OL. Variability of methylation profiles of CpG sites in microRNA genes in leukocytes and vascular tissues of patients with atherosclerosis. BIOCHEMISTRY (MOSCOW) 2017; 82:698-706. [DOI: 10.1134/s0006297917060062] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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Chen Q, Qiu F, Zhou K, Matlock HG, Takahashi Y, Rajala RVS, Yang Y, Moran E, Ma JX. Pathogenic Role of microRNA-21 in Diabetic Retinopathy Through Downregulation of PPARα. Diabetes 2017; 66:1671-1682. [PMID: 28270521 PMCID: PMC5440012 DOI: 10.2337/db16-1246] [Citation(s) in RCA: 125] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Accepted: 03/01/2017] [Indexed: 02/06/2023]
Abstract
Fenofibrate, a specific agonist of peroxisome proliferator-activated receptor-α (PPARα), displays robust therapeutic effects on diabetic retinopathy (DR) in patients with type 2 diabetes. Our recent studies have shown that PPARα is downregulated in the diabetic retina, which contributes to the pathogenesis of DR. However, the mechanism for diabetes-induced downregulation of PPARα remains unknown. We investigated the role of microRNA-21 (miR-21) in regulating PPARα in DR. miR-21 was overexpressed, while PPARα levels were decreased in the retina of db/db mice, a model of type 2 diabetes. Such alterations were also observed in palmitate-treated retinal endothelial cells. miR-21 targeted PPARα by inhibiting its mRNA translation. Knockout of miR-21 prevented the decrease of PPARα, alleviated microvascular damage, ameliorated inflammation, and reduced cell apoptosis in the retina of db/db mice. Intravitreal injection of miR-21 inhibitor attenuated PPARα downregulation and ameliorated retinal inflammation in db/db mice. Further, retinal miR-21 levels were increased, while PPARα levels were decreased in oxygen-induced retinopathy (OIR). Knockout of miR-21 prevented PPARα downregulation and ameliorated retinal neovascularization and inflammation in OIR retinas. In conclusion, diabetes-induced overexpression of miR-21 in the retina is at least partly responsible for PPARα downregulation in DR. Targeting miR-21 may represent a novel therapeutic strategy for DR.
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Affiliation(s)
- Qian Chen
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Fangfang Qiu
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Kelu Zhou
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - H Greg Matlock
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Yusuke Takahashi
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK
- Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Raju V S Rajala
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
- Dean A. McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Yanhui Yang
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
- Tianjin Metabolic Diseases Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Elizabeth Moran
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK
- Department of Ophthalmology, Boston Children's Hospital, Boston, MA
| | - Jian-Xing Ma
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK
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41
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Rodrigues PM, Afonso MB, Simão AL, Carvalho CC, Trindade A, Duarte A, Borralho PM, Machado MV, Cortez-Pinto H, Rodrigues CM, Castro RE. miR-21 ablation and obeticholic acid ameliorate nonalcoholic steatohepatitis in mice. Cell Death Dis 2017; 8:e2748. [PMID: 28406477 PMCID: PMC5477590 DOI: 10.1038/cddis.2017.172] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Revised: 03/01/2017] [Accepted: 03/06/2017] [Indexed: 02/06/2023]
Abstract
microRNAs were recently suggested to contribute to the pathogenesis of nonalcoholic fatty liver disease (NAFLD), a disease lacking specific pharmacological treatments. In that regard, nuclear receptors are arising as key molecular targets for the treatment of nonalcoholic steatohepatitis (NASH). Here we show that, in a typical model of NASH-associated liver damage, microRNA-21 (miR-21) ablation results in a progressive decrease in steatosis, inflammation and lipoapoptosis, with impairment of fibrosis. In a complementary fast food (FF) diet NASH model, mimicking features of the metabolic syndrome, miR-21 levels increase in both liver and muscle, concomitantly with decreased expression of peroxisome proliferator-activated receptor α (PPARα), a key miR-21 target. Strikingly, miR-21 knockout mice fed the FF diet supplemented with farnesoid X receptor (FXR) agonist obeticholic acid (OCA) display minimal steatosis, inflammation, oxidative stress and cholesterol accumulation. In addition, lipoprotein metabolism was restored, including decreased fatty acid uptake and polyunsaturation, and liver and muscle insulin sensitivity fully reinstated. Finally, the miR-21/PPARα axis was found amplified in liver and muscle biopsies, and in serum, of NAFLD patients, co-substantiating its role in the development of the metabolic syndrome. By unveiling that miR-21 abrogation, together with FXR activation by OCA, significantly improves whole body metabolic parameters in NASH, our results highlight the therapeutic potential of nuclear receptor multi-targeting therapies for NAFLD.
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Affiliation(s)
- Pedro M Rodrigues
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Marta B Afonso
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - André L Simão
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Catarina C Carvalho
- Reproduction and Development, Interdisciplinary Centre of Research in Animal Health (CIISA), Faculty of Veterinary Medicine, Universidade de Lisboa, Lisbon, Portugal
| | - Alexandre Trindade
- Reproduction and Development, Interdisciplinary Centre of Research in Animal Health (CIISA), Faculty of Veterinary Medicine, Universidade de Lisboa, Lisbon, Portugal.,Gulbenkian Institute of Science, Oeiras, Portugal
| | - António Duarte
- Reproduction and Development, Interdisciplinary Centre of Research in Animal Health (CIISA), Faculty of Veterinary Medicine, Universidade de Lisboa, Lisbon, Portugal.,Gulbenkian Institute of Science, Oeiras, Portugal
| | - Pedro M Borralho
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | | | | | - Cecília Mp Rodrigues
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Rui E Castro
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
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Desgagné V, Bouchard L, Guérin R. microRNAs in lipoprotein and lipid metabolism: from biological function to clinical application. Clin Chem Lab Med 2017; 55:667-686. [PMID: 27987357 DOI: 10.1515/cclm-2016-0575] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Accepted: 10/31/2016] [Indexed: 12/21/2022]
Abstract
microRNAs (miRNAs) are short (~22 nucleotides), non-coding, single-stranded RNA molecules that regulate the expression of target genes by partial sequence-specific base-pairing to the targeted mRNA 3'UTR, blocking its translation, and promoting its degradation or its sequestration into processing bodies. miRNAs are important regulators of several physiological processes including developmental and metabolic functions, but their concentration in circulation has also been reported to be altered in many pathological conditions such as familial hypercholesterolemia, cardiovascular diseases, obesity, type 2 diabetes, and cancers. In this review, we focus on the role of miRNAs in lipoprotein and lipid metabolism, with special attention to the well-characterized miR-33a/b, and on the huge potential of miRNAs for clinical application as biomarkers and therapeutics in the context of cardiometabolic diseases.
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Affiliation(s)
| | - Luigi Bouchard
- Département de biochimie, Université de Sherbrooke, Sherbrooke, Québec
| | - Renée Guérin
- Département de biochimie, Université de Sherbrooke, Sherbrooke, Québec
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43
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Dubois V, Eeckhoute J, Lefebvre P, Staels B. Distinct but complementary contributions of PPAR isotypes to energy homeostasis. J Clin Invest 2017; 127:1202-1214. [PMID: 28368286 DOI: 10.1172/jci88894] [Citation(s) in RCA: 273] [Impact Index Per Article: 34.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) regulate energy metabolism and hence are therapeutic targets in metabolic diseases such as type 2 diabetes and non-alcoholic fatty liver disease. While they share anti-inflammatory activities, the PPAR isotypes distinguish themselves by differential actions on lipid and glucose homeostasis. In this Review we discuss the complementary and distinct metabolic effects of the PPAR isotypes together with the underlying cellular and molecular mechanisms, as well as the synthetic PPAR ligands that are used in the clinic or under development. We highlight the potential of new PPAR ligands with improved efficacy and safety profiles in the treatment of complex metabolic disorders.
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44
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MicroRNAs-Dependent Regulation of PPARs in Metabolic Diseases and Cancers. PPAR Res 2017; 2017:7058424. [PMID: 28167956 PMCID: PMC5266863 DOI: 10.1155/2017/7058424] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2016] [Accepted: 12/05/2016] [Indexed: 12/23/2022] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) are a family of ligand-dependent nuclear receptors, which control the transcription of genes involved in energy homeostasis and inflammation and cell proliferation/differentiation. Alterations of PPARs' expression and/or activity are commonly associated with metabolic disorders occurring with obesity, type 2 diabetes, and fatty liver disease, as well as with inflammation and cancer. Emerging evidence now indicates that microRNAs (miRNAs), a family of small noncoding RNAs, which fine-tune gene expression, play a significant role in the pathophysiological mechanisms regulating the expression and activity of PPARs. Herein, the regulation of PPARs by miRNAs is reviewed in the context of metabolic disorders, inflammation, and cancer. The reciprocal control of miRNAs expression by PPARs, as well as the therapeutic potential of modulating PPAR expression/activity by pharmacological compounds targeting miRNA, is also discussed.
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45
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Yung DE, Sykes C, Koulaouzidis A. The validity of suspected blood indicator software in capsule endoscopy: a systematic review and meta-analysis. Expert Rev Gastroenterol Hepatol 2017; 11:43-51. [PMID: 27842442 DOI: 10.1080/17474124.2017.1257384] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Software tools have been developed as capsule endoscopy (CE) reading aids. The suspected blood indicator (SBI) tags possible areas of haemorrhage in the gastrointestinal (GI) tract. This meta-analysis aims to investigate the diagnostic accuracy of SBI in CE. Areas covered: A systematic literature search was conducted for studies on the use of SBI in CE. Sensitivity, specificity and diagnostic odds ratio (DOR) of SBI in diagnosing GI bleeding was evaluated. 2040 patients from 16 studies underwent 2049 CE examinations. The overall sensitivity of SBI for bleeding or potentially bleeding lesions was 0.553, specificity 0.578, DOR 12.354. The sensitivity of SBI for active bleeding was 0.988, specificity 0.646, DOR 229.89. Expert commentary: Currently, SBI has limited validity in CE reading. However, in active GI bleeding, it has good sensitivity, supporting its use in the acute setting.
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Affiliation(s)
- Diana E Yung
- a Centre for Liver & Digestive Disorders , The Royal Infirmary of Edinburgh , Edinburgh , UK
| | - Catherine Sykes
- a Centre for Liver & Digestive Disorders , The Royal Infirmary of Edinburgh , Edinburgh , UK
| | - Anastasios Koulaouzidis
- a Centre for Liver & Digestive Disorders , The Royal Infirmary of Edinburgh , Edinburgh , UK
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46
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Abstract
Obesity is a worldwide epidemic that predisposes individuals to cardiometabolic complications, such as type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD), which are all related to inappropriate ectopic lipid deposition. Identification of the pathogenic molecular mechanisms and effective therapeutic approaches are highly needed. The peroxisome proliferator-activated receptors (PPARs) modulate several biological processes that are perturbed in obesity, including inflammation, lipid and glucose metabolism and overall energy homeostasis. Here, we review how PPARs regulate the functions of adipose tissues, such as adipogenesis, lipid storage and adaptive thermogenesis, under healthy and pathological conditions. We also discuss the clinical use and mechanism of PPAR agonists in the treatment of obesity comorbidities such as dyslipidaemia, T2DM and NAFLD. First generation PPAR agonists, primarily those acting on PPARγ, are associated with adverse effects that outweigh their clinical benefits, which led to the discontinuation of their development. An improved understanding of the physiological roles of PPARs might, therefore, enable the development of safe, new PPAR agonists with improved therapeutic potential.
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Affiliation(s)
- Barbara Gross
- Université de Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
| | - Michal Pawlak
- International Institute of Molecular and Cell Biology, 4 Ks. Trojdena Street, 02-109 Warsaw, Poland
| | - Philippe Lefebvre
- Université de Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
| | - Bart Staels
- Université de Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
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47
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Lee J, Kim Y, Friso S, Choi SW. Epigenetics in non-alcoholic fatty liver disease. Mol Aspects Med 2016; 54:78-88. [PMID: 27889327 DOI: 10.1016/j.mam.2016.11.008] [Citation(s) in RCA: 102] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Revised: 11/18/2016] [Accepted: 11/22/2016] [Indexed: 12/16/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD), a common hepatic disorder ranging from simple steatosis through steatohepatitis to fibrosis and cirrhosis, is an emerging health concern. NAFLD is a pathologic condition characterized by the buildup of extra fat in liver cells that is not caused by alcohol consumption. Excess hepatic fat accumulation results from increased delivery of triglycerides (TG) to the liver or conversion of surplus carbohydrates to TG. Importantly, a subgroup of NAFLD results in hepatocellular injury and inflammation, which is referred to as non-alcoholic steatohepatitis (NASH), and may progress to irreversible cirrhosis and hepatocellular carcinoma (HCC). NAFLD shares, in part, the common pathogenesis of metabolic syndrome including obesity, hyperlipidemia, insulin resistance, mitochondrial damage, oxidative stress response, and the release of inflammatory cytokines. Epigenetics, an inheritable phenomenon that affects gene expression without altering the DNA sequence, provides a new perspective on the pathogenesis of NAFLD. Reversible epigenetic changes take place at the transcriptional level and provide a phenotypic connection between the host and environment. An accumulating body of evidence suggests the importance of epigenetic roles in NAFLD, which in turn can be identified as potential therapeutic targets and non-invasive biomarkers of NAFLD. It is anticipated that the epigenetic modifiers in NAFLD may provide novel molecular indicators that can determine not only the initial risk but also the disease progression and prognosis. In the present review, we update the roles of epigenetics as pathologic mechanisms, therapeutic targets and biomarkers in NAFLD.
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Affiliation(s)
- Jooho Lee
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, CHA Bundang Medical Center, CHA University of Medicine and Science, Seongnam, 13496, South Korea
| | - Yuri Kim
- Department of Nutritional Science and Food Management, Ewha Womans University, Seoul, 03760, South Korea
| | - Simonetta Friso
- University of Verona School of Medicine, Verona, 37134, Italy
| | - Sang-Woon Choi
- Chaum Life Center, CHA University of Medicine and Science, Seoul, 06062, South Korea.
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48
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Li MP, Hu YD, Hu XL, Zhang YJ, Yang YL, Jiang C, Tang J, Chen XP. MiRNAs and miRNA Polymorphisms Modify Drug Response. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2016; 13:ijerph13111096. [PMID: 27834829 PMCID: PMC5129306 DOI: 10.3390/ijerph13111096] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Revised: 10/17/2016] [Accepted: 10/31/2016] [Indexed: 12/13/2022]
Abstract
Differences in expression of drug response-related genes contribute to inter-individual variation in drugs’ biological effects. MicroRNAs (miRNAs) are small noncoding RNAs emerging as new players in epigenetic regulation of gene expression at post-transcriptional level. MiRNAs regulate the expression of genes involved in drug metabolism, drug transportation, drug targets and downstream signal molecules directly or indirectly. MiRNA polymorphisms, the genetic variations affecting miRNA expression and/or miRNA-mRNA interaction, provide a new insight into the understanding of inter-individual difference in drug response. Here, we provide an overview of the recent progress in miRNAs mediated regulation of biotransformation enzymes, drug transporters, and nuclear receptors. We also describe the implications of miRNA polymorphisms in cancer chemotherapy response.
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Affiliation(s)
- Mu-Peng Li
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, China.
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, China.
| | - Yao-Dong Hu
- Department of Cardiology, Heping Hospital Affiliated to Changzhi Medical College, Changzhi 046000, China.
| | - Xiao-Lei Hu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, China.
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, China.
| | - Yan-Jiao Zhang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, China.
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, China.
| | - Yong-Long Yang
- Haikou People's Hospital and Affiliated Haikou Hospital of Xiangya Medical School, Central South University, Haikou 570311, China.
| | - Chun Jiang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, China.
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, China.
| | - Jie Tang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, China.
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, China.
| | - Xiao-Ping Chen
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, China.
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, China.
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49
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Raghuraman S, Donkin I, Versteyhe S, Barrès R, Simar D. The Emerging Role of Epigenetics in Inflammation and Immunometabolism. Trends Endocrinol Metab 2016; 27:782-795. [PMID: 27444065 DOI: 10.1016/j.tem.2016.06.008] [Citation(s) in RCA: 90] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Revised: 06/15/2016] [Accepted: 06/20/2016] [Indexed: 12/12/2022]
Abstract
Recent research developments have shed light on the risk factors contributing to metabolic complications, implicating both genetic and environmental factors, potentially integrated by epigenetic mechanisms. Distinct epigenetic changes in immune cells are frequently observed in obesity and type 2 diabetes mellitus, and these are associated with alterations in the phenotype, function, and trafficking patterns of these cells. The first step in the development of effective therapeutic strategies is the identification of distinct epigenetic signatures associated with metabolic disorders. In this review we provide an overview of the epigenetic mechanisms influencing immune cell phenotype and function, summarize current knowledge about epigenetic changes affecting immune functions in the context of metabolic diseases, and discuss the therapeutic options currently available to counteract epigenetically driven metabolic complications.
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Affiliation(s)
- Sukanya Raghuraman
- Inflammation and Infection Research, School of Medical Sciences, University of New South Wales, Sydney, Australia
| | - Ida Donkin
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Soetkin Versteyhe
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Romain Barrès
- Inflammation and Infection Research, School of Medical Sciences, University of New South Wales, Sydney, Australia; The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - David Simar
- Inflammation and Infection Research, School of Medical Sciences, University of New South Wales, Sydney, Australia; The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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50
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Liu XL, Cao HX, Fan JG. MicroRNAs as biomarkers and regulators of nonalcoholic fatty liver disease. J Dig Dis 2016; 17:708-715. [PMID: 27628945 DOI: 10.1111/1751-2980.12408] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Revised: 08/29/2016] [Accepted: 09/11/2016] [Indexed: 12/11/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a complicated disease affected by the interaction of environmental and genetic factors; however, the precise pathogenesis of the disease has not been fully determined. There is a need to better understand the pathogenesis of NAFLD and to identify non-invasive diagnostic modalities. Recent advances in systematic biology and epigenetics have improved our understanding of the genotype-phenotype relationships in NAFLD. MicroRNAs (miRNAs) are important regulators of a wide range of biological processes. MiRNAs are extremely stable and protect from RNAase-mediated degradation in body fluids, making them attractive candidate biomarkers for the early detection of the disease and the monitoring of disease progression. In this review, we summarized the current knowledge on miRNAs as potential biomarkers of NAFLD at different stages and for the prognosis of advanced diseases. Furthermore, we discussed the implications of miRNAs that functioning in lipid metabolism and hepatic steatosis as well as in hepatic inflammation and fibrosis with regard to the pathogenesis of NAFLD.
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Affiliation(s)
- Xiao Lin Liu
- Department of Gastroenterology and Center for Fatty Liver, XinHua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Hai Xia Cao
- Department of Gastroenterology and Center for Fatty Liver, XinHua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jian Gao Fan
- Department of Gastroenterology and Center for Fatty Liver, XinHua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
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