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Kiełbowski K, Żychowska J, Bakinowska E, Pawlik A. Non-Coding RNA Involved in the Pathogenesis of Atherosclerosis-A Narrative Review. Diagnostics (Basel) 2024; 14:1981. [PMID: 39272765 PMCID: PMC11394555 DOI: 10.3390/diagnostics14171981] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 09/05/2024] [Accepted: 09/05/2024] [Indexed: 09/15/2024] Open
Abstract
Atherosclerosis is a highly prevalent condition associated with lipid accumulation in the intima layer of arterial blood vessels. The development of atherosclerotic plaques is associated with the incidence of major cardiovascular events, such as acute coronary syndrome or ischemic stroke. Due to the significant prevalence of atherosclerosis and its subclinical progression, it is associated with severe and potentially lethal complications. The pathogenesis of atherosclerosis is complex and not entirely known. The identification of novel non-invasive diagnostic markers and treatment methods that could suppress the progression of this condition is highly required. Non-coding RNA (ncRNA) involves several subclasses of RNA molecules. microRNA (miRNA), long non-coding RNA (lncRNA), and circular RNA (circRNA) differently regulate gene expression. Importantly, these molecules are frequently dysregulated under pathological conditions, which is associated with enhanced or suppressed expression of their target genes. In this review, we aim to discuss the involvement of ncRNA in crucial mechanisms implicated in the pathogenesis of atherosclerosis. We summarize current evidence on the potential use of these molecules as diagnostic and therapeutic targets.
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Affiliation(s)
- Kajetan Kiełbowski
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland
| | - Justyna Żychowska
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland
| | - Estera Bakinowska
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland
| | - Andrzej Pawlik
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland
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Liu Y, Liang Z, Li Y, Zhu W, Feng B, Xu W, Fu J, Wei P, Luo M, Dong Z. Integrated transcriptome and microRNA analysis reveals molecular responses to high-temperature stress in the liver of American shad (Alosa sapidissima). BMC Genomics 2024; 25:656. [PMID: 38956484 PMCID: PMC11218383 DOI: 10.1186/s12864-024-10567-w] [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: 03/11/2024] [Accepted: 06/26/2024] [Indexed: 07/04/2024] Open
Abstract
BACKGROUND Fish reproduction, development and growth are directly affected by temperature, investigating the regulatory mechanisms behind high temperature stress is helpful to construct a finer molecular network. In this study, we systematically analyzed the transcriptome and miRNA information of American shad (Alosa sapidissima) liver tissues at different cultivation temperatures of 24 ℃ (Low), 27 ℃ (Mid) and 30 ℃ (High) based on a high-throughput sequencing platform. RESULTS The results showed that there were 1594 differentially expressed genes (DEGs) and 660 differentially expressed miRNAs (DEMs) in the LowLi vs. MidLi comparison group, 473 DEGs and 84 DEMs in the MidLi vs. HighLi group, 914 DEGs and 442 DEMs in the LowLi vs. HighLi group. These included some important genes and miRNAs such as calr, hsp90b1, hsp70, ssa-miR-125a-3p, ssa-miR-92b-5p, dre-miR-15a-3p and novel-m1018-5p. The DEGs were mainly enriched in the protein folding, processing and export pathways of the endoplasmic reticulum; the target genes of the DEMs were mainly enriched in the focal adhesion pathway. Furthermore, the association analysis revealed that the key genes were mainly enriched in the metabolic pathway. Interestingly, we found a significant increase in the number of genes and miRNAs involved in the regulation of heat stress during the temperature change from 24 °C to 27 °C. In addition, we examined the tissue expression characteristics of some key genes and miRNAs by qPCR, and found that calr, hsp90b1 and dre-miR-125b-2-3p were significantly highly expressed in the liver at 27 ℃, while novel-m0481-5p, ssa-miR-125a-3p, ssa-miR-92b-5p, dre-miR-15a-3p and novel-m1018-5p had the highest expression in the heart at 30℃. Finally, the quantitative expression trends of 10 randomly selected DEGs and 10 DEMs were consistent with the sequencing data, indicating the reliability of the results. CONCLUSIONS In summary, this study provides some fundamental data for subsequent in-depth research into the molecular regulatory mechanisms of A. sapidissima response to heat stress, and for the selective breeding of high temperature tolerant varieties.
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Affiliation(s)
- Ying Liu
- Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, Jiangsu, China
| | - Zhengyuan Liang
- Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, Jiangsu, China
| | - Yulin Li
- Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, Jiangsu, China
| | - Wenbin Zhu
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, Jiangsu, China
| | - Bingbing Feng
- Fisheries Technology Extension Center of Jiangsu Province, Nanjing, Jiangsu, China
| | - Wei Xu
- Fisheries Technology Extension Center of Jiangsu Province, Nanjing, Jiangsu, China
| | - Jianjun Fu
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, Jiangsu, China
| | - Panpan Wei
- Qinghai Provincial Key Laboratory of Breeding and Protection of Gymnocypris przewalskii, Rescue Center of Qinghai Lake Naked Carp, Xining, Qinghai, China
| | - Mingkun Luo
- Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, Jiangsu, China.
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, Jiangsu, China.
| | - Zaijie Dong
- Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, Jiangsu, China.
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, Jiangsu, China.
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Zhao J, Ma X, Xu H. miR‑29b‑3p inhibits 22Rv1 prostate cancer cell proliferation through the YWHAE/BCL‑2 regulatory axis. Oncol Lett 2022; 24:289. [PMID: 35928803 PMCID: PMC9344263 DOI: 10.3892/ol.2022.13409] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Accepted: 06/06/2022] [Indexed: 11/06/2022] Open
Abstract
Prostate cancer (PCa) is one of the most common malignant tumours in the world and seriously affects health of men. Studies have shown that microRNA (miR)-29b-3p and tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein epsilon (YWHAE) play important roles in influencing the proliferation and apoptosis of PCa cells. However, the molecular mechanism of miR-29b-3p and YWHAE in the proliferation and apoptosis of PCa cells remains unclear. In the present study, bioinformatics as well as in vivo and in vitro experiments were used to predict and verify the targeting relationship between YWHAE and mir-29B-3p and investigate the potential roles of YWHAE and mir-29b-3p in the proliferation and apoptosis of 22RV1 cells. Using bioinformatics and a double luciferase system assay, it was confirmed that miR-29b-3p can target YWHAE 3′untranslated region and affect the expression of YWHAE, suggesting that miR-29b-3p may be a potential miRNA of YWHAE. Reverse transcription-quantitative PCR, Cell Counting Kit-8, Transwell and cell scratch assays showed that miR-29b-3p significantly inhibited the proliferation, invasion and migration of 22Rv1 cells (P<0.01). Rescue experiments demonstrated that YWHAE gene introduction reversed the inhibitory effect of miR-29b-3p on 22Rv1 cells. Western blotting revealed that the upregulation of miR-29b-3p inhibited YWHAE expression, resulting in a very significant decrease in the ratio of p-BAD/BAD and full-length caspase 3/cleaved caspase 3 (P<0.01) and an extremely significant increase in the ratio of BAX/BCL-2 (P<0.01). A tumourigenesis test in nude mice in vivo confirmed that the upregulation of miR-29b-3p inhibited tumour growth by targeting YWHAE. The present experiments confirmed that miR-29b-3p plays a tumour suppressor role in 22Rv1 PCa cells, and the YWHAE/BCL-2 regulatory axis plays a vital role in miR-29b-3p regulating the proliferation and apoptosis of 22Rv1 cells. These results may provide a theoretical basis for the diagnosis and targeted treatment of PCa.
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Affiliation(s)
- Jiafu Zhao
- Key Laboratory of Animal Genetics, Breeding and Reproduction in the Plateau Mountainous Region, Ministry of Education, Guizhou University, Guiyang, Guizhou 550025, P.R. China
| | - Xiaoyan Ma
- Key Laboratory of Animal Genetics, Breeding and Reproduction in the Plateau Mountainous Region, Ministry of Education, Guizhou University, Guiyang, Guizhou 550025, P.R. China
| | - Houqiang Xu
- Key Laboratory of Animal Genetics, Breeding and Reproduction in the Plateau Mountainous Region, Ministry of Education, Guizhou University, Guiyang, Guizhou 550025, P.R. China
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Xie HL, Zhang YH, Tan XD, Zheng Y, Ni HY, Dong LP, Zheng JL, Diao JZ, Yin YJ, Zhang JB, Sun XQ, Yang YW. miR-375 Induced the Formation and Transgenerational Inheritance of Fatty Liver in Poultry by Targeting MAP3K1. DNA Cell Biol 2022; 41:590-599. [PMID: 35533015 DOI: 10.1089/dna.2022.0078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
The liver of poultry is the primary site of lipid synthesis. The excessive production of lipids accumulates in liver tissues causing lipid metabolism disorders, which result in fatty liver disease and have a transgenerational effect of acquired phenotypes. However, its specific mechanisms have not yet been fully understood. In this study, the differentially expressed miR-375 as well as its target gene MAP3K1 (mitogen-activated protein kinase kinase kinase 1) were screened out by interaction network analysis of microRNA sequencing results and transcriptome profiling in the fatty liver group of the F0-F3 generation (p < 0.05 or p < 0.01). Furthermore, the results showed that the number of lipid droplets and triglyceride content were significantly decreased after upregulation of miR-375 in primary hepatocyte culture in vitro (p < 0.05 or p < 0.01). The MAP3K1 knockdown group exhibited the opposite trends (p < 0.05 or p < 0.01). P53, Bcl-x, PMP22, and CDKN2C related to cell proliferation were significantly upregulated or downregulated after knocking down MAP3K1 (p < 0.05). This research uniquely revealed that silencing miR-375 inhibits lipid biosynthesis and promotes cell proliferation, which may be due to the partial regulation of the expression level of MAP3K1, thereby further participating in the transgenerational inheritance process of regulating liver lipid metabolism. These results reveal the pathogenesis of fatty liver in noncoding RNA and provide good candidate genes for breeding progress of disease resistance in chickens.
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Affiliation(s)
- Heng-Li Xie
- College of Animal Science, Jilin University, Changchun, P.R. China
| | - Yong-Hong Zhang
- College of Animal Science, Jilin University, Changchun, P.R. China
| | - Xiao-Dong Tan
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, P.R. China
| | - Yi Zheng
- College of Animal Science, Jilin University, Changchun, P.R. China
| | - Hong-Yu Ni
- College of Animal Science, Jilin University, Changchun, P.R. China
| | - Li-Ping Dong
- College of Animal Science, Jilin University, Changchun, P.R. China
| | - Jin-Lei Zheng
- College of Animal Science, Jilin University, Changchun, P.R. China
| | - Ji-Zhe Diao
- College of Animal Science, Jilin University, Changchun, P.R. China
| | - Yi-Jing Yin
- College of Animal Science, Jilin University, Changchun, P.R. China
| | - Jia-Bao Zhang
- College of Animal Science, Jilin University, Changchun, P.R. China
| | - Xue-Qi Sun
- College of Animal Science, Jilin University, Changchun, P.R. China.,Jilin Academy of Agricultural Sciences, Changchun, P.R. China
| | - Yu-Wei Yang
- College of Animal Science, Jilin University, Changchun, P.R. China
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Chen W, Ma H, Li B, Yang F, Xiao Y, Gong Y, Li Z, Li T, Zeng Q, Xu K, Duan Y. Spatiotemporal Regulation of Circular RNA Expression during Liver Development of Chinese Indigenous Ningxiang Pigs. Genes (Basel) 2022; 13:746. [PMID: 35627131 PMCID: PMC9141790 DOI: 10.3390/genes13050746] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 04/22/2022] [Accepted: 04/22/2022] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND There have been many studies on the relationship between circRNAs and fat deposition. Although the liver is a central organ for fat metabolism, there are few reports on the relationship between circRNAs in the liver and fat deposition. METHODS In this study, we systematically analyzed circular RNAs in the liver of Ningxiang pigs, at four time points after birth (30 days, 90 days, 150 days and 210 days). RESULTS A total of 3705 circRNAs were coexpressed in four time periods were found, and KEGG analysis showed that the significantly upregulated pathways were mainly enriched in lipid metabolism and amino acid metabolism, while significantly downregulated pathways were mainly related to signal transduction, such as ECM-receptor interaction, MAPK signaling pathway, etc. Short time-series expression miner (STEM) analysis showed multiple model spectra that were significantly enriched over time in the liver. By constructing a competing endogenous RNA (ceRNA) regulatory network, 9187 pairs of networks related to the change in development time were screened. CONCLUSIONS The expression profiles of circRNAs in Ningxiang pig liver were revealed at different development periods, and it was determined that there is differential coexpression. Through enrichment analysis of these circRNAs, it was revealed that host genes were involved in metabolism-related signaling pathways and fatty acid anabolism. Through STEM analysis, many circRNAs involved in fat metabolism, transport, and deposition pathways were screened, and the first circRNA-miRNA-mRNA regulation network map in Ningxiang pig liver was constructed. The highly expressed circRNAs related to fat deposition were verified and were consistent with RNA-Seq results.
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Affiliation(s)
- Wenwu Chen
- College of Animal Science and Technology, Hunan Agricultural University, Changsha 410128, China; (W.C.); (F.Y.); (Y.X.); (Y.G.); (Z.L.); (T.L.); (Q.Z.)
| | - Haiming Ma
- College of Animal Science and Technology, Hunan Agricultural University, Changsha 410128, China; (W.C.); (F.Y.); (Y.X.); (Y.G.); (Z.L.); (T.L.); (Q.Z.)
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, China
| | - Biao Li
- College of Animal Science and Technology, Hunan Agricultural University, Changsha 410128, China; (W.C.); (F.Y.); (Y.X.); (Y.G.); (Z.L.); (T.L.); (Q.Z.)
- College of Animal and Veterinary Sciences, Southwest Minzu University, Chengdu 610000, China
| | - Fang Yang
- College of Animal Science and Technology, Hunan Agricultural University, Changsha 410128, China; (W.C.); (F.Y.); (Y.X.); (Y.G.); (Z.L.); (T.L.); (Q.Z.)
| | - Yu Xiao
- College of Animal Science and Technology, Hunan Agricultural University, Changsha 410128, China; (W.C.); (F.Y.); (Y.X.); (Y.G.); (Z.L.); (T.L.); (Q.Z.)
| | - Yan Gong
- College of Animal Science and Technology, Hunan Agricultural University, Changsha 410128, China; (W.C.); (F.Y.); (Y.X.); (Y.G.); (Z.L.); (T.L.); (Q.Z.)
| | - Zhi Li
- College of Animal Science and Technology, Hunan Agricultural University, Changsha 410128, China; (W.C.); (F.Y.); (Y.X.); (Y.G.); (Z.L.); (T.L.); (Q.Z.)
| | - Ting Li
- College of Animal Science and Technology, Hunan Agricultural University, Changsha 410128, China; (W.C.); (F.Y.); (Y.X.); (Y.G.); (Z.L.); (T.L.); (Q.Z.)
| | - Qinghua Zeng
- College of Animal Science and Technology, Hunan Agricultural University, Changsha 410128, China; (W.C.); (F.Y.); (Y.X.); (Y.G.); (Z.L.); (T.L.); (Q.Z.)
- Laboratory of Animal Nutritional Physiology and Metabolic Process, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
| | - Kang Xu
- Ningxiang Pig Farm of Dalong Livestock Technology Co., Ltd., Ningxiang 410600, China; (K.X.); (Y.D.)
| | - Yehui Duan
- Ningxiang Pig Farm of Dalong Livestock Technology Co., Ltd., Ningxiang 410600, China; (K.X.); (Y.D.)
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Ahn J, Lee H, Jung CH, Ha SY, Seo HD, Kim YI, Ha T. 6-Gingerol Ameliorates Hepatic Steatosis via HNF4α/miR-467b-3p/GPAT1 Cascade. Cell Mol Gastroenterol Hepatol 2021; 12:1201-1213. [PMID: 34139323 PMCID: PMC8445893 DOI: 10.1016/j.jcmgh.2021.06.007] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 06/10/2021] [Accepted: 06/10/2021] [Indexed: 12/25/2022]
Abstract
BACKGROUND & AIMS The development of nonalcoholic fatty liver disease (NAFLD) can be modulated by microRNAs (miRNA). Dietary polyphenols modulate the expression of miRNA such as miR-467b-3p in the liver. In addition, 6-gingerol (6-G), the functional polyphenol of ginger, has been reported to ameliorate hepatic steatosis; however, the exact mechanism involved and the role of miRNA remain elusive. In this study, we assessed the role of miR-467b-3p in the pathogenesis of hepatic steatosis and the regulation of miR-467b-3p by 6-G through the hepatocyte nuclear factor 4α (HNF4α). METHODS miR-467b-3p expression was measured in free fatty acid (FFA)-treated hepatocytes or liver from high-fat diet (HFD)-fed mice. Gain- or loss-of-function of miR-467b-3p was induced using miR-467b-3p-specific miRNA mimic or miRNA inhibitor, respectively. 6-G was exposed to FFA-treated cells and HFD-fed mice. The HNF4α/miR-467b-3p/GPAT1 axis was measured in mouse and human fatty liver tissues. RESULTS We found that miR-467b-3p was down-regulated in liver tissues from HFD-fed mice and in FFA-treated Hepa1-6 cells. Overexpression of miR-467b-3p decreased intracellular lipid accumulation in FFA-treated hepatocytes and mitigated hepatic steatosis in HFD-fed mice via negative regulation of glycerol-3-phosphate acyltransferase-1 (GPAT1). In addition, miR-467b-3p up-regulation by 6-G was observed. 6-G inhibited FFA-induced lipid accumulation and mitigated hepatic steatosis. Moreover, it increased the transcriptional activity of HNF4α, resulting in the increase of miR-467b-3p and subsequent decrease of GPAT1. HNF4α/miR-467b-3p/GPAT1 signaling also was observed in human samples with hepatic steatosis. CONCLUSIONS Our findings establish a novel mechanism by which 6-G improves NAFLD. This suggests that targeting of the HNF4α/miR-467b-3p/GPAT1 cascade may be used as a potential therapeutic strategy to control NAFLD.
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Affiliation(s)
- Jiyun Ahn
- Metabolism and Nutrition Research Group, Korea Food Research Institute, Wanju-gun, Korea,Division of Food Biotechnology, University of Science and Technology, Daejeon, Korea,Correspondence Address correspondence to: Jiyun Ahn, PhD, DVM, Metabolism and Nutrition Research Group, Korea Food Research Institute, 245, Nongsaengmyeong-ro, Iseo-myeon, Wanju-gun, Jeollabuk-do 55365, Korea.
| | - Hyunjung Lee
- Metabolism and Nutrition Research Group, Korea Food Research Institute, Wanju-gun, Korea
| | - Chang Hwa Jung
- Metabolism and Nutrition Research Group, Korea Food Research Institute, Wanju-gun, Korea,Division of Food Biotechnology, University of Science and Technology, Daejeon, Korea
| | - Seung Yeon Ha
- Department of Pathology, Gachon University of Medicine and Science, Incheon, Korea
| | - Hyo-Deok Seo
- Metabolism and Nutrition Research Group, Korea Food Research Institute, Wanju-gun, Korea
| | - Young In Kim
- Metabolism and Nutrition Research Group, Korea Food Research Institute, Wanju-gun, Korea,Department of Food Science and Technology, Jeonbuk National University, Jeonju-si, South Korea
| | - Taeyoul Ha
- Metabolism and Nutrition Research Group, Korea Food Research Institute, Wanju-gun, Korea,Division of Food Biotechnology, University of Science and Technology, Daejeon, Korea,Correspondence Address correspondence to: Jiyun Ahn, PhD, DVM, Metabolism and Nutrition Research Group, Korea Food Research Institute, 245, Nongsaengmyeong-ro, Iseo-myeon, Wanju-gun, Jeollabuk-do 55365, Korea.
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MacDonald-Ramos K, Martínez-Ibarra A, Monroy A, Miranda-Ríos J, Cerbón M. Effect of Dietary Fatty Acids on MicroRNA Expression Related to Metabolic Disorders and Inflammation in Human and Animal Trials. Nutrients 2021; 13:1830. [PMID: 34072137 PMCID: PMC8226960 DOI: 10.3390/nu13061830] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 04/02/2021] [Accepted: 04/06/2021] [Indexed: 12/18/2022] Open
Abstract
Dietary fatty acids (DFAs) play key roles in different metabolic processes in humans and other mammals. DFAs have been considered beneficial for health, particularly polyunsaturated (PUFAs) and monounsaturated fatty acids (MUFAs). Additionally, microRNAs (miRNAs) exert their function on DFA metabolism by modulating gene expression, and have drawn great attention for their potential as biomarkers and therapeutic targets. This review explicitly examined the effects of DFAs on miRNA expression associated with metabolic diseases, such as obesity, non-alcoholic fatty liver disease (NAFLD), and cardiovascular disease (CVD), as well as inflammation, published in the last ten years. DFAs have been shown to induce and repress miRNA expression associated with metabolic disease and inflammation in different cell types and organisms, both in vivo and in vitro, depending on varying combinations of DFAs, doses, and the duration of treatment. However, studies are limited and heterogeneous in methodology. Additionally, recent studies demonstrated that high fat ketogenic diets, many enriched with saturated fats, do not increase serum saturated fat content in humans, and are not associated with increased inflammation. Thus, these findings shed light on the complexity of novel treatment and DFA interventions for metabolic disease and to maintain health. Further studies are needed to advance molecular therapeutic approaches, including miRNA-based strategies in human health and disease.
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Affiliation(s)
- Karla MacDonald-Ramos
- Unidad de Investigación en Reproducción Humana, Instituto Nacional de Perinatología “Isidro Espinosa de los Reyes”-Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México 11000, Mexico; (K.M.-R.); (A.M.-I.)
| | - Alejandra Martínez-Ibarra
- Unidad de Investigación en Reproducción Humana, Instituto Nacional de Perinatología “Isidro Espinosa de los Reyes”-Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México 11000, Mexico; (K.M.-R.); (A.M.-I.)
- Doctorado en Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana, Ciudad de México 04960, Mexico
| | - Adriana Monroy
- Servicio de Oncología, Hospital General de México Dr. Eduardo Liceaga, Ciudad de México 06720, Mexico;
| | - Juan Miranda-Ríos
- Unidad de Genética de la Nutrición, Departamento de Biología Molecular y Biotecnología, Instituto de Investigaciones Biomédicas de la Universidad Nacional Autónoma de México, Ciudad de México 04530, Mexico;
- Instituto Nacional de Pediatría, Ciudad de México 04530, Mexico
| | - Marco Cerbón
- Unidad de Investigación en Reproducción Humana, Instituto Nacional de Perinatología “Isidro Espinosa de los Reyes”-Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México 11000, Mexico; (K.M.-R.); (A.M.-I.)
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8
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Epigenetics in NAFLD/NASH: Targets and therapy. Pharmacol Res 2021; 167:105484. [PMID: 33771699 DOI: 10.1016/j.phrs.2021.105484] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Revised: 02/02/2021] [Accepted: 02/03/2021] [Indexed: 12/15/2022]
Abstract
Recently non-alcoholic fatty liver disease (NAFLD) has grabbed considerable scientific attention, owing to its rapid increase in prevalence worldwide and growing burden on end-stage liver diseases. Metabolic syndrome including obesity, diabetes, and hypertension poses a grave risk to NAFLD etiology and progression. With no drugs available, the mainstay of NAFLD management remains lifestyle changes with exercise and dietary modifications. Nonselective drugs such as metformin, thiazolidinediones (TZDs), ursodeoxycholic acid (UDCA), silymarin, etc., are also being used to target the interrelated pathways for treating NAFLD. Considering the enormous disease burden and the unmet need for drugs, fresh insights into pathogenesis and drug discovery are required. The emergence of the field of epigenetics offers a convincing explanation for the basis of lifestyle, environmental, and other risk factors to influence NAFLD pathogenesis. Therefore, understanding these epigenetic modifications to target the primary cause of the disease might prove a rational strategy to prevent the disease and develop novel therapeutic interventions. Apart from describing the role of epigenetics in the pathogenesis of NAFLD as in other reviews, this review additionally provides an elaborate discussion on exploiting the high plasticity of epigenetic modifications in response to environmental cues, for developing novel therapeutics for NAFLD. Besides, this extensive review provides evidence for epigenetic mechanisms utilized by several potential drugs for NAFLD.
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9
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Jin F, Liao L, Zhu Y. MiR-467b alleviates lipopolysaccharide-induced inflammation through targeting STAT1 in chondrogenic ATDC5 cells. Int J Immunogenet 2021; 48:435-442. [PMID: 33650224 DOI: 10.1111/iji.12534] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 02/01/2021] [Accepted: 02/18/2021] [Indexed: 12/13/2022]
Abstract
Osteoarthritis (OA) is one of the most common degenerative joint diseases worldwide. Chondrocytes are activated in OA patients, accompanied by excessive chondrogenic proliferation and production of inflammatory cytokines. MiR-467b is implicated in the regulation of artherosclerosis and pro-inflammatory cytokine secretion. However, the precise role of miR-467b in OA remains unclear. In the present study, we induced inflammation in chondrogenic ATDC5 cells using lipopolysaccharide (LPS). LPS treatment significantly elevated the production of interleukin-6 (IL-6), IL-1β and tumour necrosis factor-α (TNF-α) in ATDC5 cells, accompanied by decreased miR-467 level. Then, we over-expressed miR-467b using its specific mimics in ATDC5 cells, and LPS-induced inflammation was significantly inhibited as evidenced by decreased IL-6, IL-1β and TNF-α levels. MiR-467b agomir also alleviated inflammation in rat knee osteoarthritis (KOA) model. In addition, we validated that signal transducer and activator of transcription 1 (STAT1) was a downstream target of miR-467b. LPS treatment significantly increased the STAT1 expression while miR-467b mimic transfection partially reversed this effect. Moreover, STAT1 knockout reversed the increased contents of IL-6, IL-1β and TNF-α. Furthermore, miR-467b over-expression significantly decreased the production of IL-6, IL-1β and TNF-α induced by LPS treatment, which was partially reversed by further STAT1 over-expression. In summary, our findings demonstrated that miR-467b alleviated LPS-induced inflammation through targeting STAT1, and this miR-467b/STAT1 regulation axis may provide a new therapeutic target for OA clinical management.
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Affiliation(s)
- Feng Jin
- Department of Orthopedics, Community Health Service Center of Shouxiang, Hangzhou, Zhejiang Province, China
| | - Leming Liao
- Department of Orthopedics, First People's Hospital of Fuyang District, Hangzhou, Zhejiang Province, China
| | - Yongjun Zhu
- Department of Orthopedics, Community Health Service Center of Shouxiang, Hangzhou, Zhejiang Province, China
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10
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Gajeton J, Krukovets I, Yendamuri R, Verbovetskiy D, Vasanji A, Sul L, Stenina‐Adognravi O. miR-467 regulates inflammation and blood insulin and glucose. J Cell Mol Med 2021; 25:2549-2562. [PMID: 33566451 PMCID: PMC7933977 DOI: 10.1111/jcmm.16224] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 09/24/2020] [Accepted: 10/18/2020] [Indexed: 12/12/2022] Open
Abstract
Obesity is associated with inflammation and insulin resistance (IR), but the regulation of insulin sensitivity (IS) and connections between IS and inflammation remain unclear. We investigated the role of miR-467a-5p, a miRNA induced by hyperglycaemia, in regulating inflammation and blood glucose handling. We previously demonstrated that miR-467a-5p is induced by hyperglycaemia and inhibits the production of thrombospondin-1 (TSP-1), a protein implicated in regulating inflammation. To investigate the role of miR-467 in blood glucose handling and tissue inflammation, WT C57BL/6 mice were fed chow or Western diet from 5 to 32 weeks of age and injected weekly with miR-467a-5p antagonist. Inhibiting miR-467a-5p resulted in 47% increase in macrophage infiltration and increased Il6 levels in adipose tissue, higher plasma insulin levels (98 ng/mL vs 63 ng/mL), and 17% decrease in glucose clearance without increase in weight or HDL/LDL. The antagonist effect was lost in mice on Western diet. Mice lacking TSP-1 lost some but not all of the miR-467 effects, suggesting Thbs1 (and other unknown transcripts) are targeted by miR-467 to regulate inflammation. miR-467a-5p provides a physiological feedback when blood glucose is elevated to avoid inflammation and increased blood glucose and insulin levels, which may prevent IR.
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Affiliation(s)
- Jasmine Gajeton
- Department of Cardiovascular and Metabolic SciencesCleveland ClinicClevelandOHUSA
- Department of Molecular MedicineCase Western Reserve UniversityClevelandOHUSA
| | - Irene Krukovets
- Department of Cardiovascular and Metabolic SciencesCleveland ClinicClevelandOHUSA
| | - Revanth Yendamuri
- Department of Cardiovascular and Metabolic SciencesCleveland ClinicClevelandOHUSA
- Present address:
Northeast Ohio Medical UniversityRootstownOHUSA
| | - Dmitriy Verbovetskiy
- Department of Cardiovascular and Metabolic SciencesCleveland ClinicClevelandOHUSA
| | | | - Lidiya Sul
- Department of Cardiovascular and Metabolic SciencesCleveland ClinicClevelandOHUSA
- Present address:
Ohio University Heritage College of Osteopathic MedicineAthensOHUSA
| | - Olga Stenina‐Adognravi
- Department of Cardiovascular and Metabolic SciencesCleveland ClinicClevelandOHUSA
- Department of Molecular MedicineCase Western Reserve UniversityClevelandOHUSA
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11
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Wu T, Lei Y, Jin S, Zhao Q, Cheng W, Xi Y, Wang L, Wang Z, Niu X, Chen G. miRNA-467b inhibits Th17 differentiation by targeting eIF4E in experimental autoimmune encephalomyelitis. Mol Immunol 2021; 133:23-33. [PMID: 33621940 DOI: 10.1016/j.molimm.2021.02.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 11/23/2020] [Accepted: 02/08/2021] [Indexed: 12/30/2022]
Abstract
Multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) are neuroinflammatory autoimmune diseases characterized by the axonal loss, demyelination, and neurodegeneration of the central nervous system. Overactivation of CD4+ T cells, especially the migration of the Th1 and Th17 subsets into the central nervous system (CNS), leads to the secretion of inflammatory mediators and destruction of the contact between neurons and activated macrophages, which can then result in a series of neurocognitive and motor deficits. In this study, we intended to explore the role of miRNA-467b in regulating Th cell development in EAE. We found that the level of miRNA-467b was decreased and eukaryotic initiation factor 4 F (eIF4E) was increased in lymph nodes and the CNS at EAE peak. eIF4E was confirmed as the direct target of miRNA467b. Overexpression of miRNA-467b could suppress a percentage of CD4+ IL-17+ cells in EAE CD4 + T cells in vitro. In addition, we also identified miRNA-467b, which could suppress Th17 cell differentiation by targeting eIF4E in vitro. Furthermore, injecting miRNA-467b mimics into the caudal vein of EAE mice contributed to less inflammation in the peripheral lymphoid organs and CNS and alleviated disease severity. Taken together, our findings imply that miRNA-467b inhibits the differentiation and function of Th17 cells by targeting eIF4E, thereby alleviating EAE.
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Affiliation(s)
- Ting Wu
- Department of Immunology and Microbiology, Shanghai JiaoTong University School of Medicine, Shanghai Institute of Immunology, Shanghai 200025, China; RenJi(North) Hospital Shanghai Jiaotong University School of Medicine, Shanghai 200135, China
| | - Yunxuan Lei
- Department of Immunology and Microbiology, Shanghai JiaoTong University School of Medicine, Shanghai Institute of Immunology, Shanghai 200025, China
| | - Shuxin Jin
- Department of Immunology and Microbiology, Shanghai JiaoTong University School of Medicine, Shanghai Institute of Immunology, Shanghai 200025, China
| | - Qing Zhao
- Department of Immunology and Microbiology, Shanghai JiaoTong University School of Medicine, Shanghai Institute of Immunology, Shanghai 200025, China; Shanghai Key Laboratory of Diabetes Mellitus and Center for Translational Medicine, Shanghai JiaoTong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Wenjing Cheng
- Department of Immunology and Microbiology, Shanghai JiaoTong University School of Medicine, Shanghai Institute of Immunology, Shanghai 200025, China; The Fifth People's Hospital of YuHang District, Hangzhou 311100, China
| | - Yebin Xi
- Department of Immunology and Microbiology, Shanghai JiaoTong University School of Medicine, Shanghai Institute of Immunology, Shanghai 200025, China
| | - Li Wang
- Department of Immunology and Microbiology, Shanghai JiaoTong University School of Medicine, Shanghai Institute of Immunology, Shanghai 200025, China
| | - Zhaojun Wang
- Department of Immunology and Microbiology, Shanghai JiaoTong University School of Medicine, Shanghai Institute of Immunology, Shanghai 200025, China
| | - Xiaoyin Niu
- Department of Immunology and Microbiology, Shanghai JiaoTong University School of Medicine, Shanghai Institute of Immunology, Shanghai 200025, China.
| | - Guangjie Chen
- Department of Immunology and Microbiology, Shanghai JiaoTong University School of Medicine, Shanghai Institute of Immunology, Shanghai 200025, China.
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12
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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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13
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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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14
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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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15
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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: 84] [Impact Index Per Article: 12.0] [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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16
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Matboli M, Shafei A, Ali M, Kamal KM, Noah M, Lewis P, Habashy A, Ehab M, Gaber AI, Abdelzaher H. Emerging role of nutrition and the non-coding landscape in type 2 diabetes mellitus: A review of literature. Gene 2018; 675:54-61. [PMID: 29960068 DOI: 10.1016/j.gene.2018.06.082] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Revised: 06/22/2018] [Accepted: 06/25/2018] [Indexed: 12/23/2022]
Abstract
With the advent of recent advances in molecular techniques and whole genome sequencing, we have come to know that the non-coding landscape (including non-coding RNAs, tRNAs and even telomeres) plays a major role in the regulation of cellular processes. Furthermore, the deregulation of this landscape has been found to contribute to and even bring about the pathogenesis of a large number of diseases. One of such diseases is diabetes mellitus (type 2 specifically) whose incidence rate and global burden is constantly increasing. Nutrition has been proven to be a key player in the development, onset and control of type 2 diabetes mellitus. Additionally, non-coding DNA based molecular markers are emerging as biomarkers of T2D, susceptibility, and perhaps dietary supplements can modulate non-coding DNA based markers expression and function in T2D management. In this review, we provide a brief overview of the developmental origins and genetics of type 2 diabetes mellitus, how each component of the non-coding landscape contributes to the development and progression of the disease and finally we discuss how dietary interventions modulate the non-coding landscape in T2D.
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Affiliation(s)
- Marwa Matboli
- Medical Biochemistry and Molecular biology, Department, Faculty of Medicine, Ain Shams University Medical Research Institute (MASRI), Cairo, Egypt.
| | - Ayman Shafei
- Biomedical Research Department, Armed Forces College of Medicine, Cairo, Egypt
| | - Mahmoud Ali
- Biomedical Research Department, Armed Forces College of Medicine, Cairo, Egypt
| | | | | | - Paula Lewis
- Armed Forces College of Medicine, Cairo, Egypt
| | | | | | | | - Hana Abdelzaher
- Medical Education Development Unit (MEDU), Armed Forces College of Medicine, Cairo, Egypt.
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17
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Yang F, Dai Y, Min C, Li X. Neonatal overfeeding induced glucocorticoid overexposure accelerates hepatic lipogenesis in male rats. Nutr Metab (Lond) 2018; 15:30. [PMID: 29743929 PMCID: PMC5930793 DOI: 10.1186/s12986-018-0272-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Accepted: 04/18/2018] [Indexed: 02/07/2023] Open
Abstract
Background Postnatal overfeeding activates tissue glucocorticoid (GC) activity by up-regulating 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) and increasing sensitivity to high-fat (HF) diet-induced non-alcoholic fatty liver disease (NAFLD). The present study aimed to evaluate the effects of postnatal overfeeding on GC regulation and lipogenesis in the liver and to observe the impact of GC on hepatocyte lipid metabolism. Methods In vivo, Male Sprague-Dawley rat pup litters were adjusted to litter sizes of three (small litter, SL) or ten (normal litter, NL) on postnatal day 3 and then given standard chow from postnatal week 3 (W3) to W13. In vitro, HepG2 cells were stimulated by GC, mifepristone (Mi) or GC + Mi within 48 h, followed by sodium oleate (OA) intervention (or not) for 24 h. Intracellular lipid droplets, triglyceride (TG) concentrations and gene expression related to lipid metabolism were measured in hepatic tissues or HepG2 cells. Results In vivo, weight gain in the body and liver and TG concentrations in the liver were significantly increased in the SL rats compared to the NL rats at W3 and W13 (p < 0.05); mRNA expression of hepatic 11β-HSD1, acetyl-CoA carboxylase 1 (ACC), stearoyl-CoA desaturase-1 (SCD1), fatty acid synthase (FASN) and their nuclear transcription factor, sterol regulatory element binding protein-1c (SREBP-1c) (p < 0.05), was also increased. In vitro, intracellular lipid droplets and TG content in HepG2 cells increased under stimulation with GC or OA (p < 0.05); the increase was more significant following treatment with GC and OA together (p < 0.05). The ACC, SCD1, FASN and SREBP-1c mRNA expression changes were highly similar to the changes in TG content in cells. All the changes induced by GC disappeared when the glucocorticoid receptor (GR) was blocked by Mi. Conclusions Postnatal overfeeding induced GC overexposure through 11β-HSD1 up-regulation in the liver. GC activated hepatic de novo lipogenesis (DNL) via GR and led to hepatic lipid accumulation, which increased the risk of NAFLD during adulthood.
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Affiliation(s)
- Fan Yang
- 1Department of Child Health Care, Children's Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing, China
| | - Yanyan Dai
- 1Department of Child Health Care, Children's Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing, China
| | - Cuiting Min
- 1Department of Child Health Care, Children's Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing, China
| | - Xiaonan Li
- 1Department of Child Health Care, Children's Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing, China.,2Institute of Paediatric Research, Nanjing Medical University, 140 Hanzhong Road, Nanjing, China
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18
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He PP, Jiang T, OuYang XP, Liang YQ, Zou JQ, Wang Y, Shen QQ, Liao L, Zheng XL. Lipoprotein lipase: Biosynthesis, regulatory factors, and its role in atherosclerosis and other diseases. Clin Chim Acta 2018; 480:126-137. [PMID: 29453968 DOI: 10.1016/j.cca.2018.02.006] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Revised: 02/06/2018] [Accepted: 02/07/2018] [Indexed: 01/20/2023]
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19
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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: 41] [Impact Index Per Article: 5.9] [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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20
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Gong R, Lv X, Liu F. MiRNA-17 encoded by the miR-17-92 cluster increases the potential for steatosis in hepatoma cells by targeting CYP7A1. Cell Mol Biol Lett 2018; 23:16. [PMID: 29721023 PMCID: PMC5907481 DOI: 10.1186/s11658-018-0083-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Accepted: 04/13/2018] [Indexed: 12/12/2022] Open
Abstract
Background The miRNA cluster miR-17-92 is known to act as an oncogene in various cancers. Members of this cluster were also found to be involved in some other pathological process, such as steatosis, which is a pivotal event in the initiation and progression of nonalcoholic fatty liver disease (NAFLD). This study aimed to explore whether miR-17, one of the most functional miRNAs in the miR-17-92 family, participates in the process of steatosis in hepatoma cells. Methods We developed both a miR-17-expressing transgenic mouse model and a miR-17-expressing HepG2 cell model, the latter was established via stable transfection. Real-time PCR and western blot were applied to measure the expression levels of miR-17 and the potential target gene CYP7A1. The luciferase assay was used to confirm direct binding of miR-17 and CYP7A1. The oleic acid induction assay and Oil-Red-O staining were performed to support the determination of steatotic changes in HepG2 cell. Results Extensive steatotic changes were observed in the livers of transgenic mice. Fewer were seen in the wild-type animals. CYP7A1 was confirmed as a target gene of miR-17, and the expression of CYP7A1 was found to be negatively regulated in both the transgenic mice liver cells and the miR-17-expressing HepG2 cells. CYP7A1 was found to participate in miR-17-induced steatosis, as its repressed expression in miR-17 HepG2 cells exacerbated steatotic change. Re-introduction of CYP7A1 into miR-17 HepG2 cell partially alleviated steatosis. Conclusions miR-17 is a novel regulator of CYP7A1 signaling in hepatic lipid metabolism, suggesting a potential therapeutic approach for fatty liver. Electronic supplementary material The online version of this article (10.1186/s11658-018-0083-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Ruijie Gong
- 1Fujian Provincial Key Laboratory of Environment Factors and Cancer, School of Public Health, Fujian Medical University, Fuzhou, Fujian 350008 People's Republic of China
| | - Xiaofei Lv
- 3Department of Internal Medicine, Guangdong Women and Children's Hospital, Guangzhou Medical University, 521 Xingnan Road, Guangzhou, China
| | - Fengqiong Liu
- 1Fujian Provincial Key Laboratory of Environment Factors and Cancer, School of Public Health, Fujian Medical University, Fuzhou, Fujian 350008 People's Republic of China.,2Department of Epidemiology and Health Statistics, School of Public Health, Fujian Medical University, Fujian, China
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21
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Kasiappan R, Rajarajan D. Role of MicroRNA Regulation in Obesity-Associated Breast Cancer: Nutritional Perspectives. Adv Nutr 2017; 8:868-888. [PMID: 29141971 PMCID: PMC5682994 DOI: 10.3945/an.117.015800] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Breast cancer is the most common malignancy diagnosed in women, and the incidence of breast cancer is increasing every year. Obesity has been identified as one of the major risk factors for breast cancer progression. The mechanisms by which obesity contributes to breast cancer development is not yet understood; however, there are a few mechanisms counted as potential producers of breast cancer in obesity, including insulin resistance, chronic inflammation and inflammatory cytokines, adipokines, and sex hormones. Recent emerging evidence suggests that alterations in microRNA (miRNA) expressions are found in several diseases, including breast cancer and obesity; however, miRNA roles in obesity-linked breast cancer are beginning to unravel. miRNAs are thought to be potential noninvasive biomarkers for diagnosis and prognosis of cancer patients with comorbid conditions of obesity as well as therapeutic targets. Recent studies have evidenced that nutrients and other dietary factors protect against cancer and obesity through modulation of miRNA expressions. Herein, we summarize a comprehensive overview of up-to-date information related to miRNAs and their molecular targets involved in obesity-associated breast cancer. We also address the mechanisms by which dietary factors modulate miRNA expression and its protective roles in obesity-associated breast cancer. It is hoped that this review would provide new therapeutic strategies for the treatment of obesity-associated breast cancer to reduce the burden of breast cancer.
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Affiliation(s)
- Ravi Kasiappan
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore, Karnataka, India
| | - Dheeran Rajarajan
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore, Karnataka, India
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22
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Bai P, Xia N, Sun H, Kong Y. Pleiotrophin, a target of miR-384, promotes proliferation, metastasis and lipogenesis in HBV-related hepatocellular carcinoma. J Cell Mol Med 2017; 21:3023-3043. [PMID: 28557334 PMCID: PMC5661149 DOI: 10.1111/jcmm.13213] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2016] [Accepted: 03/29/2017] [Indexed: 12/27/2022] Open
Abstract
Hepatitis B virus (HBV) infection plays a crucial role and is a major cause of hepatocellular carcinoma (HCC) in China. microRNAs (miRNAs) have emerged as key players in hepatic steatosis and carcinogenesis. We found that down-regulation of miR-384 expression was a common event in HCC, especially HBV-related HCC. However, the possible function of miR-384 in HBV-related HCC remains unclear. The oncogene pleiotrophin (PTN) was a target of miR-384. HBx inhibited miR-384, increasing PTN expression. The PTN receptor N-syndecan was highly expressed in HCC. PTN induced by HBx acted as a growth factor via N-syndecan on hepatocytes and further promoted cell proliferation, metastasis and lipogenesis. PTN up-regulated sterol regulatory element-binding protein 1c (SREBP-1c) through the N-syndecan/PI3K/Akt/mTORC1 pathway and the expression of lipogenic genes, including fatty acid synthesis (FAS). PTN-mediated de novo lipid synthesis played an important role in HCC proliferation and metastasis. PI3K/AKT and an mTORC1 inhibitor diminished PTN-induced proliferation, metastasis and lipogenesis. Taken together, these data strongly suggest that the dysregulation of miR-384 could play a crucial role in HBV related to HCC, and the target gene of miR-384, PTN, represents a new potential therapeutic target for the prevention of hepatic steatosis and further progression to HCC after chronic HBV infection.
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Affiliation(s)
- Pei‐song Bai
- Department of OncologyFirst Hospital of Xi'an Jiaotong UniversityXi'anShaanxiChina
| | - Nan Xia
- Institute of Cancer Prevention and ControlPeking University Cancer HospitalBei'jingChina
| | - Hong Sun
- Department of OncologyFirst Hospital of Xi'an Jiaotong UniversityXi'anShaanxiChina
| | - Ying Kong
- Department of OncologyFirst Hospital of Xi'an Jiaotong UniversityXi'anShaanxiChina
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23
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Abstract
It is now evident that elevated circulating levels of triglycerides in the non-fasting state, a marker for triglyceride (TG)-rich remnant particles, are associated with increased risk of premature cardiovascular disease (CVD). Recent findings from basic and clinical studies have begun to elucidate the mechanisms that contribute to the atherogenicity of these apoB-containing particles. Here, we review current knowledge of the formation, intravascular remodelling and catabolism of TG-rich lipoproteins and highlight (i) the pivotal players involved in this process, including lipoprotein lipase, glycosylphosphatidylinositol HDL binding protein 1 (GPIHBP1), apolipoprotein (apo) C-II, apoC-III, angiopoietin-like protein (ANGPTL) 3, 4 and 8, apoA-V and cholesteryl ester transfer protein; (ii) key determinants of triglyceride (TG) levels and notably rates of production of very-low-density lipoprotein 1 (VLDL1) particles; and (iii) the mechanisms which underlie the atherogenicity of remnant particles. Finally, we emphasise the polygenic nature of moderate hypertriglyceridemia and briefly discuss modalities for its clinical management. Several new therapeutic strategies to attenuate hypertriglyceridemia have appeared recently, among which those targeted to apoC-III appear to hold considerable promise.
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Affiliation(s)
- Geesje M Dallinga-Thie
- Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands. .,Department of Experimental Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
| | - Jeffrey Kroon
- Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.,Department of Experimental Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands
| | - Jan Borén
- Department of Molecular and Clinical Medicine, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden
| | - M John Chapman
- INSERM and University of Pierre and Marie Curie, Pitie-Salpetriere University Hospital, 75651, Paris Cedex 13, France
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24
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Geisler CE, Renquist BJ. Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones. J Endocrinol 2017; 234:R1-R21. [PMID: 28428362 DOI: 10.1530/joe-16-0513] [Citation(s) in RCA: 129] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Accepted: 04/20/2017] [Indexed: 12/11/2022]
Abstract
Fatty liver can be diet, endocrine, drug, virus or genetically induced. Independent of cause, hepatic lipid accumulation promotes systemic metabolic dysfunction. By acting as peroxisome proliferator-activated receptor (PPAR) ligands, hepatic non-esterified fatty acids upregulate expression of gluconeogenic, beta-oxidative, lipogenic and ketogenic genes, promoting hyperglycemia, hyperlipidemia and ketosis. The typical hormonal environment in fatty liver disease consists of hyperinsulinemia, hyperglucagonemia, hypercortisolemia, growth hormone deficiency and elevated sympathetic tone. These endocrine and metabolic changes further encourage hepatic steatosis by regulating adipose tissue lipolysis, liver lipid uptake, de novo lipogenesis (DNL), beta-oxidation, ketogenesis and lipid export. Hepatic lipid accumulation may be induced by 4 separate mechanisms: (1) increased hepatic uptake of circulating fatty acids, (2) increased hepatic de novo fatty acid synthesis, (3) decreased hepatic beta-oxidation and (4) decreased hepatic lipid export. This review will discuss the hormonal regulation of each mechanism comparing multiple physiological models of hepatic lipid accumulation. Nonalcoholic fatty liver disease (NAFLD) is typified by increased hepatic lipid uptake, synthesis, oxidation and export. Chronic hepatic lipid signaling through PPARgamma results in gene expression changes that allow concurrent activity of DNL and beta-oxidation. The importance of hepatic steatosis in driving systemic metabolic dysfunction is highlighted by the common endocrine and metabolic disturbances across many conditions that result in fatty liver. Understanding the mechanisms underlying the metabolic dysfunction that develops as a consequence of hepatic lipid accumulation is critical to identifying points of intervention in this increasingly prevalent disease state.
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Affiliation(s)
- Caroline E Geisler
- School of Animal and Comparative Biomedical SciencesUniversity of Arizona, Tucson, Arizona, USA
| | - Benjamin J Renquist
- School of Animal and Comparative Biomedical SciencesUniversity of Arizona, Tucson, Arizona, USA
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25
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Wilson RA, Deasy W, Hayes A, Cooke MB. High fat diet and associated changes in the expression of micro-RNAs in tissue: Lessons learned from animal studies. Mol Nutr Food Res 2017; 61. [PMID: 28233461 DOI: 10.1002/mnfr.201600943] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Revised: 01/15/2017] [Accepted: 02/13/2017] [Indexed: 12/13/2022]
Abstract
Environment and genetic factors play an important role in the development of obesity, and diet is one of the main contributing factors to this disease. High fat intake is associated with body weight gain, leading to obesity and other metabolic diseases. MicroRNAs (miRNAs) are a group of small, noncoding RNAs that are important regulators of gene expression at posttranscriptional level. Studies have shown that high fat intake, independent of body weight status, can significantly impact both negatively and positively the expression of miRNAs and thus the biological function of tissues such as adipose, skeletal, and cardiac muscle, liver, neuronal, and endothelial. This review will summarize the effects of high calorie diet in the form of high fat intake on miRNA expression in various tissues of animal models and of high fat fed offspring. We will also briefly review the impact of different dietary lipids on miRNA expression. Given changes in miRNA expression have been associated with the development of many diseases including obesity, understanding their biological role could have important clinical implications and offer tangible therapeutic targets for the prevention, management, and/or treatment of obesity and other lifestyle-related disorders.
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Affiliation(s)
- Robin A Wilson
- College of Health and Biomedicine, Victoria University, Melbourne, VIC, Australia.,Australian Institute for Musculoskeletal Science (AIMSS), Western Health, Melbourne, VIC, Australia
| | - William Deasy
- College of Health and Biomedicine, Victoria University, Melbourne, VIC, Australia.,Australian Institute for Musculoskeletal Science (AIMSS), Western Health, Melbourne, VIC, Australia
| | - Alan Hayes
- College of Health and Biomedicine, Victoria University, Melbourne, VIC, Australia.,Australian Institute for Musculoskeletal Science (AIMSS), Western Health, Melbourne, VIC, Australia
| | - Matthew B Cooke
- College of Health and Biomedicine, Victoria University, Melbourne, VIC, Australia.,Australian Institute for Musculoskeletal Science (AIMSS), Western Health, Melbourne, VIC, Australia
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26
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Wang B, He PP, Zeng GF, Zhang T, Ou Yang XP. miR-467b regulates the cholesterol ester formation via targeting ACAT1 gene in RAW 264.7 macrophages. Biochimie 2017; 132:38-44. [DOI: 10.1016/j.biochi.2016.09.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Revised: 09/22/2016] [Accepted: 09/22/2016] [Indexed: 12/01/2022]
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Abstract
Non-alcoholic fatty liver disease (NAFLD) is a major cause of liver cirrhosis and hepatocellular carcinoma and is a considerable threat to public health. miRNAs are important post-transcriptional regulators of gene expression, and the dysregulation of miRNAs is involved in various biological processes in the liver, including lipid homeostasis, inflammation, apoptosis, and cell proliferation. Recently, a number of studies have described the association between miRNAs and NAFLD progression and have shown that circulating miRNAs reflect histological changes in the liver. Therefore, circulating miRNAs have potential use for the evaluation of NAFLD severity. In this review, we discuss the involvement of miRNAs in NAFLD pathogenesis and the key role of miRNAs in the screening, diagnosis, and staging of NAFLD.
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28
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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] [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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29
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Cheng Y, Mai J, Hou T, Ping J. MicroRNA-421 induces hepatic mitochondrial dysfunction in non-alcoholic fatty liver disease mice by inhibiting sirtuin 3. Biochem Biophys Res Commun 2016; 474:57-63. [PMID: 27107702 DOI: 10.1016/j.bbrc.2016.04.065] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Accepted: 04/13/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIM Mitochondrial dysfunction plays a major role in critical initiating or propagating events in nonalcoholic fatty liver disease (NAFLD), but its pathogenesis remains obscure. Recently, microRNAs have been found to affect oxidant stress and lipid metabolism. In this study, we elucidated the functions of microRNA-421 in the development of NAFLD and identified its potential targets. METHODS An experimental model for the study of NAFLD was constructed by feeding a high fat diet to C57BL/6J mice. Differentially expressed miRNA in livers of NAFLD mice compared with controls were identified by high-throughput sequencing. Relative repression of luciferase expression standardized to a transfection control was analyzed by luciferase reporter assays. RESULTS The microRNA profiling presented that microRNA-421 expression was significantly upregulated in hepatic tissues of NAFLD model mouse. The sirtuin 3 was identified as a functionally relevant target of microRNA-421. The microRNA-421 acts upstream of SIRT3/FOXO3 pathway in modulation the oxidant stress and lipid metabolism. Overexpression of microRNA-421 decreased SIRT3 and FOXO3 protein levels, and then led to MnSOD and CAT decrease, the downstream targets of SIRT3/FOXO3 pathway. On the contrary, suppression of microRNA-421 had adverse effects on performance of celluar oxidative damage. CONCLUSIONS Regulating or inhibiting hepatic microRNA-421 could decrease celluar oxidative damage and contribute to therapeutic potential in NAFLD.
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Affiliation(s)
- Yang Cheng
- Institute of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Jingyin Mai
- Department of Internal Medicine, Shanghai Pudong New Area Hospital of Traditional Chinese Medicine, Shanghai 201299, China
| | - Tianlu Hou
- Institute of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jian Ping
- Institute of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
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30
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Mechanistically linked serum miRNAs distinguish between drug induced and fatty liver disease of different grades. Sci Rep 2016; 6:23709. [PMID: 27045805 PMCID: PMC4820692 DOI: 10.1038/srep23709] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2015] [Accepted: 03/10/2016] [Indexed: 02/08/2023] Open
Abstract
Hepatic steatosis is characterised by excessive triglyceride accumulation in the form of lipid droplets (LD); however, mechanisms differ in drug induced (DIS) and/or non-alcoholic fatty liver disease (NAFLD). Here we hypothesized distinct molecular circuits of microRNA/LD-associated target genes and searched for mechanistically linked serum and tissue biomarkers that would distinguish between DIS and human NAFLD of different grades. We analysed >800 rat hepatic whole genome data for 17 steatotic drugs and identified 157 distinct miRNAs targeting 77 DIS regulated genes. Subsequently, genomic data of N = 105 cases of human NAFLD and N = 32 healthy controls were compared to serum miRNA profiles of N = 167 NAFLD patients. This revealed N = 195 tissue-specific miRNAs being mechanistically linked to LD-coding genes and 24 and 9 miRNAs were commonly regulated in serum and tissue of advanced and mild NAFLD, respectively. The NASH serum regulated miRNAs informed on hepatic inflammation, adipocytokine and insulin signalling, ER-and caveolae associated activities and altered glycerolipid metabolism. Conversely, serum miRNAs associated with blunt steatosis specifically highlighted activity of FOXO1&HNF4α on CPT2, the lipid droplet and ER-lipid-raft associated PLIN3 and Erlin1. Altogether, serum miRNAs informed on the molecular pathophysiology of NAFLD and permitted differentiation between DIS and NAFLD of different grades.
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31
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Zhang L, Zhang Z, Li Y, Liao S, Wu X, Chang Q, Liang B. Cholesterol induces lipoprotein lipase expression in a tree shrew (Tupaia belangeri chinensis) model of non-alcoholic fatty liver disease. Sci Rep 2015; 5:15970. [PMID: 26522240 PMCID: PMC4629153 DOI: 10.1038/srep15970] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Accepted: 10/06/2015] [Indexed: 12/28/2022] Open
Abstract
Animal models are indispensible to investigate the pathogenesis and treatments of non-alcoholic fatty liver diseases (NAFLD). Altered cholesterol metabolism has been implicated into the pathogenesis of NAFLD. Here, using high fat, cholesterol and cholate diet (HFHC), we generated a novel tree shrew (Tupaia belangeri chinensis) model of NAFLD, which displayed dyslipidemia with increased levels of plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST), total cholesterol (TC), low density lipoprotein-cholesterol (LDL-c) and high density lipoprotein-cholesterol (HDL-c), but decreased level of triglycerides (TG). Liver histopathology and genes expression indicated that HFHC diet successfully induced liver steatosis to inflammation and fibrosis progressively within 10 weeks. Moreover, HFHC induced the transcriptional expression of lipoprotein lipase (lpl) in the liver, but repressed the expression of LDL receptor, and the endogenous synthesis pathway and excretion of cholesterol. Notably, Poloxamer 407 (P-407) inhibition of LPL improved the severity of steatosis and reduced inflammation. These results illustrated that LPL plays an important role in cholesterol metabolism in NAFLD, and the tree shrew may be a valuable animal model for further research into NAFLD.
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Affiliation(s)
- Linqiang Zhang
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Science &Yunnan province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China.,Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan 650204, China
| | - Zhiguo Zhang
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Science &Yunnan province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China.,Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan 650204, China
| | - Yunhai Li
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Science &Yunnan province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China
| | - Shasha Liao
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Science &Yunnan province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China.,School of Life Sciences, Anhui University, Hefei, Anhui 230601, China
| | - Xiaoyun Wu
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Science &Yunnan province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China
| | - Qing Chang
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Science &Yunnan province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China
| | - Bin Liang
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Science &Yunnan province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China
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32
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Leti F, Malenica I, Doshi M, Courtright A, Van Keuren-Jensen K, Legendre C, Still CD, Gerhard GS, DiStefano JK. High-throughput sequencing reveals altered expression of hepatic microRNAs in nonalcoholic fatty liver disease-related fibrosis. Transl Res 2015; 166:304-14. [PMID: 26001595 PMCID: PMC4537840 DOI: 10.1016/j.trsl.2015.04.014] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2015] [Revised: 04/08/2015] [Accepted: 04/28/2015] [Indexed: 12/11/2022]
Abstract
Recent evidence suggests that microRNAs (miRNAs), small, noncoding RNA molecules that regulate gene expression, may play a role in the regulation of metabolic disorders, including nonalcoholic fatty liver disease (NAFLD). To identify miRNAs that mediate NAFLD-related fibrosis, we used high-throughput sequencing to assess miRNAs obtained from liver biopsies of 15 individuals without NAFLD fibrosis (F0) and 15 individuals with severe NAFLD fibrosis or cirrhosis (F3-F4), matched for age, sex, body mass index, type 2 diabetes status, hemoglobin A1c, and use of diabetes medications. We used DESeq2 and Kruskal-Wallis test to identify miRNAs that were differentially expressed between NAFLD patients with or without fibrosis, adjusting for multiple testing using Bonferroni correction. We identified a total of 75 miRNAs showing statistically significant evidence (adjusted P value <0.05) for differential expression between the 2 groups, including 30 upregulated and 45 downregulated miRNAs. Quantitative reverse-transcription polymerase chain reaction analysis of selected miRNAs identified by sequencing validated 9 of 11 of the top differentially expressed miRNAs. We performed functional enrichment analysis of dysregulated miRNAs and identified several potential gene targets related to NAFLD-related fibrosis including hepatic fibrosis, hepatic stellate cell activation, transforming growth factor beta signaling, and apoptosis signaling. We identified forkhead box O3 and F-box WD repeat domain containing 7, E3 ubiquitin protein ligase (FBXW7) as potential targets of miR-182, and found that levels of forkhead box O3, but not FBXW7, were significantly decreased in fibrotic samples. These findings support a role for hepatic miRNAs in the pathogenesis of NAFLD-related fibrosis and yield possible new insight into the molecular mechanisms underlying the initiation and progression of liver fibrosis and cirrhosis.
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Affiliation(s)
- Fatjon Leti
- Division of Diabetes, Cardiovascular and Metabolic Diseases, Translational Genomics Research Institute, Phoenix, Ariz
| | - Ivana Malenica
- Division of Diabetes, Cardiovascular and Metabolic Diseases, Translational Genomics Research Institute, Phoenix, Ariz
| | - Meera Doshi
- Division of Diabetes, Cardiovascular and Metabolic Diseases, Translational Genomics Research Institute, Phoenix, Ariz
| | - Amanda Courtright
- Division of Diabetes, Cardiovascular and Metabolic Diseases, Translational Genomics Research Institute, Phoenix, Ariz
| | - Kendall Van Keuren-Jensen
- Division of Diabetes, Cardiovascular and Metabolic Diseases, Translational Genomics Research Institute, Phoenix, Ariz
| | - Christophe Legendre
- Division of Diabetes, Cardiovascular and Metabolic Diseases, Translational Genomics Research Institute, Phoenix, Ariz
| | - Christopher D Still
- Department of Gastroenterology and Nutrition, Geisinger Obesity Institute, Danville, PA
| | - Glenn S Gerhard
- Department of Biochemistry and Molecular Biology, Temple University School of Medicine, Philadelphia, PA
| | - Johanna K DiStefano
- Division of Diabetes, Cardiovascular and Metabolic Diseases, Translational Genomics Research Institute, Phoenix, Ariz.
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Liu W, Cao H, Yan J, Huang R, Ying H. 'Micro-managers' of hepatic lipid metabolism and NAFLD. WILEY INTERDISCIPLINARY REVIEWS-RNA 2015. [PMID: 26198708 DOI: 10.1002/wrna.1295] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is tightly associated with insulin resistance, type 2 diabetes, and obesity. As the defining feature of NAFLD, hepatic steatosis develops as a consequence of metabolic dysregulation of de novo lipogenesis, fatty acid uptake, fatty acid oxidation, and triglycerides (TG) export. MicroRNAs (miRNAs), a class of endogenous small noncoding RNAs, play critical roles in various biological processes through regulating gene expression at post-transcriptional level. A growing body of evidence suggests that miRNAs not only maintain hepatic TG homeostasis under physiological condition, but also participate in the pathogenesis of NAFLD. In this review, we focus on the current knowledge of the hepatic miRNAs associated with the development of liver steatosis and the regulatory mechanisms involved, which might be helpful to further understand the nature of NAFLD and provide a sound scientific basis for the drug development.
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Affiliation(s)
- Wei Liu
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.,Shanghai Xuhui Central Hospital, Shanghai Clinical Center, Chinese Academy of Sciences, Shanghai, China
| | - Hongchao Cao
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.,Shanghai Xuhui Central Hospital, Shanghai Clinical Center, Chinese Academy of Sciences, Shanghai, China
| | - Jun Yan
- Model Animal Research Center, and MOE Key Laboratory of Model Animals for Disease Study, Nanjing University, Nanjing, China
| | - Ruimin Huang
- SIBS (Institute of Health Sciences)-Changhai Hospital Joint Center for Translational Research, Institutes for Translational Research (CAS-SMMU), Shanghai, China
| | - Hao Ying
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.,Shanghai Xuhui Central Hospital, Shanghai Clinical Center, Chinese Academy of Sciences, Shanghai, China.,Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing, China
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Zhang D, Lu K, Jiang G, Liu W, Dong Z, Tian H, Li X. A global transcriptional analysis of Megalobrama amblycephala revealing the molecular determinants of diet-induced hepatic steatosis. Gene 2015; 570:255-63. [PMID: 26074088 DOI: 10.1016/j.gene.2015.06.025] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2014] [Revised: 03/19/2015] [Accepted: 06/09/2015] [Indexed: 02/07/2023]
Abstract
Blunt snout bream (Megalobrama amblycephala), a prevalent species in China's intensive polyculture systems, is highly susceptible to hepatic steatosis, resulting in considerable losses to the fish farming industry. Due to a lack of genomic resources, the molecular mechanisms of lipid metabolism in M. amblycephala are poorly understood. Here, a hepatic cDNA library was generated from equal amounts of mRNAs isolated from M. amblycephala fed normal-fat and high-fat diets. Sequencing of this library using the Illumina/Solexa platform produced approximately 51.87 million clean reads, which were assembled into 48,439 unigenes with an average length of 596 bp and an N50 value of 800 bp. These unigenes were searched against the nucleotide (NT), non-redundant (NR), Swiss-Prot, Cluster of Orthologous Groups (COG), and Kyoto Encyclopedia of Genes and Genome (KEGG) databases using the BLASTn or BLASTx algorithms (E-value ≤ 10(-5)). A total of 8602 unigenes and 22,155 unigenes were functionally classified into 25 COG categories and 259 KEGG pathways, respectively. Furthermore, 22,072 unigenes were grouped into 62 sub-categories belonging to three main Gene Ontology (GO) terms. Using a digital gene expression analysis and the M. amblycephala transcriptome as a reference, 477 genes (134 up-regulated and 343 down-regulated) were identified as differentially expressed in fish fed a high-fat diet versus a normal-fat diet. KEGG and GO functional enrichment analyses of the differentially expressed unigenes were performed and 12 candidate genes related to lipid metabolism were identified. This study provides a global survey of hepatic transcriptome profiles and identifies candidate genes that may be related to lipid metabolism in M. amblycephala. These findings will facilitate further investigations of the mechanisms underlying hepatic steatosis in M. amblycephala.
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Affiliation(s)
- Dingdong Zhang
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China; Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China
| | - Kangle Lu
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Guangzhen Jiang
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Wenbin Liu
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China.
| | - Zaijie Dong
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China.
| | - Hongyan Tian
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Xiangfei Li
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
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Ross SA, Davis CD. The emerging role of microRNAs and nutrition in modulating health and disease. Annu Rev Nutr 2015; 34:305-36. [PMID: 25033062 DOI: 10.1146/annurev-nutr-071813-105729] [Citation(s) in RCA: 99] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Understanding the molecular mechanisms that inform how diet and dietary supplements influence health and disease is an active research area. One such mechanism concerns the role of diet in modulating the activity and function of microRNAs (miRNAs). miRNAs are small noncoding RNA molecules that are involved in posttranscriptional gene silencing and have been shown to control gene expression in diverse biological processes including development, differentiation, cell proliferation, metabolism, and inflammation as well as in human diseases. Recent evidence described in this review highlights how dietary factors may influence cancer, cardiovascular disease, type 2 diabetes mellitus, obesity, and nonalcoholic fatty liver disease through modulation of miRNA expression. Additionally, circulating miRNAs are emerging as putative biomarkers of disease, susceptibility, and perhaps dietary exposure. Research needs to move beyond associations in cells and animals to understanding the direct effects of diet and dietary supplements on miRNA expression and function in human health and disease.
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Affiliation(s)
- Sharon A Ross
- Nutritional Science Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland 20892;
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Sun C, Fan JG, Qiao L. Potential epigenetic mechanism in non-alcoholic Fatty liver disease. Int J Mol Sci 2015; 16:5161-79. [PMID: 25751727 PMCID: PMC4394469 DOI: 10.3390/ijms16035161] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2014] [Revised: 02/14/2015] [Accepted: 02/25/2015] [Indexed: 12/13/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive fat accumulation in the liver. It ranges from simple steatosis to its more aggressive form, non-alcoholic steatohepatitis (NASH), which may develop into hepatic fibrosis, cirrhosis, or hepatocellular carcinoma (HCC) if it persists for a long time. However, the exact pathogenesis of NAFLD and the related metabolic disorders remain unclear. Epigenetic changes are stable alterations that take place at the transcriptional level without altering the underlying DNA sequence. DNA methylation, histone modifications and microRNA are among the most common forms of epigenetic modification. Epigenetic alterations are involved in the regulation of hepatic lipid metabolism, insulin resistance, mitochondrial damage, oxidative stress response, and the release of inflammatory cytokines, all of which have been implicated in the development and progression of NAFLD. This review summarizes the current advances in the potential epigenetic mechanism of NAFLD. Elucidation of epigenetic factors may facilitate the identification of early diagnositic biomarkers and development of therapeutic strategies for NAFLD.
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Affiliation(s)
- Chao Sun
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China.
| | - Jian-Gao Fan
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China.
| | - Liang Qiao
- Storr Liver Centre, Westmead Millennium Institute for Medical Research, University of Sydney, the Westmead Clinical School, Westmead Hospital, Westmead, NSW 2145, Australia.
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Gerhard GS, DiStefano JK. Micro RNAs in the development of non-alcoholic fatty liver disease. World J Hepatol 2015; 7:226-234. [PMID: 25729477 PMCID: PMC4342604 DOI: 10.4254/wjh.v7.i2.226] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2014] [Revised: 10/16/2014] [Accepted: 11/19/2014] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease or nonalcoholic fatty liver disease (NAFLD) refers to a group of disorders that arise from the accrual of fat in hepatocytes. Although various factors have been associated with the development of NAFLD, including genetic predisposition and environmental exposures, little is known about the underlying pathogenesis of the disease. Research efforts are ongoing to identify biological targets and signaling pathways that mediate NAFLD. Emerging evidence has implicated a role for micro RNAs (miRNAs), short single-stranded molecules that regulate gene expression either transcriptionally, through targeting of promoter regions, or post-transcriptionally, by blocking translation or promoting cleavage of specific target mRNAs. Several miRNAs have been associated with NAFLD, although our understanding of the biology underlying their role is still emerging. The goal of this review is to present an overview of the current state of knowledge of miRNAs involved in the development of NAFLD across a range of in vitro and in vivo models, including miRNAs that contribute to pathological mechanisms related to fatty liver in humans. Much less is known about the specific targets of miRNAs in cells, nor the molecular mechanisms involved in the development and progression NAFLD and related outcomes. More recently, the identification and validation of miRNA signatures in serum may facilitate the development of improved methods for diagnosis and clinical monitoring of disease progression.
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Li Y, He PP, Zhang DW, Zheng XL, Cayabyab FS, Yin WD, Tang CK. Lipoprotein lipase: from gene to atherosclerosis. Atherosclerosis 2014; 237:597-608. [PMID: 25463094 DOI: 10.1016/j.atherosclerosis.2014.10.016] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2014] [Revised: 10/13/2014] [Accepted: 10/13/2014] [Indexed: 01/21/2023]
Abstract
Lipoprotein lipase (LPL) is a key enzyme in lipid metabolism and responsible for catalyzing lipolysis of triglycerides in lipoproteins. LPL is produced mainly in adipose tissue, skeletal and heart muscle, as well as in macrophage and other tissues. After synthesized, it is secreted and translocated to the vascular lumen. LPL expression and activity are regulated by a variety of factors, such as transcription factors, interactive proteins and nutritional state through complicated mechanisms. LPL with different distributions may exert distinct functions and have diverse roles in human health and disease with close association with atherosclerosis. It may pose a pro-atherogenic or an anti-atherogenic effect depending on its locations. In this review, we will discuss its gene, protein, synthesis, transportation and biological functions, and then focus on its regulation and relationship with atherosclerosis and potential underlying mechanisms. The goal of this review is to provide basic information and novel insight for further studies and therapeutic targets.
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Affiliation(s)
- Yuan Li
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Discovery, Life Science Research Center, University of South China, Hengyang, Hunan 421001, China
| | - Ping-Ping He
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Discovery, Life Science Research Center, University of South China, Hengyang, Hunan 421001, China; School of Nursing, University of South China, Hengyang, Hunan 421001, China
| | - Da-Wei Zhang
- Department of Pediatrics and Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta T6G 2S2, Canada
| | - Xi-Long Zheng
- Department of Biochemistry and Molecular Biology, The Libin Cardiovascular Institute of Alberta, The Cumming School of Medicine, The University of Calgary, Health Sciences Center, 3330 Hospital Dr NW, Calgary, Alberta T2N 4N1, Canada
| | - Fracisco S Cayabyab
- Department of Surgery, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Wei-Dong Yin
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Discovery, Life Science Research Center, University of South China, Hengyang, Hunan 421001, China.
| | - Chao-Ke Tang
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Discovery, Life Science Research Center, University of South China, Hengyang, Hunan 421001, China.
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Monson MS, Settlage RE, McMahon KW, Mendoza KM, Rawal S, El-Nezami HS, Coulombe RA, Reed KM. Response of the hepatic transcriptome to aflatoxin B1 in domestic turkey (Meleagris gallopavo). PLoS One 2014; 9:e100930. [PMID: 24979717 PMCID: PMC4076218 DOI: 10.1371/journal.pone.0100930] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2014] [Accepted: 06/02/2014] [Indexed: 12/21/2022] Open
Abstract
Dietary exposure to aflatoxin B1 (AFB1) is detrimental to avian health and leads to major economic losses for the poultry industry. AFB1 is especially hepatotoxic in domestic turkeys (Meleagris gallopavo), since these birds are unable to detoxify AFB1 by glutathione-conjugation. The impacts of AFB1 on the turkey hepatic transcriptome and the potential protection from pretreatment with a Lactobacillus-based probiotic mixture were investigated through RNA-sequencing. Animals were divided into four treatment groups and RNA was subsequently recovered from liver samples. Four pooled RNA-seq libraries were sequenced to produce over 322 M reads totaling 13.8 Gb of sequence. Approximately 170,000 predicted transcripts were de novo assembled, of which 803 had significant differential expression in at least one pair-wise comparison between treatment groups. Functional analysis linked many of the transcripts significantly affected by AFB1 exposure to cancer, apoptosis, the cell cycle or lipid regulation. Most notable were transcripts from the genes encoding E3 ubiquitin-protein ligase Mdm2, osteopontin, S-adenosylmethionine synthase isoform type-2, and lipoprotein lipase. Expression was modulated by the probiotics, but treatment did not completely mitigate the effects of AFB1. Genes identified through transcriptome analysis provide candidates for further study of AFB1 toxicity and targets for efforts to improve the health of domestic turkeys exposed to AFB1.
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Affiliation(s)
- Melissa S. Monson
- Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, Minnesota, United States of America
| | - Robert E. Settlage
- Data Analysis Core, Virginia Bioinformatics Institute, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America
| | - Kevin W. McMahon
- Data Analysis Core, Virginia Bioinformatics Institute, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America
| | - Kristelle M. Mendoza
- Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, Minnesota, United States of America
| | - Sumit Rawal
- Department of Animal, Dairy and Veterinary Sciences, College of Agriculture, Utah State University, Logan, Utah, United States of America
| | - Hani S. El-Nezami
- School of Biological Sciences, University of Hong Kong, Hong Kong, China
| | - Roger A. Coulombe
- Department of Animal, Dairy and Veterinary Sciences, College of Agriculture, Utah State University, Logan, Utah, United States of America
| | - Kent M. Reed
- Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, Minnesota, United States of America
- * E-mail:
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Angiotensin II-regulated microRNA 483-3p directly targets multiple components of the renin-angiotensin system. J Mol Cell Cardiol 2014; 75:25-39. [PMID: 24976017 DOI: 10.1016/j.yjmcc.2014.06.008] [Citation(s) in RCA: 82] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2014] [Revised: 06/16/2014] [Accepted: 06/18/2014] [Indexed: 11/21/2022]
Abstract
Improper regulation of signaling in vascular smooth muscle cells (VSMCs) by angiotensin II (AngII) can lead to hypertension, vascular hypertrophy and atherosclerosis. The extent to which the homeostatic levels of the components of signaling networks are regulated through microRNAs (miRNA) modulated by AngII type 1 receptor (AT1R) in VSMCs is not fully understood. Whether AT1R blockers used to treat vascular disorders modulate expression of miRNAs is also not known. To report differential miRNA expression following AT1R activation by AngII, we performed microarray analysis in 23 biological and technical replicates derived from humans, rats and mice. Profiling data revealed a robust regulation of miRNA expression by AngII through AT1R, but not the AngII type 2 receptor (AT2R). The AT1R-specific blockers, losartan and candesartan antagonized >90% of AT1R-regulated miRNAs and AngII-activated AT2R did not modulate their expression. We discovered VSMC-specific modulation of 22 miRNAs by AngII, and validated AT1R-mediated regulation of 17 of those miRNAs by real-time polymerase chain reaction analysis. We selected miR-483-3p as a novel representative candidate for further study because mRNAs of multiple components of the renin-angiotensin system (RAS) were predicted to contain the target sequence for this miRNA. MiR-483-3p inhibited the expression of luciferase reporters bearing 3'-UTRs of four different RAS genes and the inhibition was reversed by antagomir-483-3p. The AT1R-regulated expression levels of angiotensinogen and angiotensin converting enzyme 1 (ACE-1) proteins in VSMCs are modulated specifically by miR-483-3p. Our study demonstrates that the AT1R-regulated miRNA expression fingerprint is conserved in VSMCs of humans and rodents. Furthermore, we identify the AT1R-regulated miR-483-3p as a potential negative regulator of steady-state levels of RAS components in VSMCs. Thus, miRNA-regulation by AngII to affect cellular signaling is a novel aspect of RAS biology, which may lead to discovery of potential candidate prognostic markers and therapeutic targets.
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Zhang D, Lu K, Dong Z, Jiang G, Xu W, Liu W. The effect of exposure to a high-fat diet on microRNA expression in the liver of blunt snout bream (Megalobrama amblycephala). PLoS One 2014; 9:e96132. [PMID: 24788396 PMCID: PMC4008502 DOI: 10.1371/journal.pone.0096132] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2014] [Accepted: 04/02/2014] [Indexed: 12/15/2022] Open
Abstract
Blunt snout bream (Megalobrama amblycephala) are susceptible to hepatic steatosis when maintained in modern intensive culture systems. The aim of this study was to investigate the potential roles of microRNAs (miRNAs) in diet-induced hepatic steatosis in this species. MiRNAs, small non-coding RNAs that regulate gene expression at the posttranscriptional level, are involved in diverse biological processes, including lipid metabolism. Deep sequencing of hepatic small RNA libraries from blunt snout bream fed normal-fat and high-fat diets identified 202 (193 known and 9 novel) miRNAs, of which 12 were differentially expressed between the normal-fat and high-fat diet groups. Quantitative stem-loop reverse transcriptase-polymerase chain reaction analyses confirmed the upregulation of miR-30c and miR-30e-3p and the downregulation of miR-145 and miR-15a-5p in high-fat diet-fed fish. Bioinformatics tools were used to predict the targets of these verified miRNAs and to explore potential downstream gene ontology biological process categories and Kyoto Encyclopedia of Genes and Genomes pathways. Six putative lipid metabolism-related target genes (fetuin-B, Cyp7a1, NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 2, 3-oxoacid CoA transferase 1b, stearoyl-CoA desaturase, and fatty-acid synthase) were identified as having potential important roles in the development of diet-induced hepatic steatosis in blunt snout bream. The results presented here are a foundation for future studies of miRNA-controlled lipid metabolism regulatory networks in blunt snout bream.
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Affiliation(s)
- Dingdong Zhang
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, China
- Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, China
| | - Kangle Lu
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Zaijie Dong
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, China
- Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, China
- * E-mail: (WL); (ZD)
| | - Guangzhen Jiang
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Weina Xu
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Wenbin Liu
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
- * E-mail: (WL); (ZD)
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Mohamed JS, Hajira A, Pardo PS, Boriek AM. MicroRNA-149 inhibits PARP-2 and promotes mitochondrial biogenesis via SIRT-1/PGC-1α network in skeletal muscle. Diabetes 2014; 63:1546-59. [PMID: 24757201 DOI: 10.2337/db13-1364] [Citation(s) in RCA: 120] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
High-fat diet (HFD) plays a central role in the initiation of mitochondrial dysfunction that significantly contributes to skeletal muscle metabolic disorders in obesity. However, the mechanism by which HFD weakens skeletal muscle metabolism by altering mitochondrial function and biogenesis is unknown. Given the emerging roles of microRNAs (miRNAs) in the regulation of skeletal muscle metabolism, we sought to determine whether activation of a specific miRNA pathway would rescue the HFD-induced mitochondrial dysfunction via the sirtuin-1 (SIRT-1)/ peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) pathway, a pathway that governs genes necessary for mitochondrial function. We here report that miR-149 strongly controls SIRT-1 expression and activity. Interestingly, miR-149 inhibits poly(ADP-ribose) polymerase-2 (PARP-2) and so increased cellular NAD(+) levels and SIRT-1 activity that subsequently increases mitochondrial function and biogenesis via PGC-1α activation. In addition, skeletal muscles from HFD-fed obese mice exhibit low levels of miR-149 and high levels of PARP-2, and they show reduced mitochondrial function and biogenesis due to a decreased activation of the SIRT-1/PGC-1α pathway, suggesting that mitochondrial dysfunction in the skeletal muscle of obese mice may be because of, at least in part, miR-149 dysregulation. Overall, miR-149 may be therapeutically useful for treating HFD-induced skeletal muscle metabolic disorders in such pathophysiological conditions as obesity and type 2 diabetes.
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Affiliation(s)
- Junaith S Mohamed
- Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Baylor College of Medicine, Houston, TX
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Ferreira DMS, Simão AL, Rodrigues CMP, Castro RE. Revisiting the metabolic syndrome and paving the way for microRNAs in non-alcoholic fatty liver disease. FEBS J 2014; 281:2503-24. [PMID: 24702768 DOI: 10.1111/febs.12806] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2013] [Revised: 03/16/2014] [Accepted: 04/03/2014] [Indexed: 12/11/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum of stages from simple steatosis to non-alcoholic steatohepatitis, which can progress to fibrosis, cirrhosis and, ultimately, hepatocellular carcinoma. Despite being one of the most common chronic liver diseases, NAFLD pathogenesis remains largely unknown. In this review, we discuss the key molecular mechanisms involved in NAFLD development and progression, focusing on the emerging role of microRNAs. NAFLD is intrinsically related to obesity and the metabolic syndrome. Changes in lipid metabolism increase free fatty acids in blood, which in turn induces peripheral insulin resistance and increases oxidative and endoplasmic reticulum stress. Although not yet considered in the diagnosis of NAFLD, recent reports also reinforce the crucial role of apoptosis in disease progression via activation of either death receptor or mitochondrial pathways and p53. In addition, the role of gut microbiota and the gut-liver axis has been recently associated with NAFLD. Finally, there is an accumulating and growing body of evidence supporting the role of microRNAs in NAFLD pathogenesis and progression, as well as hinting at their use as biomarkers or therapeutic tools. The ultimate goal is to review different molecular pathways that may underlie NAFLD pathogenesis in the hope of finding targets for new and efficient therapeutic interventions.
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Affiliation(s)
- Duarte M S Ferreira
- Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Lisbon, Portugal
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Novák J, Bienertová-Vašků J, Kára T, Novák M. MicroRNAs involved in the lipid metabolism and their possible implications for atherosclerosis development and treatment. Mediators Inflamm 2014; 2014:275867. [PMID: 24876669 PMCID: PMC4020222 DOI: 10.1155/2014/275867] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Revised: 03/21/2014] [Accepted: 04/03/2014] [Indexed: 02/07/2023] Open
Abstract
Hyperlipidemia is a well-accepted risk factor in the development of atherosclerosis. MicroRNAs (miRNAs), a novel class of posttranscriptional regulators of gene expression, are involved in a variety of biological and pathological processes, including the regulation of the lipid metabolism and atherosclerosis. As our knowledge of miRNAs expands, a new class of "circulating miRNAs" has recently been described. It includes miRNAs which may be found in various bodily fluids packaged in microvesicles/exosomes, or bound to specific transporting proteins. High-density lipoprotein (HDL) particles have been identified as one such carrier. As this class of miRNAs likely plays a role in intercellular communication, it may also contribute to the atherosclerosis development and progression. This review aims to provide a comprehensive explanation of the roles of distinct miRNAs involved in the regulation of the lipid metabolism. These microRNAs seem to be promising therapeutic agents, as documented in rodents and African green monkeys. The second part of the review focuses on circulating miRNAs and their involvement in the atherosclerosis, especially as their levels have been described as altered in patients with dyslipidemia/hyperlipidemia. Special emphasis is placed on miRNAs transported in a complex with HDL particles and on those which may be considered potential atherosclerosis biomarkers.
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Affiliation(s)
- Jan Novák
- International Clinical Research Center, Department of Cardiovascular Diseases, St. Anne's University Hospital Brno, Pekarska 53, 656 91, Brno, Czech Republic
- Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, Building A20, 625 00 Brno, Czech Republic
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, Building A18, 625 00 Brno, Czech Republic
| | - Julie Bienertová-Vašků
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, Building A18, 625 00 Brno, Czech Republic
| | - Tomáš Kára
- International Clinical Research Center, Department of Cardiovascular Diseases, St. Anne's University Hospital Brno, Pekarska 53, 656 91, Brno, Czech Republic
| | - Miroslav Novák
- International Clinical Research Center, Department of Cardiovascular Diseases, St. Anne's University Hospital Brno, Pekarska 53, 656 91, Brno, Czech Republic
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Finch ML, Marquardt JU, Yeoh GC, Callus BA. Regulation of microRNAs and their role in liver development, regeneration and disease. Int J Biochem Cell Biol 2014; 54:288-303. [PMID: 24731940 DOI: 10.1016/j.biocel.2014.04.002] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2013] [Revised: 03/25/2014] [Accepted: 04/03/2014] [Indexed: 12/12/2022]
Abstract
Since their discovery more than a decade ago microRNAs have been demonstrated to have profound effects on almost every aspect of biology. Numerous studies in recent years have shown that microRNAs have important roles in development and in the etiology and progression of disease. This review is focused on microRNAs and the roles they play in liver development, regeneration and liver disease; particularly chronic liver diseases such as alcoholic liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, viral hepatitis and primary liver cancer. The key microRNAs identified in liver development and chronic liver disease will be discussed together with, where possible, the target messenger RNAs that these microRNAs regulate to profoundly alter these processes. This article is part of a Directed Issue entitled: The Non-coding RNA Revolution.
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Affiliation(s)
- Megan L Finch
- School of Chemistry and Biochemistry, University of Western Australia, Crawley 6009, WA, Australia.
| | - Jens U Marquardt
- Department of Medicine I, Johannes Gutenberg University, Mainz, Germany.
| | - George C Yeoh
- School of Chemistry and Biochemistry, University of Western Australia, Crawley 6009, WA, Australia; Harry Perkins Institute of Medical Research, Nedlands 6000, WA, Australia.
| | - Bernard A Callus
- School of Chemistry and Biochemistry, University of Western Australia, Crawley 6009, WA, Australia.
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Nezami BG, Mwangi SM, Lee JE, Jeppsson S, Anitha M, Yarandi SS, Farris AB, Srinivasan S. MicroRNA 375 mediates palmitate-induced enteric neuronal damage and high-fat diet-induced delayed intestinal transit in mice. Gastroenterology 2014; 146:473-83.e3. [PMID: 24507550 PMCID: PMC3920196 DOI: 10.1053/j.gastro.2013.10.053] [Citation(s) in RCA: 81] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2013] [Revised: 10/02/2013] [Accepted: 10/22/2013] [Indexed: 01/01/2023]
Abstract
BACKGROUND & AIMS A high-fat diet (HFD) can cause serious health problems, including alteration of gastrointestinal transit, the exact mechanism of which is not clear. Several microRNAs (miRNAs) are involved in energy homeostasis, lipid metabolism, and HFD-induced weight gain. We investigated the role of miRNAs in HFD-induced damage to the enteric nervous system. METHODS Male mice were fed a HFD (60% calories from fat) or regular diets (18% calories from fat) for 11 weeks. Mice on regular diets and HFDs were given intraperitoneal injections of Mir375 inhibitor or a negative control. Body weights, food intake, stool indices, and gastrointestinal transit (following Evans blue gavage) were measured. An enteric neuronal cell line (immorto-fetal enteric neuronal) and primary enteric neurons were used for in vitro studies. RESULTS HFD delayed intestinal transit, which was associated with increased apoptosis and loss of colonic myenteric neurons. Mice fed a low-palmitate HFD did not develop a similar phenotype. Palmitate caused apoptosis of enteric neuronal cells associated with mitochondrial dysfunction and endoplasmic reticulum stress. Palmitate significantly increased the expression of Mir375 in vitro; transfection of cells with a Mir375 inhibitor prevented the palmitate-induced enteric neuronal cell apoptosis. Mir375 expression was increased in myenteric ganglia of mice fed HFD and associated with decreased levels of Mir375 target messenger RNAs, including Pdk1. Systemic injection of a Mir375 inhibitor for 5 weeks prevented HFD-induced delay in intestinal transit and morphologic changes. CONCLUSIONS HFDs delay colonic transit, partly by inducing apoptosis in enteric neuronal cells. This effect is mediated by Mir375 and is associated with reduced levels of Pdk1. Mir375 might be targeted to increase survival of enteric neurons and gastrointestinal motility.
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Affiliation(s)
- Behtash Ghazi Nezami
- Department of Digestive Diseases, Emory University School of Medicine, Atlanta & Atlanta VA Medical Center, Decatur, GA, USA
| | - Simon M. Mwangi
- Department of Digestive Diseases, Emory University School of Medicine, Atlanta & Atlanta VA Medical Center, Decatur, GA, USA
| | - Jai Eun Lee
- Department of Digestive Diseases, Emory University School of Medicine, Atlanta & Atlanta VA Medical Center, Decatur, GA, USA
| | - Sabrina Jeppsson
- Department of Digestive Diseases, Emory University School of Medicine, Atlanta & Atlanta VA Medical Center, Decatur, GA, USA
| | - Mallappa Anitha
- Department of Digestive Diseases, Emory University School of Medicine, Atlanta & Atlanta VA Medical Center, Decatur, GA, USA
| | - Shadi S. Yarandi
- Department of Digestive Diseases, Emory University School of Medicine, Atlanta & Atlanta VA Medical Center, Decatur, GA, USA
| | - Alton B Farris
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA
| | - Shanthi Srinivasan
- Department of Digestive Diseases, Emory University School of Medicine, Atlanta, Georgia; Atlanta VA Medical Center, Decatur, Georgia.
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Bouvy-Liivrand M, Heinäniemi M, John E, Schneider JG, Sauter T, Sinkkonen L. Combinatorial regulation of lipoprotein lipase by microRNAs during mouse adipogenesis. RNA Biol 2014; 11:76-91. [PMID: 24457907 PMCID: PMC3929427 DOI: 10.4161/rna.27655] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2013] [Revised: 12/20/2013] [Accepted: 12/23/2013] [Indexed: 11/19/2022] Open
Abstract
MicroRNAs (miRNAs) regulate gene expression directly through base pairing to their targets or indirectly through participating in multi-scale regulatory networks. Often miRNAs take part in feed-forward motifs where a miRNA and a transcription factor act on shared targets to achieve accurate regulation of processes such as cell differentiation. Here we show that the expression levels of miR-27a and miR-29a inversely correlate with the mRNA levels of lipoprotein lipase (Lpl), their predicted combinatorial target, and its key transcriptional regulator peroxisome proliferator-activated receptor gamma (Pparg) during 3T3-L1 adipocyte differentiation. More importantly, we show that Lpl, a key lipogenic enzyme, can be negatively regulated by the two miRNA families in a combinatorial fashion on the mRNA and functional level in maturing adipocytes. This regulation is mediated through the Lpl 3'UTR as confirmed by reporter gene assays. In addition, a small mathematical model captures the dynamics of this feed-forward motif and predicts the changes in Lpl mRNA levels upon network perturbations. The obtained results might offer an explanation to the dysregulation of LPL in diabetic conditions and could be extended to quantitative modeling of regulation of other metabolic genes under similar regulatory network motifs.
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Affiliation(s)
- Maria Bouvy-Liivrand
- Life Sciences Research Unit; University of Luxembourg; Luxembourg, Luxembourg
- Luxembourg Centre for Systems Biomedicine; University of Luxembourg; Esch-Sur-Alzette, Luxembourg
| | - Merja Heinäniemi
- Life Sciences Research Unit; University of Luxembourg; Luxembourg, Luxembourg
- Institute of Biomedicine; School of Medicine; University of Eastern Finland; Kuopio, Finland
| | - Elisabeth John
- Life Sciences Research Unit; University of Luxembourg; Luxembourg, Luxembourg
| | - Jochen G Schneider
- Luxembourg Centre for Systems Biomedicine; University of Luxembourg; Esch-Sur-Alzette, Luxembourg
- Saarland University Medical Center; Department of Medicine II; Homburg, Saar, Germany
| | - Thomas Sauter
- Life Sciences Research Unit; University of Luxembourg; Luxembourg, Luxembourg
| | - Lasse Sinkkonen
- Life Sciences Research Unit; University of Luxembourg; Luxembourg, Luxembourg
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Fatima A, Waters S, O’Boyle P, Seoighe C, Morris DG. Alterations in hepatic miRNA expression during negative energy balance in postpartum dairy cattle. BMC Genomics 2014; 15:28. [PMID: 24428929 PMCID: PMC3902422 DOI: 10.1186/1471-2164-15-28] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2013] [Accepted: 01/14/2014] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Negative energy balance (NEB), an altered metabolic state, occurs in early postpartum dairy cattle when energy demands to support lactation exceed energy intake. During NEB the liver undergoes oxidative stress and increased breakdown of fatty acids accompanied by changes in gene expression. It is now known that micro RNAs (miRNA) can have a role in mediating such alterations in gene expression through repression or degradation of target mRNAs. miRNA expression is known to be altered by metabolism and environmental factors and miRNAs are implicated in expression modulation of metabolism related genes. RESULTS miRNA expression was profiled in the liver of moderate yielding dairy cattle under severe NEB (SNEB) and mild NEB (MNEB) using the Affymetrix Gene Chip miRNA_2.0 array with 679 probe sets for Bos-taurus miRNAs. Ten miRNAs were found to be differentially expressed using the 'samr' statistical package (delta = 0.6) at a q-value FDR of < 12%. Five miRNAs including miR-17-5p, miR-31, miR-140, miR-1281 and miR-2885 were validated using RT-qPCR, to be up-regulated under SNEB. Liver diseases associated with these miRNAs include non-alcoholic fatty liver (NAFLD) and hepatocellular carcinoma (HCC). miR-140 and miR-17-5p are known to show differential expression under oxidative stress. A total of 32 down-regulated putative target genes were also identified among 418 differentially expressed hepatic genes previously reported for the same animal model. Among these, GPR37 (G protein-coupled receptor 37), HEYL (hairy/enhancer-of-split related with YRPW motif-like), DNJA1, CD14 (Cluster of differentiation 14) and GNS (glucosamine (N-acetyl)-6-sulfatase) are known to be associated with hepatic metabolic disorders. In addition miR-140 and miR-2885 have binding sites on the most down-regulated of these genes, FADS2 (Fatty acid desaturase 2) which encodes an enzyme critical in lipid biosynthesis. Furthermore, HNF3-gamma (Hepatocyte nuclear factor 3-gamma), a hepatic transcription factor (TF) that is involved in IGF-1 expression regulation and maintenance of glucose homeostasis is a putative target of miR-31. CONCLUSIONS This study shows that SNEB affects liver miRNA expression and these miRNAs have putative targets in hepatic genes down-regulated under this condition. This study highlights the potential role of miRNAs in transcription regulation of hepatic gene expression during SNEB in dairy cattle.
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Affiliation(s)
- Attia Fatima
- School of Mathematics, Statistics and Applied Mathematics National University of Ireland Galway, Galway, Ireland
- Animal and Bioscience Research Department, Animal & Grassland Research and Innovation Centre, Teagasc, Mellows Campus, Athenry, Co., Galway, Ireland
| | - Sinead Waters
- Animal and Bioscience Research Department, Animal & Grassland Research and Innovation Centre, Teagasc, Mellows Campus, Athenry, Co., Galway, Ireland
| | - Padraig O’Boyle
- Animal and Bioscience Research Department, Animal & Grassland Research and Innovation Centre, Teagasc, Mellows Campus, Athenry, Co., Galway, Ireland
| | - Cathal Seoighe
- School of Mathematics, Statistics and Applied Mathematics National University of Ireland Galway, Galway, Ireland
| | - Dermot G Morris
- Animal and Bioscience Research Department, Animal & Grassland Research and Innovation Centre, Teagasc, Mellows Campus, Athenry, Co., Galway, Ireland
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Evans D, Beil FU, Aberle J. Resequencing the untranslated regions of the lipoprotein lipase (LPL) gene reveals that variants in microRNA target sequences are associated with triglyceride levels. J Clin Lipidol 2013; 7:610-4. [PMID: 24314358 DOI: 10.1016/j.jacl.2013.09.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2013] [Revised: 08/01/2013] [Accepted: 09/25/2013] [Indexed: 11/25/2022]
Abstract
BACKGROUND Rare variants in the protein coding regions of the lipoprotein lipase (LPL) gene have been shown to be important in the development of hypertriglyceridemia. OBJECTIVES The aim of this study was to determine whether rare variants in the 3' and 5' untranslated regions (UTRs) of the LPL gene are also associated with severe hypertriglyceridemia. METHODS The DNA sequences of the 3' and 5' UTRs of the LPL gene of 63 patients with triglycerides > 875 mg/dL (10 mmol) and 69 probands with triglycerides below the 25th percentile for age and sex were determined. The sequence at the 5' end was extended to include 2 further elements (-702 to -666 and -468 to -430) shown to be associated with the control of LPL expression. RESULTS No statistically significant difference was found in the occurrence of rare mutations in either the 3' or the 5' UTRs between the 2 groups. Sequence analysis allowed the genotyping of 47 single nucleotide polymorphisms (SNPs) in the 3' UTR and 11 in the 5' UTR. Two groups of SNPs in the 3' UTR, based on allelic association, were statistically significantly associated with plasma triglycerides. Each of these groups contained SNPs in the target sequences for microRNAs. These findings were replicated in independently formed groups. CONCLUSION We provide genetic evidence that microRNAs may play a role in the expression of LPL and thus plasma triglyceride levels.
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Affiliation(s)
- David Evans
- Endokrinologie und Stoffwechsel, Medizinische Klinik III, Zentrum für Innere Medizin, Universitätsklinikum Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
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50
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Tian GP, Tang YY, He PP, Lv YC, Ouyang XP, Zhao GJ, Tang SL, Wu JF, Wang JL, Peng J, Zhang M, Li Y, Cayabyab FS, Zheng XL, Zhang DW, Yin WD, Tang CK. The effects of miR-467b on lipoprotein lipase (LPL) expression, pro-inflammatory cytokine, lipid levels and atherosclerotic lesions in apolipoprotein E knockout mice. Biochem Biophys Res Commun 2013; 443:428-34. [PMID: 24309104 DOI: 10.1016/j.bbrc.2013.11.109] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2013] [Accepted: 11/25/2013] [Indexed: 11/19/2022]
Abstract
Atherosclerosis is a lipid disorder disease characterized by chronic blood vessel wall inflammation driven by the subendothelial accumulation of macrophages. Studies have shown that lipoprotein lipase (LPL) participates in lipid metabolism, but it is not yet known whether post-transcriptional regulation of LPL gene expression by microRNAs (miRNAs) occurs in vivo. Here, we tested that miR-467b provides protection against atherosclerosis by regulating the target gene LPL which leads to reductions in LPL expression, lipid accumulation, progression of atherosclerosis and production of inflammatory cytokines in apolipoprotein E knockout (apoE(-/-)) mice. Treatment of apoE(-/-) mice with intra-peritoneal injection of miR-467b agomir led to decreased blood plasma levels of total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), IL-1β and monocyte chemotactic protein-1 (MCP-1). Using Western blots and real time PCR, we determined that LPL expression in aorta and abdominal cavity macrophages were significantly down-regulated in the miR-467b agomir group. Furthermore, systemic treatment with miR-467b antagomir accelerated the progression of atherosclerosis in the aorta of apoE(-/-) mice. The present study showed that miR-467b protects apoE(-/-) mice from atherosclerosis by reducing lipid accumulation and inflammatory cytokine secretion via downregulation of LPL expression. Therefore, targeting miR-467b may offer a promising strategy to treat atherosclerotic vascular disease.
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Affiliation(s)
- Guo-Ping Tian
- Department of Cardiovascular Medicine, Second Affiliated Hospital of University of South China, Hengyang 421001, Hunan, China
| | - Yan-Yan Tang
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang 421001, Hunan, China
| | - Ping-Ping He
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang 421001, Hunan, China; School of Nursing, University of South China, Hengyang 421001, Hunan, China
| | - Yun-Cheng Lv
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang 421001, Hunan, China
| | - Xin-Pin Ouyang
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang 421001, Hunan, China
| | - Guo-Jun Zhao
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang 421001, Hunan, China
| | - Shi-Lin Tang
- Department of Physiology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Jian-Feng Wu
- Department of Cardiovascular Medicine, Second Affiliated Hospital of University of South China, Hengyang 421001, Hunan, China; Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang 421001, Hunan, China
| | - Jia-Lin Wang
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang 421001, Hunan, China
| | - Juan Peng
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang 421001, Hunan, China
| | - Min Zhang
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang 421001, Hunan, China
| | - Yuan Li
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang 421001, Hunan, China
| | - Francisco S Cayabyab
- Department of Physiology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Xi-Long Zheng
- Department of Biochemistry and Molecular Biology, The Libin Cardiovascular Institute of Alberta, The University of Calgary, Health Sciences Center, 3330 Hospital Dr NW, Calgary, Alberta T2N 4N1, Canada
| | - Da-Wei Zhang
- Department of Pediatrics and Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta T6G 2S2, Canada
| | - Wei-Dong Yin
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang 421001, Hunan, China.
| | - Chao-Ke Tang
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang 421001, Hunan, China.
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