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1
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Soma H, Yoshida R, Ishizuka S. Quantitative analysis of sterol balance in a mouse model of hepatic lipid accumulation induced by cholesterol and cholic acid supplementation. Biosci Biotechnol Biochem 2025; 89:438-445. [PMID: 39656874 DOI: 10.1093/bbb/zbae183] [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: 09/25/2024] [Accepted: 11/27/2024] [Indexed: 12/17/2024]
Abstract
The cholesterol balance and bile acid metabolism in a mouse model of hepatic lipid accumulation induced by a diet supplemented with cholesterol and cholic acid (CA) were quantitatively evaluated. The mice were fed diets supplemented with different levels of cholesterol (0, 3, or 6 g/kg of diet) and CA (0.5 g/kg of diet) for 6 weeks. Cholesterol supplementation doubled the hepatic triglyceride concentration, regardless of the supplementation level, without inflammation or gallstone formation. Both cholesterol supplementations enhanced fecal excretion of muricholic acid. Additionally, the higher cholesterol supplementation led to an increase in fecal cholesterol excretion, accompanied by elevated expression of hepatic cholesterol exporters and a reduction in fecal bile acid excretion. In this mouse study, supplementation with 3 g cholesterol/kg diet and 0.5 g CA/kg diet was sufficient to induce hepatic lipid accumulation.
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Affiliation(s)
- Hinata Soma
- Research Faculty of Agriculture, Hokkaido University, Sapporo, Japan
| | - Ryo Yoshida
- Research Faculty of Agriculture, Hokkaido University, Sapporo, Japan
| | - Satoshi Ishizuka
- Research Faculty of Agriculture, Hokkaido University, Sapporo, Japan
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2
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Antony F, Brough Z, Orangi M, Al-Seragi M, Aoki H, Babu M, Duong van Hoa F. Sensitive Profiling of Mouse Liver Membrane Proteome Dysregulation Following a High-Fat and Alcohol Diet Treatment. Proteomics 2024; 24:e202300599. [PMID: 39313981 DOI: 10.1002/pmic.202300599] [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: 03/29/2024] [Revised: 09/03/2024] [Accepted: 09/06/2024] [Indexed: 09/25/2024]
Abstract
Alcohol consumption and high-fat (HF) diets often coincide in Western society, resulting in synergistic negative effects on liver function. Although studies have analyzed the global protein expression in the context of alcoholic liver disease (ALD) and metabolic dysfunction-associated steatotic liver disease (MASLD), none has offered specific insights on liver dysregulation at the membrane proteome level. Membrane-specific profiling of metabolic and compensatory phenomena is usually overshadowed in conventional proteomic workflows. In this study, we use the Peptidisc method to isolate and compare the membrane protein (MP) content of the liver with its unique biological functions. From mice fed with an HF diet and ethanol in drinking water, we annotate over 1500 liver proteins with half predicted to have at least one transmembrane segment. Among them, we identify 106 integral MPs that are dysregulated compared to the untreated sample. Gene Ontology analysis reveals several dysregulated membrane-associated processes like lipid metabolism, cell adhesion, xenobiotic processing, and mitochondrial membrane formation. Pathways related to cholesterol and bile acid transport are also mutually affected, suggesting an adaptive mechanism to counter the upcoming steatosis of the liver model. Taken together, our Peptidisc-based profiling of the diet-dysregulated liver provides specific insights and hypotheses into the role of the transmembrane proteome in disease development, and flags desirable MPs for therapeutic and diagnostic targeting.
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Affiliation(s)
- Frank Antony
- Department of Biochemistry and Molecular Biology, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada
| | - Zora Brough
- Department of Biochemistry and Molecular Biology, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada
| | - Mona Orangi
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Mohammed Al-Seragi
- Department of Biochemistry and Molecular Biology, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada
| | - Hiroyuki Aoki
- Department of Biochemistry, University of Regina, Regina, Saskatchewan, Canada
| | - Mohan Babu
- Department of Biochemistry, University of Regina, Regina, Saskatchewan, Canada
| | - Franck Duong van Hoa
- Department of Biochemistry and Molecular Biology, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada
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3
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Deng B, Liu Y, Chen Y, He P, Ma J, Tan Z, Zhang J, Dong W. Exploring the butyrate metabolism-related shared genes in metabolic associated steatohepatitis and ulcerative colitis. Sci Rep 2024; 14:15949. [PMID: 38987612 PMCID: PMC11237055 DOI: 10.1038/s41598-024-66574-0] [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: 03/20/2024] [Accepted: 07/02/2024] [Indexed: 07/12/2024] Open
Abstract
Metabolic-associated steatohepatitis (MASH) and ulcerative colitis (UC) exhibit a complex interconnection with immune dysfunction, dysbiosis of the gut microbiota, and activation of inflammatory pathways. This study aims to identify and validate critical butyrate metabolism-related shared genes between both UC and MASH. Clinical information and gene expression profiles were sourced from the Gene Expression Omnibus (GEO) database. Shared butyrate metabolism-related differentially expressed genes (sBM-DEGs) between UC and MASH were identified via various bioinformatics methods. Functional enrichment analysis was performed, and UC patients were categorized into subtypes using the consensus clustering algorithm based on sBM-DEGs. Key genes within sBM-DEGs were screened through Random Forest, Support Vector Machines-Recursive Feature Elimination, and Light Gradient Boosting. The diagnostic efficacy of these genes was evaluated using receiver operating characteristic (ROC) analysis on independent datasets. Additionally, the expression levels of characteristic genes were validated across multiple independent datasets and human specimens. Forty-nine shared DEGs between UC and MASH were identified, with enrichment analysis highlighting significant involvement in immune, inflammatory, and metabolic pathways. The intersection of butyrate metabolism-related genes with these DEGs produced 10 sBM-DEGs. These genes facilitated the identification of molecular subtypes of UC patients using an unsupervised clustering approach. ANXA5, CD44, and SLC16A1 were pinpointed as hub genes through machine learning algorithms and feature importance rankings. ROC analysis confirmed their diagnostic efficacy in UC and MASH across various datasets. Additionally, the expression levels of these three hub genes showed significant correlations with immune cells. These findings were validated across independent datasets and human specimens, corroborating the bioinformatics analysis results. Integrated bioinformatics identified three significant biomarkers, ANXA5, CD44, and SLC16A1, as DEGs linked to butyrate metabolism. These findings offer new insights into the role of butyrate metabolism in the pathogenesis of UC and MASH, suggesting its potential as a valuable diagnostic biomarker.
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Affiliation(s)
- Beiying Deng
- Department of Gastroenterology, Renmin Hospital of Wuhan University, No 99 Zhangzhidong Road, Wuhan, 430060, Hubei Province, China
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yinghui Liu
- Department of Geriatric, Renmin Hospital of Wuhan University, Wuhan, China
| | - Ying Chen
- Department of Gastroenterology, Renmin Hospital of Wuhan University, No 99 Zhangzhidong Road, Wuhan, 430060, Hubei Province, China
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Pengzhan He
- Department of Gastroenterology, Renmin Hospital of Wuhan University, No 99 Zhangzhidong Road, Wuhan, 430060, Hubei Province, China
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Jingjing Ma
- Department of Geriatric, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zongbiao Tan
- Department of Gastroenterology, Renmin Hospital of Wuhan University, No 99 Zhangzhidong Road, Wuhan, 430060, Hubei Province, China
| | - Jixiang Zhang
- Department of Gastroenterology, Renmin Hospital of Wuhan University, No 99 Zhangzhidong Road, Wuhan, 430060, Hubei Province, China
| | - Weiguo Dong
- Department of Gastroenterology, Renmin Hospital of Wuhan University, No 99 Zhangzhidong Road, Wuhan, 430060, Hubei Province, China.
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4
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Han J, Lee C, Jung Y. Current Evidence and Perspectives of Cluster of Differentiation 44 in the Liver's Physiology and Pathology. Int J Mol Sci 2024; 25:4749. [PMID: 38731968 PMCID: PMC11084344 DOI: 10.3390/ijms25094749] [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: 03/24/2024] [Revised: 04/21/2024] [Accepted: 04/24/2024] [Indexed: 05/13/2024] Open
Abstract
Cluster of differentiation 44 (CD44), a multi-functional cell surface receptor, has several variants and is ubiquitously expressed in various cells and tissues. CD44 is well known for its function in cell adhesion and is also involved in diverse cellular responses, such as proliferation, migration, differentiation, and activation. To date, CD44 has been extensively studied in the field of cancer biology and has been proposed as a marker for cancer stem cells. Recently, growing evidence suggests that CD44 is also relevant in non-cancer diseases. In liver disease, it has been shown that CD44 expression is significantly elevated and associated with pathogenesis by impacting cellular responses, such as metabolism, proliferation, differentiation, and activation, in different cells. However, the mechanisms underlying CD44's function in liver diseases other than liver cancer are still poorly understood. Hence, to help to expand our knowledge of the role of CD44 in liver disease and highlight the need for further research, this review provides evidence of CD44's effects on liver physiology and its involvement in the pathogenesis of liver disease, excluding cancer. In addition, we discuss the potential role of CD44 as a key regulator of cell physiology.
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Affiliation(s)
- Jinsol Han
- Department of Integrated Biological Science, College of Natural Science, Pusan National University, Pusan 46241, Republic of Korea;
| | - Chanbin Lee
- Institute of Systems Biology, College of Natural Science, Pusan National University, Pusan 46241, Republic of Korea;
| | - Youngmi Jung
- Department of Integrated Biological Science, College of Natural Science, Pusan National University, Pusan 46241, Republic of Korea;
- Department of Biological Sciences, College of Natural Science, Pusan National University, Pusan 46241, Republic of Korea
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Zhong X, Lv M, Ma M, Huang Q, Hu R, Li J, Yi J, Sun J, Zhou X. State of CD8 + T cells in progression from nonalcoholic steatohepatitis to hepatocellular carcinoma: From pathogenesis to immunotherapy. Biomed Pharmacother 2023; 165:115131. [PMID: 37429231 DOI: 10.1016/j.biopha.2023.115131] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Revised: 06/26/2023] [Accepted: 07/02/2023] [Indexed: 07/12/2023] Open
Abstract
With the obesity epidemic, nonalcoholic steatohepatitis (NASH) is emerging as the fastest growing potential cause of hepatocellular carcinoma (HCC). NASH has been demonstrated to establish a tumor-prone liver microenvironment where both innate and adaptive immune systems are involved. As the most typical anti-tumor effector, the cell function of CD8+ T cells is remodeled by chronic inflammation, metabolic alteration, lipid toxicity and oxidative stress in the liver microenvironment along the NASH to HCC transition. Unexpectedly, NASH may blunt the effect of immune checkpoint inhibitor therapy against HCC due to the dysregulated CD8+ T cells. Growing evidence has supported that NASH is likely to facilitate the state transition of CD8+ T cells with changes in cell motility, effector function, metabolic reprogramming and gene transcription according to single-cell sequencing. However, the mechanistic insight of CD8+ T cell states in the NASH-driven HCC is not comprehensive. Herein, we focus on the characterization of state phenotypes of CD8+ T cells with both functional and metabolic signatures in NASH-driven fibrosis and HCC. The NASH-specific CD8+ T cells are speculated to mainly have a dualist effect, where its aberrant activated phenotype sustains chronic inflammation in NASH but subsequently triggers its exhaustion in HCC. As the exploration of CD8+ T cells on the distribution and phenotypic shifts will provide a new direction for the intervention strategies against HCC, we also discuss the implications for targeting different phenotypes of CD8+ T cells, shedding light on the personalized immunotherapy for NASH-driven HCC.
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Affiliation(s)
- Xin Zhong
- Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong, China; Department of Liver Disease, the fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China
| | - Minling Lv
- Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong, China; Department of Liver Disease, the fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China
| | - MengQing Ma
- Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong, China; Department of Liver Disease, the fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China
| | - Qi Huang
- Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong, China; Department of Liver Disease, the fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China
| | - Rui Hu
- Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong, China; Department of Liver Disease, the fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China
| | - Jing Li
- Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong, China; Department of Liver Disease, the fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China
| | - Jinyu Yi
- Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong, China; Department of Liver Disease, the fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China
| | - Jialing Sun
- Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong, China; Department of Liver Disease, the fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China
| | - Xiaozhou Zhou
- Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong, China; Department of Liver Disease, the fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China.
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6
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Yao M, Zhou P, Qin YY, Wang L, Yao DF. Mitochondrial carnitine palmitoyltransferase-II dysfunction: A possible novel mechanism for nonalcoholic fatty liver disease in hepatocarcinogenesis. World J Gastroenterol 2023; 29:1765-1778. [PMID: 37032731 PMCID: PMC10080702 DOI: 10.3748/wjg.v29.i12.1765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 08/04/2022] [Accepted: 03/13/2023] [Indexed: 03/28/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) or metabolic-associated fatty liver disease has been characterized by the lipid accumulation with injury of hepatocytes and has become one of the most common chronic liver diseases in the world. The complex mechanisms of NAFLD formation are still under identification. Carnitine palmitoyltransferase-II (CPT-II) on inner mitochondrial membrane (IMM) regulates long chain fatty acid β-oxidation, and its abnormality has had more and more attention paid to it by basic and clinical research in NAFLD. The sequences of its peptide chain and DNA nucleotides have been identified, and the catalytic activity of CPT-II is affected on its gene mutations, deficiency, enzymatic thermal instability, circulating carnitine level and so on. Recently, the CPT-II dysfunction has been discovered in models of liver lipid accumulation. Meanwhile, the malignant transformation of hepatocyte-related CD44+ stem T cell activation, high levels of tumor-related biomarkers (AFP, GPC3) and abnormal activation of Wnt3a expression as a key signal molecule of the Wnt/β-catenin pathway run parallel to the alterations of hepatocyte pathology. This review focuses on some of the progress of CPT-II inactivity on IMM with liver fatty accumulation as a possible novel pathogenesis for NAFLD in hepatocarcinogenesis.
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Affiliation(s)
- Min Yao
- Department of Medical Immunology, Medical School of Nantong University & Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Ping Zhou
- Department of Medical Immunology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Yan-Yan Qin
- Department of Medical Immunology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Li Wang
- Research Center for Intelligent Information Technology, Nantong University, Nantong 226019, Jiangsu Province, China
| | - Deng-Fu Yao
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
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Wikan N, Tocharus J, Oka C, Sivasinprasasn S, Chaichompoo W, Suksamrarn A, Tocharus C. The capsaicinoid nonivamide suppresses the inflammatory response and attenuates the progression of steatosis in a NAFLD-rat model. J Biochem Mol Toxicol 2023; 37:e23279. [PMID: 36541345 DOI: 10.1002/jbt.23279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 04/28/2022] [Accepted: 12/08/2022] [Indexed: 12/24/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is relatively associated with comorbidities in obesity and metabolic inflammation. Low-grade inflammation following the high-fat diet (HFD)-induced NAFLD can promote the development of nonalcoholic steatohepatitis (NASH) through particularly liver-resident immune cell recruitment and hepatic nuclear factor kappa B (NF-κB) pathway. Therefore, inflammatory intervention may contribute to NASH reduction. Pelargonic acid vanillylamide (PAVA) or nonivamide is one of the pungent capsaicinoids of Capsicum species and has been found in chili peppers. Our previous study demonstrated that PAVA improved hepatic function, decreased oxidative stress and reduced apoptotic cell death but the insight role of PAVA on NAFLD is still unclear. Thus, this study aimed to investigate the underlying anti-inflammatory mechanism of PAVA in an NAFLD-rat model. Male Sprague Dawley rats were fed with normal diet or HFD for 16 weeks. Then high-fat rats were given vehicle or PAVA (1 mg/kg/day) for another 4 weeks. We found that PAVA alleviated hepatic inflammation associated with the reducing toll-like receptor 4/NF-κB pathway, showing significantly lower recruitment of cluster of differentiation 44. PAVA also maintained activity of insulin signaling pathway, and attenuated NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome formation. NAFLD progresses to NASH through transforming growth factor (TGF-β1), and also recovery to simple stage followed by PAVA suppresses pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin-1β, interleukin-6, and Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway. Therefore, our findings suggest that PAVA provides a novel therapeutic approach for NAFLD and slows the progression to NASH.
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Affiliation(s)
- Naruemon Wikan
- Department of Anatomy, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Jiraporn Tocharus
- Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Chio Oka
- Functional Genomics and Medicine, Division of Biological Science, Nara Institute of Science and Technology, Ikoma, Nara, Japan
| | | | - Waraluck Chaichompoo
- Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ramkhamhaeng University, Bangkok, Thailand
| | - Apichart Suksamrarn
- Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ramkhamhaeng University, Bangkok, Thailand
| | - Chainarong Tocharus
- Department of Anatomy, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,Center for Research and Development of Natural Products for Health, Chiang Mai University, Chiang Mai, Thailand
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Liu J, Ding M, Bai J, Luo R, Liu R, Qu J, Li X. Decoding the role of immune T cells: A new territory for improvement of metabolic-associated fatty liver disease. IMETA 2023; 2:e76. [PMID: 38868343 PMCID: PMC10989916 DOI: 10.1002/imt2.76] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 12/13/2022] [Accepted: 12/16/2022] [Indexed: 06/14/2024]
Abstract
Metabolic-associated fatty liver disease (MAFLD) is a new emerging concept and is associated with metabolic dysfunction, generally replacing the name of nonalcoholic fatty liver disease (NAFLD) due to heterogeneous liver condition and inaccuracies in definition. The prevalence of MAFLD is rising by year due to dietary changes, metabolic disorders, and no approved therapy, affecting a quarter of the global population and representing a major economic problem that burdens healthcare systems. Currently, in addition to the common causative factors like insulin resistance, oxidative stress, and lipotoxicity, the role of immune cells, especially T cells, played in MAFLD is increasingly being emphasized by global scholars. Based on the diverse classification and pathophysiological effects of immune T cells, we comprehensively analyzed their bidirectional regulatory effects on the hepatic inflammatory microenvironment and MAFLD progression. This interaction between MAFLD and T cells was also associated with hepatic-intestinal immune crosstalk and gut microbiota homeostasis. Moreover, we pointed out several T-cell-based therapeutic approaches including but not limited to adoptive transfer of T cells, fecal microbiota transplantation, and drug therapy, especially for natural products and Chinese herbal prescriptions. Overall, this study contributes to a better understanding of the important role of T cells played in MAFLD progression and corresponding therapeutic options and provides a potential reference for further drug development.
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Affiliation(s)
- Jia Liu
- School of Life SciencesBeijing University of Chinese MedicineBeijingChina
| | - Mingning Ding
- School of Life SciencesBeijing University of Chinese MedicineBeijingChina
| | - Jinzhao Bai
- School of Chinese Materia MedicaBeijing University of Chinese MedicineBeijingChina
| | - Ranyi Luo
- School of Life SciencesBeijing University of Chinese MedicineBeijingChina
| | - Runping Liu
- School of Chinese Materia MedicaBeijing University of Chinese MedicineBeijingChina
| | - Jiaorong Qu
- School of Life SciencesBeijing University of Chinese MedicineBeijingChina
| | - Xiaojiaoyang Li
- School of Life SciencesBeijing University of Chinese MedicineBeijingChina
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Liu Y, Liu X, Zhou W, Zhang J, Wu J, Guo S, Jia S, Wang H, Li J, Tan Y. Integrated bioinformatics analysis reveals potential mechanisms associated with intestinal flora intervention in nonalcoholic fatty liver disease. Medicine (Baltimore) 2022; 101:e30184. [PMID: 36086766 PMCID: PMC10980383 DOI: 10.1097/md.0000000000030184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 07/07/2022] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease that imposes a huge economic burden on global public health. And the gut-liver axis theory supports the therapeutic role of intestinal flora in the development and progression of NAFLD. To this end, we designed bioinformatics study on the relationship between intestinal flora disorder and NAFLD, to explore the possible molecular mechanism of intestinal flora interfering with NAFLD. METHODS Differentially expressed genes for NAFLD were obtained from the GEO database. And the disease genes for NAFLD and intestinal flora disorder were obtained from the disease databases. The protein-protein interaction network was established by string 11.0 database and visualized by Cytoscape 3.7.2 software. Cytoscape plug-in MCODE and cytoHubba were used to screen the potential genes of intestinal flora disorder and NAFLD, to obtain potential targets for intestinal flora to interfere in the occurrence and process of NAFLD. Enrichment analysis of potential targets was carried out using R 4.0.2 software. RESULTS The results showed that 7 targets might be the key genes for intestinal flora to interfere with NAFLD. CCL2, IL6, IL1B, and FOS are mainly related to the occurrence and development mechanism of NAFLD, while PTGS2, SPINK1, and C5AR1 are mainly related to the intervention of intestinal flora in the occurrence and development of NAFLD. The gene function is mainly reflected in basic biological processes, including the regulation of metabolic process, epithelial development, and immune influence. The pathway is mainly related to signal transduction, immune regulation, and physiological metabolism. The TNF signaling pathway, AGE-RAGE signaling pathway in diabetic activity, and NF-Kappa B signaling pathways are important pathways for intestinal flora to interfere with NAFLD. According to the analysis results, there is a certain correlation between intestinal flora disorder and NAFLD. CONCLUSION It is speculated that the mechanism by which intestinal flora may interfere with the occurrence and development of NAFLD is mainly related to inflammatory response and insulin resistance. Nevertheless, further research is needed to explore the specific molecular mechanisms.
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Affiliation(s)
- Yingying Liu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Xinkui Liu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Wei Zhou
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Jingyuan Zhang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Jiarui Wu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Siyu Guo
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Shanshan Jia
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Haojia Wang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Jialin Li
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Yingying Tan
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
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Skat-Rørdam J, Ipsen DH, Seemann SE, Latta M, Lykkesfeldt J, Tveden-Nyborg P. Modelling Nonalcoholic Steatohepatitis In Vivo-A Close Transcriptomic Similarity Supports the Guinea Pig Disease Model. Biomedicines 2021; 9:biomedicines9091198. [PMID: 34572384 PMCID: PMC8471870 DOI: 10.3390/biomedicines9091198] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Revised: 09/07/2021] [Accepted: 09/09/2021] [Indexed: 12/29/2022] Open
Abstract
The successful development of effective treatments against nonalcoholic steatohepatitis (NASH) is significantly set back by the limited availability of predictive preclinical models, thereby delaying and reducing patient recovery. Uniquely, the guinea pig NASH model develops hepatic histopathology and fibrosis resembling that of human patients, supported by similarities in selected cellular pathways. The high-throughput sequencing of guinea pig livers with fibrotic NASH (n = 6) and matched controls (n = 6) showed a clear separation of the transcriptomic profile between NASH and control animals. A comparison to NASH patients with mild disease (GSE126848) revealed a 45.2% overlap in differentially expressed genes, while pathway analysis showed a 34% match between the top 50 enriched pathways in patients with advanced NASH (GSE49541) and guinea pigs. Gene set enrichment analysis highlighted the similarity to human patients (GSE49541), also when compared to three murine models (GSE52748, GSE38141, GSE67680), and leading edge genes THRSP, CCL20 and CD44 were highly expressed in both guinea pigs and NASH patients. Nine candidate genes were identified as highly correlated with hepatic fibrosis (correlation coefficient > 0.8), and showed a similar expression pattern in NASH patients. Of these, two candidate genes (VWF and SERPINB9) encode secreted factors, warranting further investigations as potential biomarkers of human NASH progression. This study demonstrates key similarities in guinea pig and human NASH, supporting increased predictability when translating research findings to human patients.
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Affiliation(s)
- Josephine Skat-Rørdam
- Section of Experimental Animal Models, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, DK-1870 Frederikberg, Denmark; (J.S.-R.); (D.H.I.); (J.L.)
| | - David H. Ipsen
- Section of Experimental Animal Models, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, DK-1870 Frederikberg, Denmark; (J.S.-R.); (D.H.I.); (J.L.)
| | - Stefan E. Seemann
- Center for non-coding RNA in Technology and Health, Department of Veterinary and Animal Sciences, Section for Animal Genetics, Bioinformatics and Breeding, University of Copenhagen, DK-1871 Frederiksberg, Denmark;
| | - Markus Latta
- Liver Disease Research, Global Drug Discovery, Novo Nordisk A/S, DK-2760 Måløv, Denmark;
| | - Jens Lykkesfeldt
- Section of Experimental Animal Models, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, DK-1870 Frederikberg, Denmark; (J.S.-R.); (D.H.I.); (J.L.)
| | - Pernille Tveden-Nyborg
- Section of Experimental Animal Models, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, DK-1870 Frederikberg, Denmark; (J.S.-R.); (D.H.I.); (J.L.)
- Correspondence: ; Tel.: +45-35-33-31-67
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11
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Hashimoto N, Han KH, Wakagi M, Ishikawa-Takano Y, Ippoushi K, Fukushima M. Bile acids induced hepatic lipid accumulation in mice by inhibiting mRNA expression of patatin-like phospholipase domain containing 3 and microsomal triglyceride transfer protein. Nutr Res 2021; 92:12-20. [PMID: 34174520 DOI: 10.1016/j.nutres.2021.05.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 04/16/2021] [Accepted: 05/18/2021] [Indexed: 01/07/2023]
Abstract
Preliminary studies have shown that a lithogenic diet (LG), which contains cholesterol and cholic acid, induces gallstones and hepatic lipid accumulation (HLA), and reduction of blood triglyceride in mice. We hypothesized that an LG induces HLA by diminishing hepatic triglyceride excretion; however, there is no clear understanding of the mechanism of LG-induced HLA. This study aimed to investigate transcript expression related to the synthesis, expenditure, and efflux of hepatic triglyceride, in mice fed an LG for 4 weeks. Results showed lower plasma concentrations of triglyceride in the LG group than in the control group, but no symptoms of hepatic injury were observed. Hepatic mRNA expressions of patatin-like phospholipase domain containing 3 (Pnpla3), microsomal triglyceride transfer protein (Mttp), and acyl-CoA oxidase 1 (Acox1) were also reduced in the LG group. Deoxycholic acid and lithocholic acid promoted intracellular lipid accumulation, reduced triglyceride concentration in media, and suppressed expression of PNPLA3 and MTTP in HepG2 human hepatoma cells. These findings suggest that deoxycholic acid and lithocholic acid promote HLA by inhibiting the expression of PNPLA3, ACOX1, and MTTP that are involved in lipid metabolism.
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Affiliation(s)
- Naoto Hashimoto
- Department of Life and Food Sciences, Obihiro University of Agriculture and Veterinary Medicine, Nishi 2-11, Inada, Obihiro, Hokkaido 080-8555, Japan; Division of Food Function Research, Food Research Institute, National Agriculture and Food Research Organization, 2-1-12, Kannondai, Tsukuba, Ibaraki 305-8642, Japan; Division of Field Crop Research and Development, Hokkaido Agricultural Research Center, National Agriculture and Food Research Organization, Kasai, Hokkaido 082-0071, Japan.
| | - Kyu-Ho Han
- Department of Life and Food Sciences, Obihiro University of Agriculture and Veterinary Medicine, Nishi 2-11, Inada, Obihiro, Hokkaido 080-8555, Japan
| | - Manabu Wakagi
- Division of Food Function Research, Food Research Institute, National Agriculture and Food Research Organization, 2-1-12, Kannondai, Tsukuba, Ibaraki 305-8642, Japan
| | - Yuko Ishikawa-Takano
- Division of Food Function Research, Food Research Institute, National Agriculture and Food Research Organization, 2-1-12, Kannondai, Tsukuba, Ibaraki 305-8642, Japan
| | - Katsunari Ippoushi
- Division of Food Function Research, Food Research Institute, National Agriculture and Food Research Organization, 2-1-12, Kannondai, Tsukuba, Ibaraki 305-8642, Japan
| | - Michihiro Fukushima
- Department of Life and Food Sciences, Obihiro University of Agriculture and Veterinary Medicine, Nishi 2-11, Inada, Obihiro, Hokkaido 080-8555, Japan
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12
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Kube I, Jastrow H, Führer D, Zwanziger D. Thyroid Hormone Deficiency Modifies Hepatic Lipid Droplet Morphology and Molecular Properties in Lithogenic-Diet Supplemented Mice. Exp Clin Endocrinol Diabetes 2021; 129:926-930. [PMID: 34049413 DOI: 10.1055/a-1404-7939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
OBJECTIVE Thyroid hormones have been associated with a hepatic lipid lowering effect and thyroid function has been shown to play a substantial role in development of non-alcoholic fatty liver disease. Hepatic lipid droplets differ in the number, size and molecular properties depending on metabolic state or pathological condition. However, in how far thyroid hormone deficiency affects hepatic lipid droplet morphology and molecular properties is still poorly understood. Therefore, we performed a study in mice using a lithogenic diet model of steatohepatitis and modulated the thyroid hormone status. METHODS Male and female three months old C57BL/6 mice were divided into a euthyroid (control), a lithogenic (litho) and a lithogenic+thyroid hormone deficient (litho+hypo) group and treated for six weeks. Hepatic transmission electron microscopy and gene expression analysis of lipid-droplet associated proteins were performed. RESULTS Increased mean diameters of hepatic lipid droplets and a shift towards raised electron-density in lipid droplets was observed under thyroid hormone deficiency. Furthermore thyroid hormone deficiency altered hepatic expression of genes involved in lipophagy and triacylglycerol mobilization. Interestingly, while the impact of thyroid hormone deficiency on lipid droplet morphology seems to be sex-independent, hepatic lipid droplet-associated gene expression differed significantly between both sexes. CONCLUSION This study demonstrates that thyroid hormone deficiency alters hepatic lipid droplet morphology and hepatic gene expression of lipid droplet-associated proteins in a lithogenic diet mouse model of steatohepatitis.
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Affiliation(s)
- Irina Kube
- Department of Endocrinology, Diabetes and Metabolism and Clinical Chemistry - Division of Laboratory Research, University of Duisburg-Essen, Germany
| | - Holger Jastrow
- Faculty of Medicine, University of Duisburg-Essen - Institute of Anatomy and Imaging Center Essen, Germany
| | - Dagmar Führer
- Department of Endocrinology, Diabetes and Metabolism and Clinical Chemistry - Division of Laboratory Research, University of Duisburg-Essen, Germany
| | - Denise Zwanziger
- Department of Endocrinology, Diabetes and Metabolism and Clinical Chemistry - Division of Laboratory Research, University of Duisburg-Essen, Germany
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13
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UNO K, MIYAJIMA K, TOMA M, SUZUKI-KEMURIYAMA N, NAKAE D. CD44 expression in the bile duct epithelium is related to hepatic fibrosis in nonalcoholic steatohepatitis rats induced by a choline-deficient, methionine-lowered, L-amino acid diet. J Toxicol Pathol 2021; 35:149-157. [PMID: 35516840 PMCID: PMC9018400 DOI: 10.1293/tox.2021-0069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 11/22/2021] [Indexed: 11/26/2022] Open
Abstract
Nonalcoholic steatohepatitis is a lifestyle-related disease and an increasing threat
worldwide. Hepatic fibrosis, which results from chronic hepatic diseases including
nonalcoholic steatohepatitis, is closely correlated with mortality among hepatic lesions,
such as steatosis and inflammation. Thus, it is important to identify factors that can
serve as diagnostic and therapeutic targets for hepatic fibrosis. In this study, we
examined the function of CD44 in the development of hepatic fibrosis in choline-deficient,
methionine-lowered, L-amino-acid diet-fed rats, especially with respect to the
proliferation of bile duct epithelium. Male Fischer 344 rats were fed a choline-deficient,
methionine-lowered, L-amino-acid diet for 2, 4, 13, or 26 weeks. This diet decreased the
body weight; increased the levels of serum parameters indicating liver injury, such as
aspartate and alanine aminotransferase; upregulated inflammation- and fibrosis-related
gene expression in the liver; and resulted in the development of hepatic lesions,
including fatty changes in hepatocytes, inflammatory cell infiltration, and fibrosis.
Hepatic hyaluronan was synthesized and deposited in the liver tissue. The expression of
both CD44 mRNA and protein was significantly increased throughout the experimental period.
CD44 protein was observed in some of the bile duct epithelium, around which hyaluronic
acid was deposited, and these bile duct lesions were concordant with the area of hepatic
fibrosis. Thus, CD44 expressed in the bile duct epithelium may be a target for controlling
nonalcoholic steatohepatitis-related hepatic fibrosis.
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Affiliation(s)
- Kinuko UNO
- Department of Food and Nutritional Science, Graduate School of Agriculture, Tokyo University of Agriculture, 1-1-1 Sakura-ga-Oka, Setagaya, Tokyo 156-8502, Japan
| | - Katsuhiro MIYAJIMA
- Department of Nutritional Science and Food Safety, Graduate School of Agriculture, Tokyo University of Agriculture, 1-1-1 Sakura-ga-Oka, Setagaya, Tokyo 156-8502, Japan
| | - Marika TOMA
- Department of Nutritional Science and Food Safety, Graduate School of Agriculture, Tokyo University of Agriculture, 1-1-1 Sakura-ga-Oka, Setagaya, Tokyo 156-8502, Japan
| | - Noriko SUZUKI-KEMURIYAMA
- Department of Nutritional Science and Food Safety, Faculty of Applied Biosciences, Tokyo University of Agriculture, 1-1-1 Sakura-ga-Oka, Setagaya, Tokyo 156-8502, Japan
| | - Dai NAKAE
- Department of Nutritional Science and Food Safety, Graduate School of Agriculture, Tokyo University of Agriculture, 1-1-1 Sakura-ga-Oka, Setagaya, Tokyo 156-8502, Japan
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14
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Li M, Chen L, Gao Y, Li M, Wang X, Qiang L, Wang X. Recent advances targeting C-C chemokine receptor type 2 for liver diseases in monocyte/macrophage. Liver Int 2020; 40:2928-2936. [PMID: 33025657 DOI: 10.1111/liv.14687] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 09/21/2020] [Accepted: 10/01/2020] [Indexed: 12/12/2022]
Abstract
Liver plays a critical role in metabolism, nutrient storage and detoxification. Emergency signals or appropriate immune response leads to pathological inflammation and breaks the steady state when liver dysfunction appears, which makes body more susceptible to chronic liver infection, autoimmune diseases and tumour. Compelling proof has illustrated the non-redundant importance of C-C chemokine receptor type 2 (CCR2), one of G-protein-coupled receptors, in different diseases. Selectively expressed on the surface of cells, CCR2 is involved in various signalling pathways and regulates the migration of cells. Especially, a peculiar role of CCR2 has been identified within decades in the onset and progression of hepatic diseases, which led to particular focusing on CCR2 as a new therapeutic and diagnostic target for non-alcoholic fatty liver disease and hepatocellular carcinoma. In this review, we discuss the effect of CCR2 in monocytes/macrophages on liver diseases. The application and translation of the decades of discoveries into therapies promise novel approaches in the treatment of liver disease.
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Affiliation(s)
- Min Li
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Liu Chen
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yue Gao
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Mengyuan Li
- Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.,Big Data Research Institute, China Pharmaceutical University, Nanjing, China
| | - Xiaosheng Wang
- Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.,Big Data Research Institute, China Pharmaceutical University, Nanjing, China
| | - Lei Qiang
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Xiaoping Wang
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
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15
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Abstract
The human liver is an organ with a diverse array of immunologic functions. Its unique anatomic position that leads to it receiving all the mesenteric venous blood, combined with its unique micro anatomy, allows it to serve as a sentinel for the body's immune system. Hepatocytes, biliary epithelial cells, Kupffer cells, stellate cells, and liver sinusoidal endothelial cells express key molecules that recruit and activate innate and adaptive immunity. Additionally, a diverse array of lymphoid and myeloid immune cells resides within and traffics to the liver in specific circumstances. Derangement of these trafficking mechanisms underlies the pathophysiology of autoimmune liver diseases, nonalcoholic steatohepatitis, and liver transplantation. Here, we review these pathways and interactions along with potential targets that have been identified to be exploited for therapeutic purposes.
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16
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Hasib A, Hennayake CK, Bracy DP, Bugler-Lamb AR, Lantier L, Khan F, Ashford MLJ, McCrimmon RJ, Wasserman DH, Kang L. CD44 contributes to hyaluronan-mediated insulin resistance in skeletal muscle of high-fat-fed C57BL/6 mice. Am J Physiol Endocrinol Metab 2019; 317:E973-E983. [PMID: 31550181 PMCID: PMC6957377 DOI: 10.1152/ajpendo.00215.2019] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Extracellular matrix hyaluronan is increased in skeletal muscle of high-fat-fed insulin-resistant mice, and reduction of hyaluronan by PEGPH20 hyaluronidase ameliorates diet-induced insulin resistance (IR). CD44, the main hyaluronan receptor, is positively correlated with type 2 diabetes. This study determines the role of CD44 in skeletal muscle IR. Global CD44-deficient (cd44-/-) mice and wild-type littermates (cd44+/+) were fed a chow diet or 60% high-fat diet for 16 wk. High-fat-fed cd44-/- mice were also treated with PEGPH20 to evaluate its CD44-dependent action. Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp (ICv). High-fat feeding increased muscle CD44 protein expression. In the absence of differences in body weight and composition, despite lower clamp insulin during ICv, the cd44-/- mice had sustained glucose infusion rate (GIR) regardless of diet. High-fat diet-induced muscle IR as evidenced by decreased muscle glucose uptake (Rg) was exhibited in cd44+/+ mice but absent in cd44-/- mice. Moreover, gastrocnemius Rg remained unchanged between genotypes on chow diet but was increased in high-fat-fed cd44-/- compared with cd44+/+ when normalized to clamp insulin concentrations. Ameliorated muscle IR in high-fat-fed cd44-/- mice was associated with increased vascularization. In contrast to previously observed increases in wild-type mice, PEGPH20 treatment in high-fat-fed cd44-/- mice did not change GIR or muscle Rg during ICv, suggesting a CD44-dependent action. In conclusion, genetic CD44 deletion improves muscle IR, and the beneficial effects of PEGPH20 are CD44-dependent. These results suggest a critical role of CD44 in promoting hyaluronan-mediated muscle IR, therefore representing a potential therapeutic target for diabetes.
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Affiliation(s)
- Annie Hasib
- Division of Systems Medicine, School of Medicine, University of Dundee, Dundee, Scotland, United Kingdom
| | - Chandani K Hennayake
- Division of Systems Medicine, School of Medicine, University of Dundee, Dundee, Scotland, United Kingdom
| | - Deanna P Bracy
- Department of Molecular Physiology and Biophysics and Mouse Metabolic Phenotyping Centre, Vanderbilt University, Nashville, Tennessee
| | - Aimée R Bugler-Lamb
- Division of Systems Medicine, School of Medicine, University of Dundee, Dundee, Scotland, United Kingdom
| | - Louise Lantier
- Department of Molecular Physiology and Biophysics and Mouse Metabolic Phenotyping Centre, Vanderbilt University, Nashville, Tennessee
| | - Faisel Khan
- Division of Systems Medicine, School of Medicine, University of Dundee, Dundee, Scotland, United Kingdom
| | - Michael L J Ashford
- Division of Systems Medicine, School of Medicine, University of Dundee, Dundee, Scotland, United Kingdom
| | - Rory J McCrimmon
- Division of Systems Medicine, School of Medicine, University of Dundee, Dundee, Scotland, United Kingdom
| | - David H Wasserman
- Department of Molecular Physiology and Biophysics and Mouse Metabolic Phenotyping Centre, Vanderbilt University, Nashville, Tennessee
| | - Li Kang
- Division of Systems Medicine, School of Medicine, University of Dundee, Dundee, Scotland, United Kingdom
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17
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Abstract
The liver is a key, frontline immune tissue. Ideally positioned to detect pathogens entering the body via the gut, the liver appears designed to detect, capture, and clear bacteria, viruses, and macromolecules. Containing the largest collection of phagocytic cells in the body, this organ is an important barrier between us and the outside world. Importantly, as portal blood also transports a large number of foreign but harmless molecules (e.g., food antigens), the liver's default immune status is anti-inflammatory or immunotolerant; however, under appropriate conditions, the liver is able to mount a rapid and robust immune response. This balance between immunity and tolerance is essential to liver function. Excessive inflammation in the absence of infection leads to sterile liver injury, tissue damage, and remodeling; insufficient immunity allows for chronic infection and cancer. Dynamic interactions between the numerous populations of immune cells in the liver are key to maintaining this balance and overall tissue health.
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Affiliation(s)
- Paul Kubes
- Calvin, Phoebe & Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta T2N 4N1, Canada; , .,Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta T2N 4N1, Canada
| | - Craig Jenne
- Calvin, Phoebe & Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta T2N 4N1, Canada; , .,Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, Alberta T2N 4N1, Canada
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18
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Fu Q, Xiao P, Chen Y, Wei Z, Liu X. CD44 deficiency enhanced Streptococcus equi ssp. zooepidemicus dissemination and inflammation response in a mouse model. Res Vet Sci 2017; 115:96-101. [DOI: 10.1016/j.rvsc.2017.01.027] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2016] [Revised: 12/21/2016] [Accepted: 01/11/2017] [Indexed: 12/11/2022]
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19
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Pierce AA, Duwaerts CC, Siao K, Mattis AN, Goodsell A, Baron JL, Maher JJ. CD18 deficiency improves liver injury in the MCD model of steatohepatitis. PLoS One 2017; 12:e0183912. [PMID: 28873429 PMCID: PMC5584926 DOI: 10.1371/journal.pone.0183912] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2017] [Accepted: 08/14/2017] [Indexed: 02/06/2023] Open
Abstract
Neutrophils and macrophages are important constituents of the hepatic inflammatory infiltrate in non-alcoholic steatohepatitis. These innate immune cells express CD18, an adhesion molecule that facilitates leukocyte activation. In the context of fatty liver, activation of infiltrated leukocytes is believed to enhance hepatocellular injury. The objective of this study was to determine the degree to which activated innate immune cells promote steatohepatitis by comparing hepatic outcomes in wild-type and CD18-mutant mice fed a methionine-choline-deficient (MCD) diet. After 3 weeks of MCD feeding, hepatocyte injury, based on serum ALT elevation, was 40% lower in CD18-mutant than wild-type mice. Leukocyte infiltration into the liver was not impaired in CD18-mutant mice, but leukocyte activation was markedly reduced, as shown by the lack of evidence of oxidant production. Despite having reduced hepatocellular injury, CD18-mutant mice developed significantly more hepatic steatosis than wild-type mice after MCD feeding. This coincided with greater hepatic induction of pro-inflammatory and lipogenic genes as well as a modest reduction in hepatic expression of adipose triglyceride lipase. Overall, the data indicate that CD18 deficiency curbs MCD-mediated liver injury by limiting the activation of innate immune cells in the liver without compromising intrahepatic cytokine activation. Reduced liver injury occurs at the expense of increased hepatic steatosis, which suggests that in addition to damaging hepatocytes, infiltrating leukocytes may influence lipid homeostasis in the liver.
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Affiliation(s)
- Andrew A. Pierce
- Department of Medicine, University of California, San Francisco, San Francisco, California, United States of America
- Liver Center, University of California, San Francisco, San Francisco, California, United States of America
| | - Caroline C. Duwaerts
- Department of Medicine, University of California, San Francisco, San Francisco, California, United States of America
- Liver Center, University of California, San Francisco, San Francisco, California, United States of America
| | - Kevin Siao
- Department of Medicine, University of California, San Francisco, San Francisco, California, United States of America
- Liver Center, University of California, San Francisco, San Francisco, California, United States of America
| | - Aras N. Mattis
- Liver Center, University of California, San Francisco, San Francisco, California, United States of America
- Department of Pathology, University of California, San Francisco, San Francisco, California, United States of America
| | - Amanda Goodsell
- Department of Medicine, University of California, San Francisco, San Francisco, California, United States of America
- Liver Center, University of California, San Francisco, San Francisco, California, United States of America
| | - Jody L. Baron
- Department of Medicine, University of California, San Francisco, San Francisco, California, United States of America
- Liver Center, University of California, San Francisco, San Francisco, California, United States of America
| | - Jacquelyn J. Maher
- Department of Medicine, University of California, San Francisco, San Francisco, California, United States of America
- Liver Center, University of California, San Francisco, San Francisco, California, United States of America
- * E-mail:
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20
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Patouraux S, Rousseau D, Bonnafous S, Lebeaupin C, Luci C, Canivet CM, Schneck AS, Bertola A, Saint-Paul MC, Iannelli A, Gugenheim J, Anty R, Tran A, Bailly-Maitre B, Gual P. CD44 is a key player in non-alcoholic steatohepatitis. J Hepatol 2017; 67:328-338. [PMID: 28323124 DOI: 10.1016/j.jhep.2017.03.003] [Citation(s) in RCA: 94] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Revised: 02/01/2017] [Accepted: 03/02/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Cluster of differentiation (CD)44 regulates adipose tissue inflammation in obesity and hepatic leukocyte recruitment in a lithogenic context. However, its role in hepatic inflammation in a mouse model of steatohepatitis and its relevance in humans have not yet been investigated. We aimed to evaluated the contribution of CD44 to non-alcoholic steatohepatitis (NASH) development and liver injury in mouse models and in patients at various stages of non-alcoholic fatty liver disease (NAFLD) progression. METHODS The role of CD44 was evaluated in CD44-/- mice and after injections of an αCD44 antibody in wild-type mice challenged with a methionine- and choline-deficient diet (MCDD). In obese patients, hepatic CD44 (n=30 and 5 NASH patients with a second liver biopsy after bariatric surgery) and serum sCD44 (n=64) were evaluated. RESULTS Liver inflammation (including inflammatory foci number, macrophage and neutrophil infiltration and CCL2/CCR2 levels), liver injury and fibrosis strongly decreased in CD44-/- mice compared to wild-type mice on MCDD. CD44 deficiency enhanced the M2 polarization and strongly decreased the activation of macrophages by lipopolysaccharide (LPS), hepatocyte damage-associated molecular patterns (DAMPs) and saturated fatty acids. Neutralization of CD44 in mice with steatohepatitis strongly decreased the macrophage infiltration and chemokine ligand (CCL)2 expression with a partial correction of liver inflammation and injury. In obese patients, hepatic CD44 was strongly upregulated in NASH patients (p=0.0008) and correlated with NAFLD activity score (NAS) (p=0.001), ballooning (p=0.003), alanine transaminase (p=0.005) and hepatic CCL2 (p<0.001) and macrophage marker CD68 (p<0.001) expression. Correction of NASH was associated with a strong decrease in liver CD44+ cells. Finally, the soluble form of CD44 increased with severe steatosis (p=0.0005) and NASH (p=0.007). CONCLUSION Human and experimental data suggest that CD44 is a marker and key player of hepatic inflammation and its targeting partially corrects NASH. LAY SUMMARY Human and experimental data suggest that CD44, a cellular protein mainly expressed in immune cells, is a marker and key player of non-alcoholic steatohepatitis (NASH). Indeed, CD44 enhances the non-alcoholic fatty liver (NAFL) (hepatic steatosis) to NASH progression by regulating hepatic macrophage polarization (pro-inflammatory phenotype) and infiltration (macrophage motility and the MCP1/CCL2/CCR2 system). Targeting CD44 partially corrects NASH, making it a potential therapeutic strategy.
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Affiliation(s)
- Stéphanie Patouraux
- INSERM, U1065, C3M, Team 8 "Hepatic Complications in Obesity", Nice, France; Université Côte d'Azur, Nice, France; CHU of Nice, Biological Center, Pasteur Hôpital, Nice, France
| | - Déborah Rousseau
- INSERM, U1065, C3M, Team 8 "Hepatic Complications in Obesity", Nice, France; Université Côte d'Azur, Nice, France
| | - Stéphanie Bonnafous
- INSERM, U1065, C3M, Team 8 "Hepatic Complications in Obesity", Nice, France; Université Côte d'Azur, Nice, France; CHU of Nice, Digestive Center, Nice, France
| | - Cynthia Lebeaupin
- INSERM, U1065, C3M, Team 8 "Hepatic Complications in Obesity", Nice, France; Université Côte d'Azur, Nice, France
| | - Carmelo Luci
- INSERM, U1065, C3M, Team 8 "Hepatic Complications in Obesity", Nice, France; Université Côte d'Azur, Nice, France
| | - Clémence M Canivet
- INSERM, U1065, C3M, Team 8 "Hepatic Complications in Obesity", Nice, France; Université Côte d'Azur, Nice, France; CHU of Nice, Digestive Center, Nice, France
| | - Anne-Sophie Schneck
- INSERM, U1065, C3M, Team 8 "Hepatic Complications in Obesity", Nice, France; Université Côte d'Azur, Nice, France; CHU of Nice, Digestive Center, Nice, France
| | - Adeline Bertola
- INSERM, U1065, C3M, Team 8 "Hepatic Complications in Obesity", Nice, France; Université Côte d'Azur, Nice, France
| | - Marie-Christine Saint-Paul
- INSERM, U1065, C3M, Team 8 "Hepatic Complications in Obesity", Nice, France; Université Côte d'Azur, Nice, France; CHU of Nice, Biological Center, Pasteur Hôpital, Nice, France
| | - Antonio Iannelli
- INSERM, U1065, C3M, Team 8 "Hepatic Complications in Obesity", Nice, France; Université Côte d'Azur, Nice, France; CHU of Nice, Digestive Center, Nice, France
| | - Jean Gugenheim
- INSERM, U1065, C3M, Team 8 "Hepatic Complications in Obesity", Nice, France; Université Côte d'Azur, Nice, France; CHU of Nice, Digestive Center, Nice, France
| | - Rodolphe Anty
- INSERM, U1065, C3M, Team 8 "Hepatic Complications in Obesity", Nice, France; Université Côte d'Azur, Nice, France; CHU of Nice, Digestive Center, Nice, France
| | - Albert Tran
- INSERM, U1065, C3M, Team 8 "Hepatic Complications in Obesity", Nice, France; Université Côte d'Azur, Nice, France; CHU of Nice, Digestive Center, Nice, France
| | - Béatrice Bailly-Maitre
- INSERM, U1065, C3M, Team 8 "Hepatic Complications in Obesity", Nice, France; Université Côte d'Azur, Nice, France
| | - Philippe Gual
- INSERM, U1065, C3M, Team 8 "Hepatic Complications in Obesity", Nice, France; Université Côte d'Azur, Nice, France.
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21
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Narayanan S, Surette FA, Hahn YS. The Immune Landscape in Nonalcoholic Steatohepatitis. Immune Netw 2016; 16:147-58. [PMID: 27340383 PMCID: PMC4917398 DOI: 10.4110/in.2016.16.3.147] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2016] [Revised: 04/11/2016] [Accepted: 04/22/2016] [Indexed: 02/08/2023] Open
Abstract
The liver lies at the intersection of multiple metabolic pathways and consequently plays a central role in lipid metabolism. Pathological disturbances in hepatic lipid metabolism are characteristic of chronic metabolic diseases, such as obesity-mediated insulin resistance, which can result in nonalcoholic fatty liver disease (NAFLD). Tissue damage induced in NAFLD activates and recruits liver-resident and non-resident immune cells, resulting in nonalcoholic steatohepatitis (NASH). Importantly, NASH is associated with an increased risk of significant clinical sequelae such as cirrhosis, cardiovascular diseases, and malignancies. In this review, we describe the immunopathogenesis of NASH by defining the known functions of immune cells in the progression and resolution of disease.
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Affiliation(s)
- Sowmya Narayanan
- Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia 22908, USA.; Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia 22908, USA
| | - Fionna A Surette
- Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia 22908, USA
| | - Young S Hahn
- Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia 22908, USA.; Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia 22908, USA
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Kodama K, Zhao Z, Toda K, Yip L, Fuhlbrigge R, Miao D, Fathman CG, Yamada S, Butte AJ, Yu L. Expression-Based Genome-Wide Association Study Links Vitamin D-Binding Protein With Autoantigenicity in Type 1 Diabetes. Diabetes 2016; 65:1341-9. [PMID: 26983959 PMCID: PMC4839207 DOI: 10.2337/db15-1308] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Accepted: 02/22/2016] [Indexed: 12/18/2022]
Abstract
Type 1 diabetes (T1D) is caused by autoreactive T cells that recognize pancreatic islet antigens and destroy insulin-producing β-cells. This attack results from a breakdown in tolerance for self-antigens, which is controlled by ectopic antigen expression in the thymus and pancreatic lymph nodes (PLNs). The autoantigens known to be involved include a set of islet proteins, such as insulin, GAD65, IA-2, and ZnT8. In an attempt to identify additional antigenic proteins, we performed an expression-based genome-wide association study using microarray data from 118 arrays of the thymus and PLNs of T1D mice. We ranked all 16,089 protein-coding genes by the likelihood of finding repeated differential expression and the degree of tissue specificity for pancreatic islets. The top autoantigen candidate was vitamin D-binding protein (VDBP). T-cell proliferation assays showed stronger T-cell reactivity to VDBP compared with control stimulations. Higher levels and frequencies of serum anti-VDBP autoantibodies (VDBP-Abs) were identified in patients with T1D (n = 331) than in healthy control subjects (n = 77). Serum vitamin D levels were negatively correlated with VDBP-Ab levels in patients in whom T1D developed during the winter. Immunohistochemical localization revealed that VDBP was specifically expressed in α-cells of pancreatic islets. We propose that VDBP could be an autoantigen in T1D.
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Affiliation(s)
- Keiichi Kodama
- Institute for Computational Health Sciences, Department of Pediatrics, University of California, San Francisco, San Francisco, CA
| | - Zhiyuan Zhao
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO
| | - Kyoko Toda
- Biomedical Research Center, Kitasato Institute Hospital, Kitasato University, Tokyo, Japan
| | - Linda Yip
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA
| | - Rebecca Fuhlbrigge
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA
| | - Dongmei Miao
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO
| | - C Garrison Fathman
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA
| | - Satoru Yamada
- Diabetes Center, Kitasato Institute Hospital, Kitasato University, Tokyo, Japan
| | - Atul J Butte
- Institute for Computational Health Sciences, Department of Pediatrics, University of California, San Francisco, San Francisco, CA
| | - Liping Yu
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO
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23
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Nati M, Haddad D, Birkenfeld AL, Koch CA, Chavakis T, Chatzigeorgiou A. The role of immune cells in metabolism-related liver inflammation and development of non-alcoholic steatohepatitis (NASH). Rev Endocr Metab Disord 2016; 17:29-39. [PMID: 26847547 DOI: 10.1007/s11154-016-9339-2] [Citation(s) in RCA: 99] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The low grade inflammatory state present in obesity promotes the progression of Non-Alcoholic Fatty Liver Disease (NAFLD). In Non-Alcoholic Steatohepatitis (NASH), augmented hepatic steatosis is accompanied by aberrant intrahepatic inflammation and exacerbated hepatocellular injury. NASH is an important disorder and can lead to fibrosis, cirrhosis and even neoplasia. The pathology of NASH involves a complex network of mechanisms, including increased infiltration of different subsets of immune cells, such as monocytes, T-lymphocytes and neutrophils, to the liver, as well as activation and in situ expansion of liver resident cells such as Kupffer cells or stellate cells. In this review, we summarize recent advances regarding understanding the role of the various cells of the innate and adaptive immunity in NASH development and progression, and discuss possible future therapeutic options and tools to interfere with disease progression.
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Affiliation(s)
- Marina Nati
- Department of Clinical Pathobiochemistry, Faculty of Medicine, Technische Universität Dresden, MTZ, Fiedlerstrasse 42, 01307, Dresden, Germany
| | - David Haddad
- Department of Clinical Pathobiochemistry, Faculty of Medicine, Technische Universität Dresden, MTZ, Fiedlerstrasse 42, 01307, Dresden, Germany
| | - Andreas L Birkenfeld
- Section of Metabolic Vascular Medicine, Medical Clinic III, Faculty of Medicine, TU Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
- Division of Diabetes and Nutritional Sciences, Rayne Institute, King's College London, London, UK
| | - Christian A Koch
- Division of Endocrinology, Endocrine Tumor Program, Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA
| | - Triantafyllos Chavakis
- Department of Clinical Pathobiochemistry, Faculty of Medicine, Technische Universität Dresden, MTZ, Fiedlerstrasse 42, 01307, Dresden, Germany
- Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
- Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine, TU Dresden, Dresden, Germany
| | - Antonios Chatzigeorgiou
- Department of Clinical Pathobiochemistry, Faculty of Medicine, Technische Universität Dresden, MTZ, Fiedlerstrasse 42, 01307, Dresden, Germany.
- Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany.
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
- Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine, TU Dresden, Dresden, Germany.
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24
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Yuan F, Wang H, Tian Y, Li Q, He L, Li N, Liu Z. Fish oil alleviated high-fat diet-induced non-alcoholic fatty liver disease via regulating hepatic lipids metabolism and metaflammation: a transcriptomic study. Lipids Health Dis 2016; 15:20. [PMID: 26832365 PMCID: PMC4736290 DOI: 10.1186/s12944-016-0190-y] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2015] [Accepted: 01/26/2016] [Indexed: 02/06/2023] Open
Abstract
Background Intake of fish oil rich in n-3 polyunsaturated fatty acids (PUFAs) is believed to be beneficial against development of non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanisms remain unclear. This study was to gain further understanding of the potential mechanisms of the protective effects of fish oil against NAFLD. Methods Ten male Sprague–Dawley rats were fed a control diet (CON), a Western style high-fat and high-cholesterol diet (WD), or a WD diet containing fish oil (FOH) for 16 weeks respectively. The development of liver steatosis and fibrosis were verified by histological and biochemical examination. Hepatic transcriptome were extracted for RNA-seq analysis, and particular results were confirmed by real-time polymerase chain reaction (PCR). Results The consumption of fish oil significantly ameliorated WD-induced dyslipidemia, transaminase elevation, hepatic steatosis, inflammatory infiltration, and fibrosis. Hepatic RNA-Seq analysis showed that long-term intake of fish oil restored the expression of circadian clock-related genes per2 and per3, which were reduced in WD fed animals. Fish oil consumption also corrected the expression levels of genes involved in fatty acid and cholesterol metabolism, such as Srebf1, Fasn, Scd1, Insig2, Cd36, Cyp7a1, Abcg5, Abcg8 and Pcsk9. Moreover, the expression levels of pro-inflammation genes Mcp1, Socs2, Sema4a, and Cd44 in the FOH group were lower than that of WD group, implying that fish oil protects the liver against WD-induced hepatic inflammation. Conclusion The present study demonstrates fish oil protects against WD-induced NALFD via improving lipid metabolism and ameliorating hepatic inflammation. Our findings add to the current understanding on the benefits of n-3 PUFAs against NAFLD. Electronic supplementary material The online version of this article (doi:10.1186/s12944-016-0190-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Fahu Yuan
- Wuhan Polytechnic University, School of Biology and Pharmaceutical Engineering, Wuhan, Hubei, 430023, China. .,Jianghan University, School of Medicine, Wuhan, China.
| | - Hualin Wang
- Wuhan Polytechnic University, School of Biology and Pharmaceutical Engineering, Wuhan, Hubei, 430023, China.
| | - Yu Tian
- Wuhan Polytechnic University, School of Biology and Pharmaceutical Engineering, Wuhan, Hubei, 430023, China.
| | - Qi Li
- Wuhan Polytechnic University, School of Biology and Pharmaceutical Engineering, Wuhan, Hubei, 430023, China.
| | - Lei He
- Department of Blood Transfusion, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Na Li
- Wuhan Polytechnic University, School of Biology and Pharmaceutical Engineering, Wuhan, Hubei, 430023, China.
| | - Zhiguo Liu
- Wuhan Polytechnic University, School of Biology and Pharmaceutical Engineering, Wuhan, Hubei, 430023, China.
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25
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Kim DG, Krenz A, Toussaint LE, Maurer KJ, Robinson SA, Yan A, Torres L, Bynoe MS. Non-alcoholic fatty liver disease induces signs of Alzheimer's disease (AD) in wild-type mice and accelerates pathological signs of AD in an AD model. J Neuroinflammation 2016; 13:1. [PMID: 26728181 PMCID: PMC4700622 DOI: 10.1186/s12974-015-0467-5] [Citation(s) in RCA: 179] [Impact Index Per Article: 19.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2015] [Accepted: 12/23/2015] [Indexed: 12/31/2022] Open
Abstract
Background Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease afflicting about one third of the world’s population and 30 % of the US population. It is induced by consumption of high-lipid diets and is characterized by liver inflammation and subsequent liver pathology. Obesity and consumption of a high-fat diet are known to increase the risk of Alzheimer’s disease (AD). Here, we investigated NAFLD-induced liver inflammation in the pathogenesis of AD. Methods WT and APP-Tg mice were fed with a standard diet (SD) or a high-fat diet (HFD) for 2, 5 months, or 1 year to induce NAFLD. Another set of APP-Tg mice were removed from HFD after 2 months and put back on SD for 3 months. Results During acute phase NAFLD, WT and APP-Tg mice developed significant liver inflammation and pathology that coincided with increased numbers of activated microglial cells in the brain, increased inflammatory cytokine profile, and increased expression of toll-like receptors. Chronic NAFLD induced advanced pathological signs of AD in both WT and APP-Tg mice, and also induced neuronal apoptosis. We observed decreased brain expression of low-density lipoprotein receptor-related protein-1 (LRP-1) which is involved in β-amyloid clearance, in both WT and APP-Tg mice after ongoing administration of the HFD. LRP-1 expression correlated with advanced signs of AD over the course of chronic NAFLD. Removal of mice from HFD during acute NAFLD reversed liver pathology, decreased signs of activated microglial cells and neuro-inflammation, and decreased β-amyloid plaque load. Conclusions Our findings indicate that chronic inflammation induced outside the brain is sufficient to induce neurodegeneration in the absence of genetic predisposition. Electronic supplementary material The online version of this article (doi:10.1186/s12974-015-0467-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Do-Geun Kim
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA.
| | - Antje Krenz
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA.
| | - Leon E Toussaint
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA.
| | - Kirk J Maurer
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA. .,Center for Animal Resources and Education, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA. .,Center for Comparative Medicine and Research, Dartmouth College, 1 Medical Center Drive, 302 W Borwell, Lebanon, NH 03756, USA.
| | - Sudie-Ann Robinson
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA.
| | - Angela Yan
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA.
| | - Luisa Torres
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA.
| | - Margaret S Bynoe
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA.
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26
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Liu LF, Kodama K, Wei K, Tolentino LL, Choi O, Engleman EG, Butte AJ, McLaughlin T. The receptor CD44 is associated with systemic insulin resistance and proinflammatory macrophages in human adipose tissue. Diabetologia 2015; 58:1579-86. [PMID: 25952479 DOI: 10.1007/s00125-015-3603-y] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2014] [Accepted: 04/07/2015] [Indexed: 12/13/2022]
Abstract
AIMS/HYPOTHESIS Proinflammatory immune cell infiltration in human adipose tissue is associated with the development of insulin resistance. We previously identified, via a gene expression-based genome-wide association study, the cell-surface immune cell receptor CD44 as a functionally important gene associated with type 2 diabetes. We then showed that, compared with controls, Cd44 knockout mice were protected from insulin resistance and adipose tissue inflammation during diet-induced obesity. We thus sought to test whether CD44 is associated with adipose tissue inflammation and insulin resistance in humans. METHODS Participants included 58 healthy, overweight/moderately obese white adults who met predetermined criteria for insulin resistance or insulin sensitivity based on the modified insulin-suppression test. Serum was collected from 43 participants to measure circulating concentrations of CD44. Subcutaneous adipose tissue was obtained from 17 participants to compare CD44, its ligand osteopontin (OPN, also known as SPP1) and pro-inflammatory gene expression. CD44 expression on adipose tissue macrophage (ATM) surfaces was determined by flow cytometry. RESULTS Serum CD44 concentrations were significantly increased in insulin-resistant (IR) participants. CD44 gene expression in subcutaneous adipose tissue was threefold higher in the IR subgroup. The expression of OPN, CD68 and IL6 was also significantly elevated in IR individuals. CD44 gene expression correlated significantly with CD68 and IL6 expression. CD44 density on ATMs was associated with proinflammatory M1 polarisation. CONCLUSIONS/INTERPRETATION CD44 and OPN in human adipose tissue are associated with localised inflammation and systemic insulin resistance. This receptor-ligand pair is worthy of further research as a potentially modifiable contributor to human insulin resistance and type 2 diabetes.
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Affiliation(s)
- Li Fen Liu
- Division of Endocrinology, Department of Medicine, Stanford University, 300 Pasteur Drive, Rm S025, Stanford, CA, 94305-5103, USA
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27
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Kodama K, Toda K, Morinaga S, Yamada S, Butte AJ. Anti-CD44 antibody treatment lowers hyperglycemia and improves insulin resistance, adipose inflammation, and hepatic steatosis in diet-induced obese mice. Diabetes 2015; 64:867-75. [PMID: 25294945 PMCID: PMC4392898 DOI: 10.2337/db14-0149] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Type 2 diabetes (T2D) is a metabolic disease affecting >370 million people worldwide. It is characterized by obesity-induced insulin resistance, and growing evidence has indicated that this causative link between obesity and insulin resistance is associated with visceral adipose tissue inflammation. However, using anti-inflammatory drugs to treat insulin resistance and T2D is not a common practice. We recently applied a bioinformatics methodology to open public data and found that CD44 plays a critical role in the development of adipose tissue inflammation and insulin resistance. In this report, we examined the role of CD44 in T2D by administering daily injections of anti-CD44 monoclonal antibody (mAb) in a high-fat-diet mouse model. Four weeks of therapy with CD44 mAb suppressed visceral adipose tissue inflammation compared with controls and reduced fasting blood glucose levels, weight gain, liver steatosis, and insulin resistance to levels comparable to or better than therapy with the drugs metformin and pioglitazone. These findings suggest that CD44 mAb may be useful as a prototype drug for therapy of T2D by breaking the links between obesity and insulin resistance.
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Affiliation(s)
- Keiichi Kodama
- Division of Systems Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA Lucile Packard Children's Hospital, Palo Alto, CA
| | - Kyoko Toda
- Division of Biomedical Research Center, Biomedical Laboratory, Kitasato Institute Hospital, Kitasato University, Minato-ku, Tokyo, Japan
| | - Shojiroh Morinaga
- Department of Diagnostic Pathology, Kitasato Institute Hospital, Kitasato University, Minato-ku, Tokyo, Japan
| | - Satoru Yamada
- Diabetes Center, Kitasato Institute Hospital, Kitasato University, Minato-ku, Tokyo, Japan
| | - Atul J Butte
- Division of Systems Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA Lucile Packard Children's Hospital, Palo Alto, CA
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28
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McDonald B, Kubes P. Interactions between CD44 and Hyaluronan in Leukocyte Trafficking. Front Immunol 2015; 6:68. [PMID: 25741341 PMCID: PMC4330908 DOI: 10.3389/fimmu.2015.00068] [Citation(s) in RCA: 81] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2014] [Accepted: 02/02/2015] [Indexed: 11/17/2022] Open
Abstract
Recruitment of leukocytes from the bloodstream to inflamed tissues requires a carefully regulated cascade of binding interactions between adhesion molecules on leukocytes and endothelial cells. Adhesive interactions between CD44 and hyaluronan (HA) have been implicated in the regulation of immune cell trafficking within various tissues. In this review, the biology of CD44–HA interactions in cell trafficking is summarized, with special attention to neutrophil recruitment within the liver microcirculation. We describe the molecular mechanisms that regulate adhesion between neutrophil CD44 and endothelial HA, including recent evidence implicating serum-derived hyaluronan-associated protein as an important co-factor in the binding of HA to CD44 under flow conditions. CD44–HA-mediated neutrophil recruitment has been shown to contribute to innate immune responses to invading microbes, as well as to the pathogenesis of many inflammatory diseases, including various liver pathologies. As a result, blockade of neutrophil recruitment by targeting CD44–HA interactions has proven beneficial as an anti-inflammatory treatment strategy in a number of animal models of inflammatory diseases.
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Affiliation(s)
- Braedon McDonald
- Department of Medicine, University of British Columbia , Vancouver, BC , Canada ; Snyder Institute for Chronic Diseases, University of Calgary , Calgary, AB , Canada
| | - Paul Kubes
- Snyder Institute for Chronic Diseases, University of Calgary , Calgary, AB , Canada
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29
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Marra F, Tacke F. Roles for chemokines in liver disease. Gastroenterology 2014; 147:577-594.e1. [PMID: 25066692 DOI: 10.1053/j.gastro.2014.06.043] [Citation(s) in RCA: 587] [Impact Index Per Article: 53.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2014] [Revised: 06/05/2014] [Accepted: 06/26/2014] [Indexed: 02/08/2023]
Abstract
Sustained hepatic inflammation is an important factor in progression of chronic liver diseases, including hepatitis C or non-alcoholic steatohepatitis. Liver inflammation is regulated by chemokines, which regulate the migration and activities of hepatocytes, Kupffer cells, hepatic stellate cells, endothelial cells, and circulating immune cells. However, the effects of the different chemokines and their receptors vary during pathogenesis of different liver diseases. During development of chronic viral hepatitis, CCL5 and CXCL10 regulate the cytopathic versus antiviral immune responses of T cells and natural killer cells. During development of nonalcoholic steatohepatitis, CCL2 and its receptor are up-regulated in the liver, where they promote macrophage accumulation, inflammation, fibrosis, and steatosis, as well as in adipose tissue. CCL2 signaling thereby links hepatic and systemic inflammation related to metabolic disorders and insulin resistance. Several chemokine signaling pathways also promote hepatic fibrosis. Recent studies have shown that other chemokines and immune cells have anti-inflammatory and antifibrotic activities. Chemokines and their receptors can also contribute to the pathogenesis of hepatocellular carcinoma, promoting proliferation of cancer cells, the inflammatory microenvironment of the tumor, evasion of the immune response, and angiogenesis. We review the roles of different chemokines in the pathogenesis of liver diseases and their potential use as biomarkers or therapeutic targets.
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Affiliation(s)
- Fabio Marra
- Dipartimento di Medicina Sperimentale e Clinica, University of Florence, Florence, Italy.
| | - Frank Tacke
- Department of Medicine III, RWTH University Hospital Aachen, Aachen, Germany.
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30
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McMillin M, Frampton G, Thompson M, Galindo C, Standeford H, Whittington E, Alpini G, DeMorrow S. Neuronal CCL2 is upregulated during hepatic encephalopathy and contributes to microglia activation and neurological decline. J Neuroinflammation 2014; 11:121. [PMID: 25012628 PMCID: PMC4128607 DOI: 10.1186/1742-2094-11-121] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2014] [Accepted: 06/30/2014] [Indexed: 12/31/2022] Open
Abstract
Background Acute liver failure leads to systemic complications with one of the most dangerous being a decline in neurological function, termed hepatic encephalopathy. Neurological dysfunction is exacerbated by an increase of toxic metabolites in the brain that lead to neuroinflammation. Following various liver diseases, hepatic and circulating chemokines, such as chemokine ligand 2 (CCL2), are elevated, though their effects on the brain following acute liver injury and subsequent hepatic encephalopathy are unknown. CCL2 is known to activate microglia in other neuropathies, leading to a proinflammatory response. However, the effects of CCL2 on microglia activation and the pathogenesis of hepatic encephalopathy following acute liver injury remain to be determined. Methods Hepatic encephalopathy was induced in mice via injection of azoxymethane (AOM) in the presence or absence of INCB 3284 dimesylate (INCB), a chemokine receptor 2 inhibitor, or C 021 dihydrochloride (C021), a chemokine receptor 4 inhibitor. Mice were monitored for neurological decline and time to coma (loss of all reflexes) was recorded. Tissue was collected at coma and used for real-time PCR, immunoblots, ELISA, or immunostaining analyses to assess the activation of microglia and consequences on pro-inflammatory cytokine expression. Results Following AOM administration, microglia activation was significantly increased in AOM-treated mice compared to controls. Concentrations of CCL2 in the liver, serum, and cortex were significantly elevated in AOM-treated mice compared to controls. Systemic administration of INCB or C021 reduced liver damage as assessed by serum liver enzyme biochemistry. Administration of INCB or C021 significantly improved the neurological outcomes of AOM-treated mice, reduced microglia activation, reduced phosphorylation of ERK1/2, and alleviated AOM-induced cytokine upregulation. Conclusions These findings suggest that CCL2 is elevated systemically following acute liver injury and that CCL2 is involved in both the microglia activation and neurological decline associated with hepatic encephalopathy. Methods used to modulate CCL2 levels and/or reduce CCR2/CCR4 activity may be potential therapeutic targets for the management of hepatic encephalopathy due to acute liver injury.
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Affiliation(s)
| | | | | | | | | | | | | | - Sharon DeMorrow
- Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, 1901 South 1st Street, Building 205, Temple, Texas, USA.
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