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Shu JZ, Huang YH, He XH, Liu FY, Liang QQ, Yong XT, Xie YF. Gut microbiota differences, metabolite changes, and disease intervention during metabolic - dysfunction - related fatty liver progression. World J Hepatol 2025; 17:103854. [PMID: 40177201 PMCID: PMC11959672 DOI: 10.4254/wjh.v17.i3.103854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 01/17/2025] [Accepted: 02/12/2025] [Indexed: 03/26/2025] Open
Abstract
In the current era, metabolic dysfunction-associated steatotic liver disease (MASLD) has gradually developed into a major type of chronic liver disease that is widespread globally. Numerous studies have shown that the gut microbiota plays a crucial and indispensable role in the progression of MASLD. Currently, the gut microbiota has become one of the important entry points for the research of this disease. Therefore, the aim of this review is to elaborate on the further associations between the gut microbiota and MASLD, including the changes and differences in the microbiota between the healthy liver and the diseased liver. Meanwhile, considering that metabolic dysfunction-associated fatty liver and metabolic dysfunction-associated steatohepatitis are abnormal pathological states in the development of the disease and that the liver exhibits different degrees of fibrosis (such as mild fibrosis and severe fibrosis) during the disease progression, we also conduct a comparison of the microbiota in these states and use them as markers of disease progression. It reveals the changes in the production and action mechanisms of short-chain fatty acids and bile acids brought about by changes in the gut microbiota, and the impact of lipopolysaccharide from Gram-negative bacteria on the disease. In addition, the regulation of the gut microbiota in disease and the production and inhibition of related disease factors by the use of probiotics (including new-generation probiotics) will be explored, which will help to monitor the disease progression of patients with different gut microbiota compositions in the future and carry out personalized targeted therapies for the gut microbiota. This will achieve important progress in preventing and combating this disease.
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Affiliation(s)
- Jian-Zhong Shu
- Department of Encephalopathy, Chongqing Hospital of Traditional Chinese Medicine, Chongqing 400015, China
- School of Life Health Information Science and Engineering, Chongqing University of Posts and Telecommunications, Chongqing 400065, China
- College of Integrated Traditional Chinese and Western Medicine, Chongqing University of Traditional Chinese Medicine, Chongqing 402760, China
| | - Yu-Han Huang
- School of Life Health Information Science and Engineering, Chongqing University of Posts and Telecommunications, Chongqing 400065, China
| | - Xiao-Hong He
- School of Life Health Information Science and Engineering, Chongqing University of Posts and Telecommunications, Chongqing 400065, China
| | - Feng-Ying Liu
- School of Life Health Information Science and Engineering, Chongqing University of Posts and Telecommunications, Chongqing 400065, China
| | - Qian-Qian Liang
- School of Life Health Information Science and Engineering, Chongqing University of Posts and Telecommunications, Chongqing 400065, China
| | - Xue-Tong Yong
- School of Life Health Information Science and Engineering, Chongqing University of Posts and Telecommunications, Chongqing 400065, China
| | - Yong-Fang Xie
- School of Life Health Information Science and Engineering, Chongqing University of Posts and Telecommunications, Chongqing 400065, China
- Institute of Bioinformatics, Chongqing University of Posts and Telecommunications, Chongqing 400065, China.
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Ciobârcă D, Cătoi AF, Gavrilaș L, Banc R, Miere D, Filip L. Natural Bioactive Compounds in the Management of Type 2 Diabetes and Metabolic (Dysfunction)-Associated Steatotic Liver Disease. Pharmaceuticals (Basel) 2025; 18:279. [PMID: 40006091 PMCID: PMC11859434 DOI: 10.3390/ph18020279] [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: 11/18/2024] [Revised: 02/11/2025] [Accepted: 02/13/2025] [Indexed: 02/27/2025] Open
Abstract
Type 2 diabetes (T2D) and metabolic (dysfunction)-associated steatotic liver disease (MASLD) affect a growing number of individuals worldwide. T2D and MASLD often coexist and substantially elevate the risk of adverse hepatic and cardiovascular clinical outcomes. Several common pathogenetic mechanisms are responsible for T2D and MASLD onset and progression, including insulin resistance, oxidative stress, and low-grade inflammation, among others. The latter can also be induced by gut microbiota and its derived metabolites. Natural bioactive compounds (NBCs) have been reported for their therapeutic potential in both T2D and MASLD. A large amount of evidence obtained from clinical trials suggests that compounds like berberine, curcumin, soluble fibers, and omega-3 fatty acids exhibit significant hypoglycemic, hypolipidemic, and hepatoprotective activity in humans and may be employed as adjunct therapy in T2D and MASLD management. In this review, the role of the most studied NBCs in the management of T2D and MASLD is discussed, emphasizing recent clinical evidence supporting these compounds' efficacy and safety. Also, prebiotics that act against metabolic dysfunction by modulating gut microbiota are evaluated.
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Affiliation(s)
- Daniela Ciobârcă
- Department 2, Faculty of Nursing and Health Sciences, “Iuliu Hatieganu” University of Medicine and Pharmacy, 23 Gheorghe Marinescu Street, 400337 Cluj-Napoca, Romania; (D.C.); (L.G.)
| | - Adriana Florinela Cătoi
- Department of Pathophysiology, Faculty of Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 2-4 Victor Babes Street, 400012 Cluj-Napoca, Romania
| | - Laura Gavrilaș
- Department 2, Faculty of Nursing and Health Sciences, “Iuliu Hatieganu” University of Medicine and Pharmacy, 23 Gheorghe Marinescu Street, 400337 Cluj-Napoca, Romania; (D.C.); (L.G.)
| | - Roxana Banc
- Department of Bromatology, Hygiene, Nutrition, Faculty of Pharmacy, “Iuliu Hatieganu” University of Medicine and Pharmacy, 6 Louis Pasteur Street, 400349 Cluj-Napoca, Romania; (R.B.); (D.M.); (L.F.)
| | - Doina Miere
- Department of Bromatology, Hygiene, Nutrition, Faculty of Pharmacy, “Iuliu Hatieganu” University of Medicine and Pharmacy, 6 Louis Pasteur Street, 400349 Cluj-Napoca, Romania; (R.B.); (D.M.); (L.F.)
| | - Lorena Filip
- Department of Bromatology, Hygiene, Nutrition, Faculty of Pharmacy, “Iuliu Hatieganu” University of Medicine and Pharmacy, 6 Louis Pasteur Street, 400349 Cluj-Napoca, Romania; (R.B.); (D.M.); (L.F.)
- Academy of Romanian Scientists (AOSR), 3 Ilfov Street, 050044 Bucharest, Romania
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Basumatary D, Das S, Bidyarani Devi M, Shalini Devi G, Sarma P, Mukherjee AK, Khan MR, Borah JC. Garcinol enriched fraction of Garcinia morella (Gaertn.) Desr. fruit rind improves gut health and reduces the risk of nonalcoholic fatty liver disease by regulating PCK1/ACC/SREBP1/FASn pathway in a mouse model. Food Res Int 2024; 197:115285. [PMID: 39577934 DOI: 10.1016/j.foodres.2024.115285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 10/07/2024] [Accepted: 10/31/2024] [Indexed: 11/24/2024]
Abstract
Nonalcoholic fatty liver disease (NAFLD), a fast-emerging global burden, is an umbrella term for several liver manifestations that result in excessive accumulation of fat in the liver. NAFLD leads to gut microbiome dysbiosis, loss in gut epithelia, increased gut permeability, etc. The limited availability of registered drugs for NAFLD highlights the urgent need to focus on understanding its pathogenesis and discovering new treatments, including the potential exploration of herbal therapies for managing the condition. In this study, we evaluated the bioactive potential of garcinol enriched fraction from Garcinia morella fruit rind in preventing NAFLD-associated increased gut permeability. Administration of garcinol-enriched fraction (GEF) significantly reduced body weight, serum lipids (triglyceride and total cholesterol) levels, and enzymes (alkaline phosphatase and aspartate aminotransferase) responsible for liver dysfunction in high-fat diet (HFD)-fed C57BL/6 mice. GEF treatment also regulated the alteration in signaling pathways of lipid metabolism in HFD-fed mice by inhibiting the overexpression of genes involved in de novo lipogenesis. Mice treated with GEF had increased gut microbial diversity, reduced pathogenic bacteria, and increased Lactococcus and Streptococcaceae genera. Additionally, GEF treatment could increase the expression of intestinal tight junction proteins, which were otherwise decreased in HFD-fed mice, stipulating its protective effect in maintaining gut barrier integrity. Our study demonstrated that GEF treatment reduces obesity in mice and improves gut health by keeping junctions tight and maintaining a healthy gut microbiome.
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Affiliation(s)
- Devi Basumatary
- Life Sciences Division, Institute of Advanced Study in Science and Technology (IASST), Vigyan Path, Paschim Boragaon, Guwahati 35, Assam, India; Department of Biotechnology, Gauhati University, Guwahati 781014, Assam, India
| | - Santanu Das
- Life Sciences Division, Institute of Advanced Study in Science and Technology (IASST), Vigyan Path, Paschim Boragaon, Guwahati 35, Assam, India
| | - M Bidyarani Devi
- Life Sciences Division, Institute of Advanced Study in Science and Technology (IASST), Vigyan Path, Paschim Boragaon, Guwahati 35, Assam, India; Department of Biotechnology, Gauhati University, Guwahati 781014, Assam, India
| | - G Shalini Devi
- Life Sciences Division, Institute of Advanced Study in Science and Technology (IASST), Vigyan Path, Paschim Boragaon, Guwahati 35, Assam, India; Department of Biotechnology, Gauhati University, Guwahati 781014, Assam, India
| | - Pranamika Sarma
- Life Sciences Division, Institute of Advanced Study in Science and Technology (IASST), Vigyan Path, Paschim Boragaon, Guwahati 35, Assam, India
| | - Ashis K Mukherjee
- Life Sciences Division, Institute of Advanced Study in Science and Technology (IASST), Vigyan Path, Paschim Boragaon, Guwahati 35, Assam, India; Academy of Science and Innovative Research (AcSIR), Ghaziabad, India
| | - Mojibur R Khan
- Life Sciences Division, Institute of Advanced Study in Science and Technology (IASST), Vigyan Path, Paschim Boragaon, Guwahati 35, Assam, India; Academy of Science and Innovative Research (AcSIR), Ghaziabad, India.
| | - Jagat C Borah
- Life Sciences Division, Institute of Advanced Study in Science and Technology (IASST), Vigyan Path, Paschim Boragaon, Guwahati 35, Assam, India; Academy of Science and Innovative Research (AcSIR), Ghaziabad, India; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Guwahati 781101, Assam, India.
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Nie P, Hu L, Feng X, Xu H. Gut Microbiota Disorders and Metabolic Syndrome: Tales of a Crosstalk Process. Nutr Rev 2024:nuae157. [PMID: 39504479 DOI: 10.1093/nutrit/nuae157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2024] Open
Abstract
The microbiota in humans consists of trillions of microorganisms that are involved in the regulation of the gastrointestinal tract and immune and metabolic homeostasis. The gut microbiota (GM) has a prominent impact on the pathogenesis of metabolic syndrome (MetS). This process is reciprocal, constituting a crosstalk process between the GM and MetS. In this review, GM directly or indirectly inducing MetS via the host-microbial metabolic axis has been systematically reviewed. Additionally, the specifically altered GM in MetS are detailed in this review. Moreover, short-chain fatty acids (SCFAs), as unique gut microbial metabolites, have a remarkable effect on MetS, and the role of SCFAs in MetS-related diseases is highlighted to supplement the gaps in this area. Finally, the existing therapeutics are outlined, and the superiority and shortcomings of different therapeutic approaches are discussed, in hopes that this review can contribute to the development of potential treatment strategies.
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Affiliation(s)
- Penghui Nie
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, China
| | - Liehai Hu
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, China
| | - Xiaoyan Feng
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, China
| | - Hengyi Xu
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, China
- International Institute of Food Innovation Co., Ltd, Nanchang University, Nanchang 330200, China
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Bergheim I, Moreno-Navarrete JM. The relevance of intestinal barrier dysfunction, antimicrobial proteins and bacterial endotoxin in metabolic dysfunction-associated steatotic liver disease. Eur J Clin Invest 2024; 54:e14224. [PMID: 38634717 DOI: 10.1111/eci.14224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 04/05/2024] [Accepted: 04/08/2024] [Indexed: 04/19/2024]
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of end-stage liver disease associated with increased mortality and cardiovascular disease. Obesity and diabetes are the most important risk factors of MASLD. It is well-established that obesity-associated insulin resistance leads to a situation of tissue lipotoxicity characterized by an accumulation of excess fat in non-fat tissues such as the liver, promoting the development of MASLD, and its progression into metabolic dysfunction-associated steatohepatitis. METHODS Here, we aimed to review the impact of disrupted intestinal permeability, antimicrobial proteins and bacterial endotoxin in the development and progression of MASLD. RESULTS AND CONCLUSION Recent studies demonstrated that obesity- and obesogenic diets-associated alterations of intestinal microbiota along with the disruption of intestinal barrier integrity, the alteration in antimicrobial proteins and, in consequence, an enhanced translocation of bacterial endotoxin into bloodstream might contribute to this pathological process through to impacting liver metabolism and inflammation.
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Affiliation(s)
- Ina Bergheim
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - José María Moreno-Navarrete
- Nutrition, Eumetabolism and Health Group, Institut d'Investigació Biomèdica de Girona (IDIBGI-CERCA), Girona, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
- Department of Medicine, Universitat de Girona, Girona, Spain
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Soppert J, Brandt EF, Heussen NM, Barzakova E, Blank LM, Kuepfer L, Hornef MW, Trebicka J, Jankowski J, Berres ML, Noels H. Blood Endotoxin Levels as Biomarker of Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 2023; 21:2746-2758. [PMID: 36470528 DOI: 10.1016/j.cgh.2022.11.030] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 11/19/2022] [Accepted: 11/22/2022] [Indexed: 01/02/2023]
Abstract
BACKGROUND & AIMS Growing evidence supports a role of gut-derived metabolites in nonalcoholic fatty liver disease (NAFLD), but the relation of endotoxin levels with gut permeability and NAFLD stage remains unclear. This systematic review with meta-analysis aims to provide further insights. METHODS PubMed, Embase, and Cochrane Library were searched for studies published until January 2022 assessing blood endotoxins in patients with NAFLD. Meta-analyses and univariate/multivariate meta-regression, as well as correlation analyses, were performed for endotoxin values and potential relationships to disease stage, age, sex, parameters of systemic inflammation, and metabolic syndrome, as well as liver function and histology. RESULTS Forty-three studies were included, of which 34 were used for meta-analyses. Blood endotoxin levels were higher in patients with simple steatosis vs liver-healthy controls (standardized mean difference, 0.86; 95% confidence interval, 0.62-1.11) as well as in patients with nonalcoholic steatohepatitis vs patients with nonalcoholic fatty liver/non-nonalcoholic steatohepatitis (standardized mean difference, 0.81; 95% confidence interval, 0.27-1.35; P = .0078). Consistently, higher endotoxin levels were observed in patients with more advanced histopathological gradings of liver steatosis and fibrosis. An increase of blood endotoxin levels was partially attributed to a body mass index rise in patients with NAFLD compared with controls. Nevertheless, significant increases of blood endotoxin levels in NAFLD retained after compensation for differences in body mass index, metabolic condition, or liver enzymes. Increases in blood endotoxin levels were associated with increases in C-reactive protein concentrations, and in most cases, paralleled a rise in markers for intestinal permeability. CONCLUSION Our results support blood endotoxin levels as relevant diagnostic biomarker for NAFLD, both for disease detection as well as staging during disease progression, and might serve as surrogate marker of enhanced intestinal permeability in NAFLD. Registration number in Prospero: CRD42022311166.
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Affiliation(s)
- Josefin Soppert
- Institute for Molecular Cardiovascular Research (IMCAR), University Hospital RWTH Aachen, Aachen, Germany; Department of Anesthesiology, University Hospital RWTH Aachen, Aachen, Germany
| | - Elisa Fabiana Brandt
- Department of Internal Medicine III, University Hospital of Aachen, Aachen, Germany
| | - Nicole Maria Heussen
- Department of Medical Statistics, RWTH Aachen University, Aachen, Germany; Center of Biostatistics and Epidemiology, Medical School, Sigmund Freud University, Vienna, Austria
| | - Emona Barzakova
- Department of Diagnostic and Interventional Radiology, University Hospital RWTH Aachen, Aachen, Germany
| | - Lars Mathias Blank
- Institute of Applied Microbiology - iAMB, Aachen Biology and Biotechnology - ABBt, RWTH Aachen University, Aachen, Germany
| | - Lars Kuepfer
- Institute for Systems Medicine, University Hospital RWTH Aachen, Aachen, Germany
| | | | - Jonel Trebicka
- Department of Internal Medicine B, University of Münster, Münster, Germany
| | - Joachim Jankowski
- Institute for Molecular Cardiovascular Research (IMCAR), University Hospital RWTH Aachen, Aachen, Germany; Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands
| | - Marie-Luise Berres
- Department of Internal Medicine III, University Hospital of Aachen, Aachen, Germany; Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), Site Aachen, Germany
| | - Heidi Noels
- Institute for Molecular Cardiovascular Research (IMCAR), University Hospital RWTH Aachen, Aachen, Germany; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands.
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Brown GC, Camacho M, Williams‐Gray CH. The Endotoxin Hypothesis of Parkinson's Disease. Mov Disord 2023; 38:1143-1155. [PMID: 37157885 PMCID: PMC10947365 DOI: 10.1002/mds.29432] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 04/14/2023] [Accepted: 04/19/2023] [Indexed: 05/10/2023] Open
Abstract
The endotoxin hypothesis of Parkinson's disease (PD) is the idea that lipopolysaccharide (LPS) endotoxins contribute to the pathogenesis of this disorder. LPS endotoxins are found in, and released from, the outer membrane of Gram-negative bacteria, for example in the gut. It is proposed that gut dysfunction in early PD leads to elevated LPS levels in the gut wall and blood, which promotes both α-synuclein aggregation in the enteric neurons and a peripheral inflammatory response. Communication to the brain via circulating LPS and cytokines in the blood and/or the gut-brain axis leads to neuroinflammation and spreading of α-synuclein pathology, exacerbating neurodegeneration in brainstem nuclei and loss of dopaminergic neurons in the substantia nigra, and manifesting in the clinical symptoms of PD. The evidence supporting this hypothesis includes: (1) gut dysfunction, permeability, and bacterial changes occur early in PD, (2) serum levels of LPS are increased in a proportion of PD patients, (3) LPS induces α-synuclein expression, aggregation, and neurotoxicity, (4) LPS causes activation of peripheral monocytes leading to inflammatory cytokine production, and (5) blood LPS causes brain inflammation and specific loss of midbrain dopaminergic neurons, mediated by microglia. If the hypothesis is correct, then treatment options might include: (1) changing the gut microbiome, (2) reducing gut permeability, (3) reducing circulating LPS levels, or (4) blocking the response of immune cells and microglia to LPS. However, the hypothesis has a number of limitations and requires further testing, in particular whether reducing LPS levels can reduce PD incidence, progression, or severity. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Guy C. Brown
- Department of BiochemistryUniversity of CambridgeCambridgeUK
| | - Marta Camacho
- Department of Clinical NeurosciencesUniversity of CambridgeCambridgeUK
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Cho YE, Kwon YS, Hwang S. Heterogeneous population of macrophages in the development of non-alcoholic fatty liver disease. LIVER RESEARCH 2023; 7:16-25. [PMID: 39959694 PMCID: PMC11791820 DOI: 10.1016/j.livres.2022.06.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 05/09/2022] [Accepted: 06/25/2022] [Indexed: 11/21/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is characterized by a spectrum of hepatic diseases, including fatty liver, non-alcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma. NAFLD is a hepatic manifestation of metabolic syndrome and has become the leading cause of liver transplantation, necessitating an in-depth understanding of its underlying pathogenic mechanisms and the identification of viable drug targets. Although fatty liver is benign and does not exert marked liver damage or inflammation, NAFLD progression involves inflammatory processes facilitated by immune cells. Macrophages and monocytes constitute the pool of innate immune cells that contribute to NAFLD development in association with other cell types, such as neutrophils, T cells, and natural killer cells. The concept that macrophages contribute to the inflammatory processes in NAFLD development has long been debated; however, the remarkable advances in experimental techniques have rapidly uncovered new subpopulations of macrophages and monocytes, whose functions need to be comprehensively elucidated. The current review focuses on the recent expansion of our knowledge of the heterogeneous population of macrophages crucially involved in NAFLD development. In addition, the present paper discusses ongoing efforts to target macrophages and inflammatory processes to develop optimal therapeutic agents against non-alcoholic steatohepatitis.
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Affiliation(s)
- Ye Eun Cho
- Department of Manufacturing Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, Republic of Korea
| | - Yong Seong Kwon
- Department of Manufacturing Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, Republic of Korea
| | - Seonghwan Hwang
- Department of Manufacturing Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, Republic of Korea
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Wiering L, Tacke F. Treating inflammation to combat non-alcoholic fatty liver disease. J Endocrinol 2023; 256:JOE-22-0194. [PMID: 36259984 DOI: 10.1530/joe-22-0194] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 10/19/2022] [Indexed: 11/05/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) with its more progressive form non-alcoholic steatohepatitis (NASH) has become the most common chronic liver disease, thereby representing a great burden for patients and healthcare systems. Specific pharmacological therapies for NAFLD are still missing. Inflammation is an important driver in the pathogenesis of NASH, and the mechanisms underlying inflammation in NAFLD represent possible therapeutic targets. In NASH, various intra- and extrahepatic triggers involved in the metabolic injury typically lead to the activation of different immune cells. This includes hepatic Kupffer cells, i.e. liver-resident macrophages, which can adopt an inflammatory phenotype and activate other immune cells by releasing inflammatory cytokines. As inflammation progresses, Kupffer cells are increasingly replaced by monocyte-derived macrophages with a distinct lipid-associated and scar-associated phenotype. Many other immune cells, including neutrophils, T lymphocytes - such as auto-aggressive cytotoxic as well as regulatory T cells - and innate lymphoid cells balance the progression and regression of inflammation and subsequent fibrosis. The detailed understanding of inflammatory cell subsets and their activation pathways prompted preclinical and clinical exploration of potential targets in NAFLD/NASH. These approaches to target inflammation in NASH include inhibition of immune cell recruitment via chemokine receptors (e.g. cenicriviroc), neutralization of CD44 or galectin-3 as well as agonism to nuclear factors like peroxisome proliferator-activated receptors and farnesoid X receptor that interfere with the activation of immune cells. As some of these approaches did not demonstrate convincing efficacy as monotherapies, a rational and personalized combination of therapeutic interventions may be needed for the near future.
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Affiliation(s)
- Leke Wiering
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Junior Clinician Scientist Program, Berlin, Germany
| | - Frank Tacke
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany
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Gudan A, Jamioł-Milc D, Hawryłkowicz V, Skonieczna-Żydecka K, Stachowska E. The Prevalence of Small Intestinal Bacterial Overgrowth in Patients with Non-Alcoholic Liver Diseases: NAFLD, NASH, Fibrosis, Cirrhosis-A Systematic Review, Meta-Analysis and Meta-Regression. Nutrients 2022; 14:nu14245261. [PMID: 36558421 PMCID: PMC9783356 DOI: 10.3390/nu14245261] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 11/27/2022] [Accepted: 11/30/2022] [Indexed: 12/14/2022] Open
Abstract
Bacterial overgrowth in the small intestine (SIBO) is a pathological growth of the intestinal microbiota in the small intestine that causes clinical symptoms and can lead to digestive and absorption disorders. There is increasing evidence that people with NAFLD have a distinct gut microflora profile as well metabolome changes compared to people without NAFLD. Thorough analysis of observational and RCT studies in the current databases (EMBASE, Web of Science, PubMed, Cinahl, Clinical Trials) was conducted from 3 November 2021 to 21 June 2022. The following inclusion criteria were applied: confirmed NAFLD, NASH, LIVER FIBROSIS, CIRRHOSIS due to steatosis; diagnostic methods of liver diseases—biopsy, elastography, transabdominal ultrasound; nonalcoholic fatty liver disease activity score; confirmed SIBO; diagnostic methods of SIBO−breath tests (hydrogen test; methane test and mix test; duodenal and jejunal aspiration before any type of intervention; adults above 18yo; number of participants ≥20; full articles. We excluded review articles, populations with HBV/HCV infection and alcohol etiology and interventions that may affect NAFLD or SIBO treatment. The quality of each study methodology was classified by means of the Cochrane Collaboration’s tool (RCT) and Newcastle—Ottawa Quality Assessment Scale adapted for cross-sectional, cohort and case-control studies. The random effects meta-analysis of outcomes for which ≥2 studies contributed data was conducted. The I2 index to measure heterogeneity and the χ2 test of homogeneity (statistically significant heterogeneity p < 0.05) were applied. For categorical outcome, the pooled event rate (effect size) was calculated. This systematic review was reported according to PRISMA reporting guidelines. We initially identified 6643 studies, from which 18 studies were included in final meta-analysis. The total number of patients was 1263. Accepted SIBO diagnostic methods were both available breath tests (n-total = 15) and aspirate culture (n-total = 3). We found that among patients with non-alcoholic liver diseases, the random overall event rate of SIBO was 0.350 (95% CI, 0.244−0.472), p = 0.017. The subgroup analysis regarding a type of diagnosis revealed that the lowest ER was among patients who developed simultaneously NAFLD, NASH and fibrosis: 0.197 (95% CI, 0.054−0.510) as compared to other annotated subgroups. The highest prevalence of SIBO was observed in the NASH subgroup: 0.411 (95% CI, 0.219−0.634). There were no statistically significant differences in the prevalence of SIBO in different subgroups (p = 0.854). Statistically significant heterogeneity between studies was estimated (I2 = 86.17%, p = 0.00). Egger’s test did not indicate a publication bias (df = 16, p = 0.885). A meta-regression using a random-effects model revealed that higher percentage of males in the population with liver diseases is a predisposing factor toward SIBO (Q = 4.11, df = 1, p = 0.0426 with coefficient = 0.0195, SE = 0.0096, Z = 2.03). We showed that the prevalence of SIBO in patients with chronic non-alcoholic liver diseases can be as high as 35%, and it increases with the percentage of men in the population. The prevalence of SIBO does not differ significantly depending on the type of chronic liver disease. Despite the high heterogeneity and moderate and low quality of included studies, our meta-analysis suggests the existence of a problem of SIBO in the population of patients with non-alcoholic liver diseases, and the presence of SIBO, in turn, determines the therapeutic treatment of such type of patients, which indicates the need for further research in this area. The study protocol was registered with the international Prospective Register of Systematic Reviews (PROSPERO ID: CRD42022341473).
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Affiliation(s)
- Anna Gudan
- Department of Human Nutrition and Metabolomics, Pomeranian Medical University in Szczecin, ul. Władysława Broniewskiego 24, 71-460 Szczecin, Poland
| | - Dominika Jamioł-Milc
- Department of Human Nutrition and Metabolomics, Pomeranian Medical University in Szczecin, ul. Władysława Broniewskiego 24, 71-460 Szczecin, Poland
- Correspondence: (D.J.-M.); (K.S.-Ż.); Tel.: +48-91-441-48-06 (D.J.-M. & K.S.-Ż.); Fax: +48-91-441-48-07 (D.J.-M. & K.S.-Ż.)
| | - Victoria Hawryłkowicz
- Department of Human Nutrition and Metabolomics, Pomeranian Medical University in Szczecin, ul. Władysława Broniewskiego 24, 71-460 Szczecin, Poland
| | - Karolina Skonieczna-Żydecka
- Department of Biochemical Sciences, Pomeranian Medical University in Szczecin, ul. Władysława Broniewskiego 24, 71-460 Szczecin, Poland
- Correspondence: (D.J.-M.); (K.S.-Ż.); Tel.: +48-91-441-48-06 (D.J.-M. & K.S.-Ż.); Fax: +48-91-441-48-07 (D.J.-M. & K.S.-Ż.)
| | - Ewa Stachowska
- Department of Human Nutrition and Metabolomics, Pomeranian Medical University in Szczecin, ul. Władysława Broniewskiego 24, 71-460 Szczecin, Poland
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Auguet T, Bertran L, Barrientos-Riosalido A, Fabregat B, Villar B, Aguilar C, Sabench F. Are Ingested or Inhaled Microplastics Involved in Nonalcoholic Fatty Liver Disease? INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:ijerph192013495. [PMID: 36294076 PMCID: PMC9602632 DOI: 10.3390/ijerph192013495] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 10/10/2022] [Accepted: 10/17/2022] [Indexed: 05/13/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has emerged as the predominant cause of chronic liver injury; however, the mechanisms underlying its progression have not been fully elucidated. Pathophysiological studies have stated that NAFLD is significantly influenced by dietary and environmental factors that could participate in the development of NAFLD through different mechanisms. Currently, "plastic pollution" is one of the most challenging environmental problems worldwide since several plastics have potential toxic or endocrine disputing properties. Specifically, the intake of microplastics (MPs) and nanoplastics (NPs) in water or diet and/or the inhalation from suspended particles is well established, and these particles have been found in human samples. Laboratory animals exposed to MPs develop inflammation, immunological responses, endocrine disruptions, and alterations in lipid and energy metabolism, among other disorders. MPs additives also demonstrated adverse reactions. There is evidence that MPs and their additives are potential "obesogens" and could participate in NAFLD pathogenesis by modifying gut microbiota composition or even worsen liver fibrosis. Although human exposure to MPs seems clear, their relationship with NAFLD requires further study, since its prevention could be a possible personalized therapeutic strategy. Adequate mitigation strategies worldwide, reducing environmental pollution and human exposure levels of MPs, could reduce the risk of NAFLD.
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Affiliation(s)
- Teresa Auguet
- Grup de Recerca GEMMAIR (AGAUR)—Medicina Aplicada (URV), Departament de Medicina i Cirurgia, Universitat Rovira i Virgili (URV), Institut d’Investigació Sanitària Pere Virgili (IISPV), 43007 Tarragona, Spain
- Servei Medicina Interna, Hospital Universitari de Tarragona Joan XXIII, Mallafré Guasch, 4, 43007 Tarragona, Spain
- Correspondence: ; Tel.: +34-977-29-58-33
| | - Laia Bertran
- Grup de Recerca GEMMAIR (AGAUR)—Medicina Aplicada (URV), Departament de Medicina i Cirurgia, Universitat Rovira i Virgili (URV), Institut d’Investigació Sanitària Pere Virgili (IISPV), 43007 Tarragona, Spain
| | - Andrea Barrientos-Riosalido
- Grup de Recerca GEMMAIR (AGAUR)—Medicina Aplicada (URV), Departament de Medicina i Cirurgia, Universitat Rovira i Virgili (URV), Institut d’Investigació Sanitària Pere Virgili (IISPV), 43007 Tarragona, Spain
| | - Blanca Fabregat
- Servei Medicina Interna, Hospital Universitari de Tarragona Joan XXIII, Mallafré Guasch, 4, 43007 Tarragona, Spain
| | - Beatriz Villar
- Servei Medicina Interna, Hospital Universitari de Tarragona Joan XXIII, Mallafré Guasch, 4, 43007 Tarragona, Spain
| | - Carmen Aguilar
- Grup de Recerca GEMMAIR (AGAUR)—Medicina Aplicada (URV), Departament de Medicina i Cirurgia, Universitat Rovira i Virgili (URV), Institut d’Investigació Sanitària Pere Virgili (IISPV), 43007 Tarragona, Spain
| | - Fàtima Sabench
- Grup de Recerca GEMMAIR (AGAUR)—Medicina Aplicada (URV), Departament de Medicina i Cirurgia, Universitat Rovira i Virgili (URV), Institut d’Investigació Sanitària Pere Virgili (IISPV), 43007 Tarragona, Spain
- Servei de Cirurgia, Hospital Sant Joan de Reus, Departament de Medicina i Cirurgia, URV, IISPV, Avinguda Doctor Josep Laporte, 2, 43204 Reus, Spain
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Latorre J, Díaz-Trelles R, Comas F, Gavaldà-Navarro A, Milbank E, Dragano N, Morón-Ros S, Mukthavaram R, Ortega F, Castells-Nobau A, Oliveras-Cañellas N, Ricart W, Karmali PP, Tachikawa K, Chivukula P, Villarroya F, López M, Giralt M, Fernández-Real JM, Moreno-Navarrete JM. Downregulation of hepatic lipopolysaccharide binding protein improves lipogenesis-induced liver lipid accumulation. MOLECULAR THERAPY - NUCLEIC ACIDS 2022; 29:599-613. [PMID: 36090751 PMCID: PMC9418749 DOI: 10.1016/j.omtn.2022.08.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 08/01/2022] [Indexed: 11/26/2022]
Abstract
Circulating lipopolysaccharide-binding protein (LBP) is increased in individuals with liver steatosis. We aimed to evaluate the possible impact of liver LBP downregulation using lipid nanoparticle-containing chemically modified LBP small interfering RNA (siRNA) (LNP-Lbp UNA-siRNA) on the development of fatty liver. Weekly LNP-Lbp UNA-siRNA was administered to mice fed a standard chow diet, a high-fat and high-sucrose diet, and a methionine- and choline-deficient diet (MCD). In mice fed a high-fat and high-sucrose diet, which displayed induced liver lipogenesis, LBP downregulation led to reduced liver lipid accumulation, lipogenesis (mainly stearoyl-coenzyme A desaturase 1 [Scd1]) and lipid peroxidation-associated oxidative stress markers. LNP-Lbp UNA-siRNA also resulted in significantly decreased blood glucose levels during an insulin tolerance test. In mice fed a standard chow diet or an MCD, in which liver lipogenesis was not induced or was inhibited (especially Scd1 mRNA), liver LBP downregulation did not impact on liver steatosis. The link between hepatocyte LBP and lipogenesis was further confirmed in palmitate-treated Hepa1-6 cells, in primary human hepatocytes, and in subjects with morbid obesity. Altogether, these data indicate that siRNA against liver Lbp mRNA constitutes a potential target therapy for obesity-associated fatty liver through the modulation of hepatic Scd1.
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Affiliation(s)
- Jessica Latorre
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), 17007 Girona, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 28029, Madrid, Spain
| | | | - Ferran Comas
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), 17007 Girona, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 28029, Madrid, Spain
| | - Aleix Gavaldà-Navarro
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 28029, Madrid, Spain
- Department of Biochemistry and Molecular Biomedicine, Faculty of Biology and Institute of Biomedicine (IBUB), University of Barcelona, CIBEROBN (CB06/03/025), 08028 Barcelona, Catalonia, Spain
| | - Edward Milbank
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 28029, Madrid, Spain
- NeurObesity Group, Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782 Santiago de Compostela, Spain
| | - Nathalia Dragano
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 28029, Madrid, Spain
- NeurObesity Group, Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782 Santiago de Compostela, Spain
| | - Samantha Morón-Ros
- Department of Biochemistry and Molecular Biomedicine, Faculty of Biology and Institute of Biomedicine (IBUB), University of Barcelona, CIBEROBN (CB06/03/025), 08028 Barcelona, Catalonia, Spain
| | | | - Francisco Ortega
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), 17007 Girona, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 28029, Madrid, Spain
| | - Anna Castells-Nobau
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), 17007 Girona, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 28029, Madrid, Spain
| | - Núria Oliveras-Cañellas
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), 17007 Girona, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 28029, Madrid, Spain
| | - Wifredo Ricart
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), 17007 Girona, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 28029, Madrid, Spain
| | | | | | | | - Francesc Villarroya
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 28029, Madrid, Spain
- Department of Biochemistry and Molecular Biomedicine, Faculty of Biology and Institute of Biomedicine (IBUB), University of Barcelona, CIBEROBN (CB06/03/025), 08028 Barcelona, Catalonia, Spain
| | - Miguel López
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 28029, Madrid, Spain
- NeurObesity Group, Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782 Santiago de Compostela, Spain
| | - Marta Giralt
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 28029, Madrid, Spain
- Department of Biochemistry and Molecular Biomedicine, Faculty of Biology and Institute of Biomedicine (IBUB), University of Barcelona, CIBEROBN (CB06/03/025), 08028 Barcelona, Catalonia, Spain
| | - José Manuel Fernández-Real
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), 17007 Girona, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 28029, Madrid, Spain
- Department of Medicine, University of Girona, 17003 Girona, Spain
| | - José María Moreno-Navarrete
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), 17007 Girona, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 28029, Madrid, Spain
- Corresponding author José María Moreno-Navarrete, PhD, Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), 17007 Girona, Spain.
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Sajeev A, Hegde M, Girisa S, Devanarayanan TN, Alqahtani MS, Abbas M, Sil SK, Sethi G, Chen JT, Kunnumakkara AB. Oroxylin A: A Promising Flavonoid for Prevention and Treatment of Chronic Diseases. Biomolecules 2022; 12:1185. [PMID: 36139025 PMCID: PMC9496116 DOI: 10.3390/biom12091185] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 08/10/2022] [Accepted: 08/16/2022] [Indexed: 11/16/2022] Open
Abstract
There have been magnificent advancements in the understanding of molecular mechanisms of chronic diseases over the past several years, but these diseases continue to be a considerable cause of death worldwide. Most of the approved medications available for the prevention and treatment of these diseases target only a single gene/protein/pathway and are known to cause severe side effects and are less effective than they are anticipated. Consequently, the development of finer therapeutics that outshine the existing ones is far-reaching. Natural compounds have enormous applications in curbing several disastrous and fatal diseases. Oroxylin A (OA) is a flavonoid obtained from the plants Oroxylum indicum, Scutellaria baicalensis, and S. lateriflora, which have distinctive pharmacological properties. OA modulates the important signaling pathways, including NF-κB, MAPK, ERK1/2, Wnt/β-catenin, PTEN/PI3K/Akt, and signaling molecules, such as TNF-α, TGF-β, MMPs, VEGF, interleukins, Bcl-2, caspases, HIF-1α, EMT proteins, Nrf-2, etc., which play a pivotal role in the molecular mechanism of chronic diseases. Overwhelming pieces of evidence expound on the anti-inflammatory, anti-bacterial, anti-viral, and anti-cancer potentials of this flavonoid, which makes it an engrossing compound for research. Numerous preclinical and clinical studies also displayed the promising potential of OA against cancer, cardiovascular diseases, inflammation, neurological disorders, rheumatoid arthritis, osteoarthritis, etc. Therefore, the current review focuses on delineating the role of OA in combating different chronic diseases and highlighting the intrinsic molecular mechanisms of its action.
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Affiliation(s)
- Anjana Sajeev
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Mangala Hegde
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Sosmitha Girisa
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Thulasidharan Nair Devanarayanan
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Mohammed S. Alqahtani
- Radiological Sciences Department, College of Applied Medical Sciences, King Khalid University, Abha 61421, Saudi Arabia
- BioImaging Unit, Space Research Center, Michael Atiyah Building, University of Leicester, Leicester LE1 7RH, UK
| | - Mohamed Abbas
- Electrical Engineering Department, College of Engineering, King Khalid University, Abha 61421, Saudi Arabia
- Electronics and Communications Department, College of Engineering, Delta University for Science and Technology, Gamasa 35712, Egypt
| | - Samir Kumar Sil
- Cell Physiology and Cancer Biology Laboratory, Department of Human Physiology, Tripura University, Suryamaninagar 799022, India
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
| | - Jen-Tsung Chen
- Department of Life Sciences, National University of Kaohsiung, Kaohsiung 811, Taiwan
| | - Ajaikumar B. Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
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Perng W, Friedman JE, Janssen RC, Glueck DH, Dabelea D. Endotoxin Biomarkers Are Associated With Adiposity and Cardiometabolic Risk Across 6 Years of Follow-up in Youth. J Clin Endocrinol Metab 2022; 107:e3018-e3028. [PMID: 35276001 PMCID: PMC9202713 DOI: 10.1210/clinem/dgac149] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Indexed: 11/19/2022]
Abstract
CONTEXT Metabolic endotoxemia may be a shared mechanism underlying childhood obesity and early-onset metabolic diseases (eg, type 2 diabetes, nonalcoholic fatty liver disease). OBJECTIVE Examine prospective associations of serum endotoxin biomarkers lipopolysaccharide (LPS) and its binding protein, LPS binding protein (LBP), and anti-endotoxin core immunoglobulin G (EndoCab IgG) with adiposity and cardiometabolic risk in youth. DESIGN/SETTING This prospective study included 393 youth in the Exploring Perinatal Outcomes Among Children cohort in Colorado. Participants were recruited from 2006 to 2009 at age 10 years (baseline) and followed for 6 years (follow-up). We examined associations of endotoxin biomarkers at baseline with adiposity [body mass index (BMI) z-score, visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), skinfolds, waist circumference] and cardiometabolic risk (insulin, glucose, adipokines, lipid profile, blood pressure) across both visits using mixed-effects regression, and with hepatic fat fraction (HFF) at follow-up using linear regression. RESULTS Higher LPS and LBP predicted greater adiposity across follow-up. Each 1-unit log-transformed LPS corresponded with 0.23 (95% CI 0.03, 0.43) units BMI z-score, 5.66 (95% CI 1.99, 9.33) mm3 VAT, 30.7 (95% CI 8.0, 53.3) mm3 SAT, and 8.26 (95% CI 4.13, 12.40) mm skinfold sum. EndoCab IgG was associated with VAT only [3.03 (95% CI 0.34, 5.71) mm3]. LPS was associated with higher insulin [1.93 (95% CI 0.08, 3.70) µU/mL] and leptin [2.28 (95% CI 0.66, 3.90) ng/mL] and an adverse lipid profile. No association was observed with HFF. Accounting for pubertal status and lifestyle behaviors did not change findings. However, adjustment for prepregnancy BMI and gestational diabetes attenuated most associations. CONCLUSIONS Serum endotoxin may be a marker of pathophysiological processes underlying development of childhood obesity and cardiometabolic conditions associated with exposure to fetal overnutrition.
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Affiliation(s)
- Wei Perng
- Correspondence: Wei Perng, University of Colorado Denver, Anschutz Medical Campus, 12474 E. 19th Ave, Room 208, Aurora, CO 80045, USA.
| | - Jacob E Friedman
- Harold Hamm Diabetes Center, The University of Oklahoma Health Sciences Center, School of Medicine, Oklahoma City, OK, USA
| | - Rachel C Janssen
- Harold Hamm Diabetes Center, The University of Oklahoma Health Sciences Center, School of Medicine, Oklahoma City, OK, USA
| | - Deborah H Glueck
- Lifecourse Epidemiology of Adiposity and Diabetes (LEAD) Center, University of Colorado Anschutz Medical Campus, Aurora CO, USA
- Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora CO, USA
| | - Dana Dabelea
- Lifecourse Epidemiology of Adiposity and Diabetes (LEAD) Center, University of Colorado Anschutz Medical Campus, Aurora CO, USA
- Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, CO, USA
- Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora CO, USA
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Non-alcoholic fatty liver disease: a multi-system disease influenced by ageing and sex, and affected by adipose tissue and intestinal function. Proc Nutr Soc 2022; 81:146-161. [DOI: 10.1017/s0029665121003815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
In recent years, a wealth of factors are associated with increased risk of developing non-alcoholic fatty liver disease (NAFLD) and NAFLD is now thought to increase the risk of multiple extra-hepatic diseases. The aim of this review is first to focus on the role of ageing and sex as key, poorly understood risk factors in the development and progression of NAFLD. Secondly, we aim to discuss the roles of white adipose tissue (WAT) and intestinal dysfunction, as producers of extra-hepatic factors known to further contribute to the pathogenesis of NAFLD. Finally, we aim to summarise the role of NAFLD as a multi-system disease affecting other organ systems beyond the liver. Both increased age and male sex increase the risk of NAFLD and this may be partly driven by alterations in the distribution and function of WAT. Similarly, changes in gut microbiota composition and intestinal function with ageing and chronic overnutrition are likely to contribute to the development of NAFLD both directly (i.e. by affecting hepatic function) and indirectly via exacerbating WAT dysfunction. Consequently, the presence of NAFLD significantly increases the risk of various extra-hepatic diseases including CVD, type 2 diabetes mellitus, chronic kidney disease and certain extra-hepatic cancers. Thus changes in WAT and intestinal function with ageing and chronic overnutrition contribute to the development of NAFLD – a multi-system disease that subsequently contributes to the development of other chronic cardiometabolic diseases.
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Song Q, Zhang X. The Role of Gut–Liver Axis in Gut Microbiome Dysbiosis Associated NAFLD and NAFLD-HCC. Biomedicines 2022; 10:biomedicines10030524. [PMID: 35327326 PMCID: PMC8945287 DOI: 10.3390/biomedicines10030524] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 02/18/2022] [Accepted: 02/21/2022] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is considered as one of the most prevalent chronic liver diseases worldwide due to the rapidly rising prevalence of obesity and metabolic syndrome. As a hepatic manifestation of metabolic disease, NAFLD begins with hepatic fat accumulation and progresses to hepatic inflammation, termed as non-alcoholic steatohepatitis (NASH), hepatic fibrosis/cirrhosis, and finally leading to NAFLD-related hepatocellular carcinoma (NAFLD-HCC). Accumulating evidence showed that the gut microbiome plays a vital role in the initiation and progression of NAFLD through the gut–liver axis. The gut–liver axis is the mutual communication between gut and liver comprising the portal circulation, bile duct, and systematic circulation. The gut microbiome dysbiosis contributes to NAFLD development by dysregulating the gut–liver axis, leading to increased intestinal permeability and unrestrained transfer of microbial metabolites into the liver. In this review, we systematically summarized the up-to-date information of gut microbiome dysbiosis and metabolomic changes along the stages of steatosis, NASH, fibrosis, and NAFLD-HCC. The components and functions of the gut–liver axis and its association with NAFLD were then discussed. In addition, we highlighted current knowledge of gut microbiome-based treatment strategies targeting the gut–liver axis for preventing NAFLD and its associated HCC.
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Affiliation(s)
- Qian Song
- Department of Medicine and Therapeutics, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong 999077, China;
- State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong 999077, China
| | - Xiang Zhang
- Department of Medicine and Therapeutics, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong 999077, China;
- State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong 999077, China
- Correspondence: ; Tel.: +852-3763-6102
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Kaushal K, Gupta V, Goswami P, Agarwal S, Sharma S, Das P, Yadav R, Anand A, Sonika U, Gunjan D, Saraya A. Acute Variceal Bleed in Cirrhosis is Associated With Reversible Changes in Tight Junction Protein Expression in the Intestine: A Proof-of-Concept Study. J Clin Exp Hepatol 2022; 12:89-100. [PMID: 35068789 PMCID: PMC8766542 DOI: 10.1016/j.jceh.2021.03.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 03/23/2021] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Tight junction proteins (TJPs) play an important role in gut-barrier dysfunction in cirrhosis and its complications such as acute variceal bleed (AVB). However, the dynamics of TJPs expression after AVB, its relation to bacterial translocation, and impact on clinical outcome is largely unknown. AIMS The aim of this study was to study the expression of TJPs in cirrhosis and assess its dynamic changes in AVB. In addition, the relation of TJP expression to endotoxemia and clinical outcomes was assessed. METHODS In this prospective pilot study, 17 patients of cirrhosis with AVB, 59 patients of cirrhosis without AVB (non-AVB cirrhosis), and 20 controls were assessed for claudin-2 and claudin-4 expression in the duodenal biopsy. In the AVB-cirrhosis group, additional biopsies were obtained after 3 weeks. Endotoxemia was assessed by measuring IgG anti-endotoxin antibody levels. Claudin expression was correlated with a 6-month survival. RESULTS Claudin-2 expression was downregulated in patients with AVB and non-AVB cirrhosis in villi (P < 0.001 and 0.013) and crypts (P < 0.001 and 0.012), respectively, compared with the controls. Claudin-4 expression was similar in villi (P = 0.079), but lower in crypts (P = 0.007) in patients with cirrhosis. Claudin-2 expression was upregulated on serial biopsies in both villi and crypts (P = 0.003 and 0.001, respectively) in AVB-cirrhosis with postbleed expression comparable with those with non-AVB cirrhosis. IgG anti-endotoxin antibody levels were elevated in cirrhosis with no correlation with claudin-2/4 expression. Claudin-2 expression independently predicted survival at 6 months. CONCLUSION Both claudin-2 and claudin-4 expression are downregulated in cirrhosis. AVB is associated with dynamic changes in TJPs expression. Gut-barrier dysfunction might predict outcomes independent of bacterial endotoxemia in cirrhosis.
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Key Words
- AVB, Acute Variceal Bleed
- DAB, 3,3′-Diaminobenzidine
- EBL, Endoscopic Band Ligation
- EGD, Esophagogastroduodenoscopy
- HRV, high-risk varices
- IHC, Immunohistochemistry
- NSBB, Non-selective Beta Blockers
- PAMP, Pathogen associated molecular patterns
- TJP, Tight Junction Protein
- TMB, 3, 3′, 5, 5′-tetramethylbenzidine
- acute variceal bleed
- claudin-2
- endotoxemia
- tight junction proteins
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Affiliation(s)
- Kanav Kaushal
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Vipin Gupta
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Pooja Goswami
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Samagra Agarwal
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Sanchit Sharma
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Prasenjit Das
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Rajni Yadav
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Abhinav Anand
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Ujjwal Sonika
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Deepak Gunjan
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Anoop Saraya
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, 110029, India,Address for correspondence: Anoop Saraya, Professor and Head, Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, 110029, India. Tel.: +91 9868397203.
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18
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Page MJ, Kell DB, Pretorius E. The Role of Lipopolysaccharide-Induced Cell Signalling in Chronic Inflammation. CHRONIC STRESS (THOUSAND OAKS, CALIF.) 2022; 6:24705470221076390. [PMID: 35155966 PMCID: PMC8829728 DOI: 10.1177/24705470221076390] [Citation(s) in RCA: 116] [Impact Index Per Article: 38.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Accepted: 01/11/2022] [Indexed: 12/20/2022]
Abstract
Lipopolysaccharide (LPS) is the main structural component of the outer membrane of most Gram-negative bacteria and has diverse immunostimulatory and procoagulant effects. Even though LPS is well described for its role in the pathology of sepsis, considerable evidence demonstrates that LPS-induced signalling and immune dysregulation are also relevant in the pathophysiology of many diseases, characteristically where endotoxaemia is less severe. These diseases are typically chronic and progressive in nature and span broad classifications, including neurodegenerative, metabolic, and cardiovascular diseases. This Review reappraises the mechanisms of LPS-induced signalling and emphasises the crucial contribution of LPS to the pathology of multiple chronic diseases, beyond conventional sepsis. This perspective asserts that new ways of approaching chronic diseases by targeting LPS-driven pathways may be of therapeutic benefit in a wide range of chronic inflammatory conditions.
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Affiliation(s)
| | - Douglas B Kell
- Stellenbosch University, Stellenbosch, South Africa.,Institute of Integrative Biology, University of Liverpool, Liverpool, UK.,The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Lyngby, Denmark
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19
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Kaushal K, Agarwal S, Sharma S, Goswami P, Singh N, Sachdev V, Poudel S, Das P, Yadav R, Kumar D, Pandey G, Gunjan D, Saraya A. Demonstration of Gut-Barrier Dysfunction in Early Stages of Non-alcoholic Fatty Liver Disease: A Proof-Of-Concept Study. J Clin Exp Hepatol 2022; 12:1102-1113. [PMID: 35814507 PMCID: PMC9257921 DOI: 10.1016/j.jceh.2022.01.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Accepted: 01/17/2022] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND/AIMS Gut-barrier dysfunction is well recognized in pathogenesis of both non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD). However, comparison of components of this dysfunction between the two etiologies remains unexplored especially in early stages of NAFLD. METHODS Components of gut-barrier dysfunction like alterations in intestinal permeability (IP) by lactulose mannitol ratio (LMR) in urine, systemic endotoxemia (IgG and IgM anti-endotoxin antibodies), systemic inflammation (serum tumor necrosis factor alpha [TNF-α] and interleukin-1 [IL-1] levels), tight junction (TJ) proteins expression in duodenal biopsy and stool microbiota composition using Oxford Nanopore MinION device were prospectively evaluated in patients with NAFLD (n = 34) with no cirrhosis, ALD (n = 28) and were compared with disease free controls (n = 20). RESULTS Patients with ALD had more advanced disease than those with NAFLD (median liver stiffness -NAFLD:7.1 kPa [5.9-8.9] vs. ALD:14.3 kPa [9.6-24], P < 0.001]. Median LMR was significantly higher in NAFLD and ALD group when compared to controls (NAFLD 0.054 [0.037-0.17] vs. controls 0.027 [0.021-0.045] (P = 0.001)) and ALD 0.043 [0.03-0.068] vs. controls 0.027 [0.021-0.045] (P = 0.019)]. Anti-endotoxin antibody titer (IgM) (MMU/mL) was lowest in NAFLD 72.9 [3.2-1089.5] compared to ALD 120.6 [20.1-728]) (P = 0.042) and controls 155.3 [23.8-442.9]) (P = 0.021). Median TNF-α (pg/mL) levels were elevated in patients with NAFLD (53.3 [24.5-115]) compared to controls (16.1 [10.8-33.3]) (P < 0.001) and ALD (12.3 [10.1-42.7]) (P < 0.001). Expression of zonulin-1 and claudin-3 in duodenal mucosa was lowest in NAFLD. On principal co-ordinate analysis (PCoA), the global bacterial composition was significantly different across the three groups (PERMANOVA test, P < 0.001). CONCLUSION While remaining activated in both etiologies, gut-barrier dysfunction abnormalities were more pronounced in NAFLD at early stages compared to ALD despite more advanced disease in the latter.
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Key Words
- ALD, alcoholic liver disease
- ALT, alanine transaminase
- AST, aspartate transaminase
- IL-1, interleukin-1
- IP, intestinal permeability
- KFT, kidney function test
- LFT, liver function test
- LMR, lactulose mannitol ratio
- NAFLD, non-alcoholic fatty liver disease
- TNF, tumor necrosis factor
- alcoholic liver disease
- endotoxemia
- intestinal permeability
- non-alcoholic fatty liver disease
- tight junction protein
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Affiliation(s)
- Kanav Kaushal
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, 110029 , India
| | - Samagra Agarwal
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, 110029 , India
| | - Sanchit Sharma
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, 110029 , India
| | - Pooja Goswami
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, 110029 , India
| | - Namrata Singh
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, 110029 , India
| | - Vikas Sachdev
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, 110029 , India
| | - Shekhar Poudel
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, 110029 , India
| | - Prasenjit Das
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Rajni Yadav
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Dinesh Kumar
- Centre of Biomedical Research, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, 226014, India
| | - Gaurav Pandey
- Department of Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, 226014, India
| | - Deepak Gunjan
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, 110029 , India
| | - Anoop Saraya
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, 110029 , India,Address for correspondence: Anoop Saraya, Professor and Head, Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, 110029 , India.
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20
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Liu B, Xiang L, Ji J, Liu W, Chen Y, Xia M, Liu Y, Liu W, Zhu P, Jin Y, Han Y, Lu J, Li X, Zheng M, Lu Y. Sparcl1 promotes nonalcoholic steatohepatitis progression in mice through upregulation of CCL2. J Clin Invest 2021; 131:144801. [PMID: 34651580 DOI: 10.1172/jci144801] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 08/31/2021] [Indexed: 12/14/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of chronic liver disease ranging from simple steatosis (NAFL) to nonalcoholic steatohepatitis (NASH). However, the molecular mechanisms of NASH progression remain incompletely understood. White adipose tissue (WAT) has emerged as an important endocrine organ and contributes not only to the initial stage of NAFLD, but also to its severity. In the current study, through transcriptomic analysis we identified increased expression of Sparcl1, a secreted glycoprotein, in the WAT from NASH mice. Plasma Sparcl1 levels were similarly elevated and positively correlated with hepatic pathological features in NASH patients. Functional studies showed that both chronic injection of recombinant Sparcl1 protein and overexpression of Sparcl1 exaggerated hepatic inflammation and liver injury in mice. In contrast, genetic ablation of Sparcl1, knockdown of Sparcl1 in WAT, and treatment with a Sparcl1-neutralizing antibody dramatically alleviated diet-induced NASH pathogenesis. Mechanistically, Sparcl1 promoted the expression of C-C motif chemokine ligand 2 (CCL2) in hepatocytes through binding to Toll-like receptor 4 (TLR4) and activation of the NF-κB/p65 signaling pathway. Genetically or pharmacologically blocking the CCL2/CCR2 pathway attenuated the hepatic inflammatory response evoked by Sparcl1. Thus, our results demonstrated an important role for Sparcl1 in NASH progression, suggesting a potential target for therapeutic intervention.
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Affiliation(s)
- Bin Liu
- Department of Endocrinology and Metabolism, Fudan Institute for Metabolic Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.,Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang, China
| | - Liping Xiang
- Department of Endocrinology and Metabolism, Fudan Institute for Metabolic Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jing Ji
- Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang, China
| | - Wei Liu
- Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang, China
| | - Ying Chen
- Department of Endocrinology and Metabolism, Fudan Institute for Metabolic Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Mingfeng Xia
- Department of Endocrinology and Metabolism, Fudan Institute for Metabolic Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yuejun Liu
- Department of Endocrinology and Metabolism, Fudan Institute for Metabolic Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
| | | | | | | | - Yu Han
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Jieli Lu
- Shanghai National Clinical Research Center for Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaoying Li
- Department of Endocrinology and Metabolism, Fudan Institute for Metabolic Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Minghua Zheng
- MAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.,Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease of Zhejiang Province, Wenzhou, China
| | - Yan Lu
- Department of Endocrinology and Metabolism, Fudan Institute for Metabolic Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
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21
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Huang W, Kong D. The intestinal microbiota as a therapeutic target in the treatment of NAFLD and ALD. Biomed Pharmacother 2021; 135:111235. [DOI: 10.1016/j.biopha.2021.111235] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 12/27/2020] [Accepted: 12/31/2020] [Indexed: 02/08/2023] Open
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22
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Kimura T, Singh S, Tanaka N, Umemura T. Role of G Protein-Coupled Receptors in Hepatic Stellate Cells and Approaches to Anti-Fibrotic Treatment of Non-Alcoholic Fatty Liver Disease. Front Endocrinol (Lausanne) 2021; 12:773432. [PMID: 34938271 PMCID: PMC8685252 DOI: 10.3389/fendo.2021.773432] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 11/15/2021] [Indexed: 12/12/2022] Open
Abstract
The prevalence of non-alcoholic fatty liver disease (NAFLD) is globally increasing. Gaining control over disease-related events in non-alcoholic steatohepatitis (NASH), an advanced form of NAFLD, is currently an unmet medical need. Hepatic fibrosis is a critical prognostic factor in NAFLD/NASH. Therefore, a better understanding of the pathophysiology of hepatic fibrosis and the development of related therapies are of great importance. G protein-coupled receptors (GPCRs) are cell surface receptors that mediate the function of a great variety of extracellular ligands. GPCRs represent major drug targets, as indicated by the fact that about 40% of all drugs currently used in clinical practice mediate their therapeutic effects by acting on GPCRs. Like many other organs, various GPCRs play a role in regulating liver function. It is predicted that more than 50 GPCRs are expressed in the liver. However, our knowledge of how GPCRs regulate liver metabolism and fibrosis in the different cell types of the liver is very limited. In particular, a better understanding of the role of GPCRs in hepatic stellate cells (HSCs), the primary cells that regulate liver fibrosis, may lead to the development of drugs that can improve hepatic fibrosis in NAFLD/NASH. In this review, we describe the functions of multiple GPCRs expressed in HSCs, their roles in liver fibrogenesis, and finally speculate on the development of novel treatments for NAFLD/NASH.
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Affiliation(s)
- Takefumi Kimura
- Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
- *Correspondence: Takefumi Kimura, ; ; Naoki Tanaka,
| | - Simran Singh
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur, India
| | - Naoki Tanaka
- International Relations Office, Shinshu University School of Medicine, Matsumoto, Japan
- *Correspondence: Takefumi Kimura, ; ; Naoki Tanaka,
| | - Takeji Umemura
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
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23
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Hwang S, Yun H, Moon S, Cho YE, Gao B. Role of Neutrophils in the Pathogenesis of Nonalcoholic Steatohepatitis. Front Endocrinol (Lausanne) 2021; 12:751802. [PMID: 34707573 PMCID: PMC8542869 DOI: 10.3389/fendo.2021.751802] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 09/23/2021] [Indexed: 12/18/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) includes a spectrum of liver disorders, from fatty liver to nonalcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma. Compared with fatty liver, NASH is characterized by increased liver injury and inflammation, in which liver-infiltrating immune cells, with neutrophil infiltration as a hallmark of NASH, play a critical role in promoting the progression of fatty liver to NASH. Neutrophils are the first responders to injury and infection in various tissues, establishing the first line of defense through multiple mechanisms such as phagocytosis, cytokine secretion, reactive oxygen species production, and neutrophil extracellular trap formation; however, their roles in the pathogenesis of NASH remain obscure. The current review summarizes the roles of neutrophils that facilitate the progression of fatty liver to NASH and their involvement in inflammation resolution during NASH pathogenesis. The notion that neutrophils are potential therapeutic targets for the treatment of NASH is also discussed.
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Affiliation(s)
- Seonghwan Hwang
- College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, South Korea
| | - Hwayoung Yun
- College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, South Korea
| | - Sungwon Moon
- College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, South Korea
| | - Ye Eun Cho
- College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, South Korea
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, United States
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24
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Coussa A, Hasan HA, Barber TM. Early Predictors of Gestational Diabetes Mellitus in IVF-Conceived Pregnancies. Endocr Pract 2020; 27:579-585. [PMID: 34120700 DOI: 10.1016/j.eprac.2020.10.020] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 09/27/2020] [Accepted: 10/22/2020] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Gestational diabetes mellitus (GDM) is associated with adverse maternal and fetal outcomes. This study aimed to identify early and reliable GDM predictors that would enable implementation of preventive and management measures. METHODS The participants were a 28-week prospective cohort of in vitro fertilization (IVF)-conceived pregnant women (≤39 years, body mass index [BMI] 18.5-38 kg/m2) without a known history of diabetes mellitus. Fasting blood samples were analyzed at baseline (pre-IVF) and 12 weeks' gestation for reproductive hormones, glucose, serum insulin, lipids, thyroid function, adiponectin, and lipopolysaccharide-binding protein. At 28 weeks, a 75-g oral glucose tolerance test was used to screen for GDM. RESULTS For the overall group at baseline, 22% had BMI ≥30 kg/m2, 45% had polycystic ovary syndrome, 16% had hemoglobin A1C of 5.7% to 6.1%, and 14% had a past history of GDM. At 28 weeks of gestation (n = 158), 34 women had developed GDM and 124 had not. Significant baseline predictors of GDM onset included greater BMI (29.0 vs 25.8 kg/m2), older age (34 vs 32 years), higher levels of follicle-stimulating hormone/luteinizing hormone ratio (1.2 vs 1.0), hemoglobin A1C (5.5 vs 5.2%), insulin (10.6 vs 7.1 μIU/mL), homeostatic model assessment of insulin resistance (2.2 vs 1.7), total cholesterol (199 vs 171 mg/dL), and low-density lipoprotein cholesterol (123 vs 105 mg/dL), and lower triglyceride levels (74 vs 76 mg/dL). Significant 12-week GDM predictors included greater maternal weight gain (delta: 3.4 vs 1.5 kg) and higher levels of insulin (11.3 vs 7.6 μIU/mL), triglycerides (178 vs 120 mg/dL), and homeostatic model assessment of insulin resistance (2.3 vs 1.5). Twelve-week BMI is a predictor of GDM following adjustment for polycystic ovary syndrome status and maternal age. CONCLUSION While preconception maternal BMI, age, and follicle-stimulating hormone/luteinizing hormone ratio are predictors of subsequent development of GDM, early IVF-conceived gestational weight gain is the best predictor of GDM onset.
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Affiliation(s)
- Ayla Coussa
- Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Clinical Sciences Research Laboratories, University Hospitals Coventry and Warwickshire, Clifford Bridge Road, Coventry, CV2 2DX, United Kingdom.
| | - Hayder A Hasan
- Department of Clinical Nutrition and Dietetics, University of Sharjah, City University, Muwailih, Sharjah, PO Box 27272, United Arab Emirates
| | - Thomas M Barber
- Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Clinical Sciences Research Laboratories, University Hospitals Coventry and Warwickshire, Clifford Bridge Road, Coventry, CV2 2DX, United Kingdom
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25
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He Q, Zeng J, Yao K, Wang W, Wu Q, Tang R, Xia X, Zou X. Long-term subcutaneous injection of lipopolysaccharides and high-fat diet induced non-alcoholic fatty liver disease through IKKε/ NF-κB signaling. Biochem Biophys Res Commun 2020; 532:362-369. [PMID: 32883523 DOI: 10.1016/j.bbrc.2020.08.036] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 08/12/2020] [Indexed: 12/25/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) was associated with increased level of lipopolysaccharides (LPS) which mechanism remained unclear on intervention between LPS and NAFLD. The aim was to explore the IKKε/NF-κB role and its intervention of LPS and high-fat diet (HFD) induced NAFLD. Male C57BL/6 mice were fed on high-fat diet (HFD) combined with or without simultaneously subcutaneous injection of LPS for 18 weeks. Body weight , blood biochemistry parameters, inflammatory mediator and liver lipid deposition were measured to evaluate LPS effect on NAFLD. Furthermore, IKKε selective inhibitor amlexanox (AM) was administrated by gavage to HFD + LPS induced mice. The indicators about metabolism and inflammation were examined and qRT-PCR, immunoblotting assay as well as immunohistochemistry were performed to assess IKKε/NF-κB activation and downstream gene expression. This study found that low-dose LPS + HFD aggravated more significant steatosis than simple HFD or high-dose LPS + HFD. Low-dose LPS exacerbated more prominent inflammation profile including increased IKKε and NF-κB expression in liver than HFD. Inhibiting IKKε/NF-κB signaling with amlexanox significantly prevented HFD + LPS induced metabolic disorders and hepatic steatosis. LPS-upregulated gene expression involved in glucolipid metabolism could be downregulated by amlexanox. Thus, the present study confirmed long-term combinational administration of subcutaneous low-dose LPS injection and HFD induced NAFLD model which had more significant phenotype in mice than simple HFD or high-dose LPS-induction. Targeting on IKKε/NF-κB signaling with its inhibitor amlexanox alleviated steatohepatitis, suggesting that IKKε/NF-κB signaling was responsible for effect of LPS and HFD on NAFLD.
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Affiliation(s)
- Qian He
- Department of Geriatrics, The People's Hospital of China Three Gorges University/the First People's Hospital of Yichang, Yichang, 443000, Hubei Province, China
| | - Jun Zeng
- Department of Endocrinology, The People's Hospital of China Three Gorges University/the First People's Hospital of Yichang, Yichang, 443000, Hubei Province, China
| | - Kecheng Yao
- Department of Geriatrics, The People's Hospital of China Three Gorges University/the First People's Hospital of Yichang, Yichang, 443000, Hubei Province, China
| | - Wei Wang
- Department of Endocrinology, The People's Hospital of China Three Gorges University/the First People's Hospital of Yichang, Yichang, 443000, Hubei Province, China
| | - Qiong Wu
- Department of Pediatrics, The People's Hospital of China Three Gorges University/the First People's Hospital of Yichang, Yichang, 443000, Hubei Province, China
| | - Renmin Tang
- Department of Endocrinology, The People's Hospital of China Three Gorges University/the First People's Hospital of Yichang, Yichang, 443000, Hubei Province, China
| | - Xuan Xia
- Department of Physiology and Pathophysiology, College of Medical Sciences, China Three Gorges University, Yichang, 443002, Hubei Province, China; Third-Grade Pharmacological Laboratory on Chinese Medicine Approved By State Administration of Traditional Chinese Medicine, Medical College of China Three Gorges University, Yichang, 443002, Hubei Province, China.
| | - Xiulan Zou
- Department of Geriatrics, The People's Hospital of China Three Gorges University/the First People's Hospital of Yichang, Yichang, 443000, Hubei Province, China; Healthcare Center, The People's Hospital of China Three Gorges University/the First People's Hospital of Yichang, Yichang, 443000, Hubei Province, China.
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26
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Carpino G, Del Ben M, Pastori D, Carnevale R, Baratta F, Overi D, Francis H, Cardinale V, Onori P, Safarikia S, Cammisotto V, Alvaro D, Svegliati-Baroni G, Angelico F, Gaudio E, Violi F. Increased Liver Localization of Lipopolysaccharides in Human and Experimental NAFLD. Hepatology 2020; 72:470-485. [PMID: 31808577 DOI: 10.1002/hep.31056] [Citation(s) in RCA: 247] [Impact Index Per Article: 49.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Accepted: 11/13/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Lipopolysaccharides (LPS) is increased in nonalcoholic fatty liver disease (NAFLD), but its relationship with liver inflammation is not defined. APPROACH AND RESULTS We studied Escherichia coli LPS in patients with biopsy-proven NAFLD, 25 simple steatosis (nonalcoholic fatty liver) and 25 nonalcoholic steatohepatitis (NASH), and in mice with diet-induced NASH. NASH patients had higher serum LPS and hepatocytes LPS localization than controls, which was correlated with serum zonulin and phosphorylated nuclear factor-κB expression. Toll-like receptor 4 positive (TLR4+ ) macrophages were higher in NASH than simple steatosis or controls and correlated with serum LPS. NASH biopsies showed a higher CD61+ platelets, and most of them were TLR4+ . TLR4+ platelets correlated with serum LPS values. In mice with NASH, LPS serum levels and LPS hepatocyte localization were increased compared with control mice and associated with nuclear factor-κB activation. Mice on aspirin developed lower fibrosis and extent compared with untreated ones. Treatment with TLR4 inhibitor resulted in lower liver inflammation in mice with NASH. CONCLUSIONS In NAFLD, Escherichia coli LPS may increase liver damage by inducing macrophage and platelet activation through the TLR4 pathway.
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Affiliation(s)
- Guido Carpino
- Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome "Foro Italico,", Rome, Italy
| | - Maria Del Ben
- Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
| | - Daniele Pastori
- Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
| | - Roberto Carnevale
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy.,Mediterranea Cardiocentro, Naples, Italy
| | - Francesco Baratta
- Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
| | - Diletta Overi
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Heather Francis
- Indiana Center for Liver Research, Richard L. Roudebush VA Medical Center and Indiana University, Indianapolis, IN
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
| | - Paolo Onori
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Samira Safarikia
- Department of Precision and Translational Medicine, Sapienza University of Rome, Rome, Italy
| | - Vittoria Cammisotto
- Department of General Surgery and Surgical Specialty Paride Stefanini, Sapienza University of Rome, Rome, Italy
| | - Domenico Alvaro
- Department of Precision and Translational Medicine, Sapienza University of Rome, Rome, Italy
| | | | - Francesco Angelico
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Francesco Violi
- Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy.,Mediterranea Cardiocentro, Naples, Italy
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Abstract
Nonalcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of the metabolic syndrome (MetS) and comprises one of the largest health threats of the twenty-first century. In this chapter, we review the current state of knowledge of NAFLD and underline the striking similarities with atherosclerosis. We first describe current epidemiological data showing the staggering increase of NAFLD numbers and its related clinical and economic costs. We then provide an overview of pathophysiological hepatic processes in NAFLD and highlight the systemic aspects of NAFLD that point toward metabolic crosstalk between organs as an important cause of metabolic disease. Finally, we end by highlighting the currently investigated therapeutic approaches for NAFLD, which also show strong similarities with a range of treatment options for atherosclerosis.
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28
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Kaliora AC, Gioxari A, Kalafati IP, Diolintzi A, Kokkinos A, Dedoussis GV. The Effectiveness of Mediterranean Diet in Nonalcoholic Fatty Liver Disease Clinical Course: An Intervention Study. J Med Food 2019; 22:729-740. [PMID: 31290733 DOI: 10.1089/jmf.2018.0020] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Diet is a modifiable key factor targeted in prevention and management of nonalcoholic fatty liver disease (NAFLD). The aim was to study the effect of Mediterranean Diet (MedDiet) on clinical, biochemical, and inflammatory profile in NAFLD patients with simple steatosis. Potential associations of signal transducer and activator of transcription 3 (STAT3) rs2293152 genotype to diet composition and patients' profile were investigated. In this nonrandomized, open-label, 24-week prospective intervention study, 44 untreated NAFLD patients with nonsignificant fibrosis received nutritional counsel to increase adherence to MedDiet. Adherence to MedDiet was estimated with MedDietScore. Furthermore, we genotyped STAT3 rs2293152 single nucleotide polymorphism and performed clinical and inflammatory measurements. In all patients, MedDietScore increased and anthropometric indices improved, whereas liver imaging, liver fibrosis score, blood pressure, fasting glucose, glycated hemoglobin (HbA1c), C-reactive protein (CRP), visfatin, and oxidized low-density lipoprotein levels were also significantly ameliorated compared with baseline (P < .05). No association of STAT3 polymorphism with diet composition was found. Comparisons of mean differences between G- and C-carriers at the end point of the trial showed that only visfatin was significantly associated with the STAT3 genotype (-0.0 ± 4.6 vs. -4.2 ± 3.9, P = .04, respectively). Carrying the G-allele was associated with an increase of the visfatin levels (3.4 ± 1.5 ng/mL, P = .028). Our results show amelioration of clinical, biochemical, and inflammatory biomarkers in NAFLD patients in response to MedDiet. STAT3 rs2293152 G-carriers experienced more beneficial changes at the end of the intervention compared with baseline. An association between visfatin levels and STAT3 genotype has been shown for the first time.
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Affiliation(s)
- Andriana C Kaliora
- 1 Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece
| | - Aristea Gioxari
- 2 First Department of Propaedeutic and Internal Medicine, Laiko General Hospital, Athens University Medical School, Athens, Greece
| | - Ioanna Panagiota Kalafati
- 1 Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece
| | - Anastasia Diolintzi
- 1 Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece
| | - Alexandros Kokkinos
- 2 First Department of Propaedeutic and Internal Medicine, Laiko General Hospital, Athens University Medical School, Athens, Greece
| | - George V Dedoussis
- 1 Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece
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29
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Kostrzewski T, Maraver P, Ouro-Gnao L, Levi A, Snow S, Miedzik A, Rombouts K, Hughes D. A Microphysiological System for Studying Nonalcoholic Steatohepatitis. Hepatol Commun 2019; 4:77-91. [PMID: 31909357 PMCID: PMC6939502 DOI: 10.1002/hep4.1450] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Accepted: 10/25/2019] [Indexed: 12/14/2022] Open
Abstract
Nonalcoholic steatohepatitis (NASH) is the most severe form of nonalcoholic fatty liver disease (NAFLD), which to date has no approved drug treatments. There is an urgent need for better understanding of the genetic and molecular pathways that underlie NAFLD/NASH, and currently available preclinical models, be they in vivo or in vitro, do not fully represent key aspects of the human disease state. We have developed a human in vitro co‐culture NASH model using primary human hepatocytes, Kupffer cells and hepatic stellate cells, which are cultured together as microtissues in a perfused three‐dimensional microphysiological system (MPS). The microtissues were cultured in medium containing free fatty acids for at least 2 weeks, to induce a NASH‐like phenotype. The co‐culture microtissues within the MPS display a NASH‐like phenotype, showing key features of the disease including hepatic fat accumulation, the production of an inflammatory milieu, and the expression of profibrotic markers. Addition of lipopolysaccharide resulted in a more pro‐inflammatory milieu. In the model, obeticholic acid ameliorated the NASH phenotype. Microtissues were formed from both wild‐type and patatin‐like phospholipase domain containing 3 (PNPLA3) I148M mutant hepatic stellate cells. Stellate cells carrying the mutation enhanced the overall disease state of the model and in particular produced a more pro‐inflammatory milieu. Conclusion: The MPS model displays a phenotype akin to advanced NAFLD or NASH and has utility as a tool for exploring mechanisms underlying the disease. Furthermore, we demonstrate that in co‐culture the PNPLA3 I148M mutation alone can cause hepatic stellate cells to enhance the overall NASH disease phenotype.
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Affiliation(s)
| | - Paloma Maraver
- CN Bio Innovations Ltd. Welwyn Garden City Hertfordshire United Kingdom
| | - Larissa Ouro-Gnao
- CN Bio Innovations Ltd. Welwyn Garden City Hertfordshire United Kingdom
| | - Ana Levi
- Institute for Liver and Digestive Health, Regenerative Medicine and Fibrosis Group, Royal Free University College London United Kingdom
| | - Sophie Snow
- CN Bio Innovations Ltd. Welwyn Garden City Hertfordshire United Kingdom
| | - Alina Miedzik
- CN Bio Innovations Ltd. Welwyn Garden City Hertfordshire United Kingdom
| | - Krista Rombouts
- Institute for Liver and Digestive Health, Regenerative Medicine and Fibrosis Group, Royal Free University College London United Kingdom
| | - David Hughes
- CN Bio Innovations Ltd. Welwyn Garden City Hertfordshire United Kingdom
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30
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Dornas W, Lagente V. Intestinally derived bacterial products stimulate development of nonalcoholic steatohepatitis. Pharmacol Res 2019; 141:418-428. [PMID: 30658094 DOI: 10.1016/j.phrs.2019.01.026] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Revised: 01/12/2019] [Accepted: 01/14/2019] [Indexed: 02/08/2023]
Abstract
Fatty livers are susceptible to factors that cause inflammation and fibrosis, but fat deposition and the inflammatory response can be dissociated. While nonalcoholic fatty liver disease (NAFLD), caused by pathologic fat accumulation inside the liver, can remain stable for several years, in other cases NAFLD progresses to nonalcoholic steatohepatitis (NASH), which is characterized by fat accumulation and inflammation and is not a benign condition. In this review, we discuss the NASH host cells and microbial mechanisms that stimulate inflammation and predispose the liver to hepatocyte injury and fibrotic stages via increased lipid deposition. We highlight the interactions between intestine-derived bacterial products, such as lipopolysaccharide, and nutritional models of NAFLD and/or obese individuals. The results of modulating enteric microbiota suggest that gut-derived endotoxins may be essential determinants of fibrotic progression and regression in NASH.
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Affiliation(s)
- Waleska Dornas
- NuMeCan Institute (Nutrition, Metabolism and Cancer), Université de Rennes, INSERM, INRA, F-35000 Rennes, France.
| | - Vincent Lagente
- NuMeCan Institute (Nutrition, Metabolism and Cancer), Université de Rennes, INSERM, INRA, F-35000 Rennes, France.
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31
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Tanaka N, Kimura T, Fujimori N, Nagaya T, Komatsu M, Tanaka E. Current status, problems, and perspectives of non-alcoholic fatty liver disease research. World J Gastroenterol 2019; 25:163-177. [PMID: 30670907 PMCID: PMC6337019 DOI: 10.3748/wjg.v25.i2.163] [Citation(s) in RCA: 100] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Revised: 12/24/2018] [Accepted: 12/27/2018] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a major chronic liver disease that can lead to liver cirrhosis, liver cancer, and ultimately death. NAFLD is pathologically classified as non-alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH) based on the existence of ballooned hepatocytes, although the states have been known to transform into each other. Moreover, since the detection of ballooned hepatocytes may be difficult with limited biopsied specimens, its clinical significance needs reconsideration. Repeated liver biopsy to assess histological NAFLD activity for therapeutic response is also impractical, creating the need for body fluid biomarkers and less invasive imaging modalities. Recent longitudinal observational studies have emphasized the importance of advanced fibrosis as a determinant of NAFLD outcome. Thus, identifying predictors of fibrosis progression and developing better screening methods will enable clinicians to isolate high-risk NAFLD patients requiring early intensive intervention. Despite the considerable heterogeneity of NAFLD with regard to underlying disease, patient age, and fibrosis stage, several clinical trials are underway to develop a first-in-class drug. In this review, we summarize the present status and future direction of NAFLD/NASH research towards solving unmet medical needs.
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Affiliation(s)
- Naoki Tanaka
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
- International Research Center for Agricultural Food Industry, Shinshu University, Matsumoto 390-8621, Japan
| | - Takefumi Kimura
- Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Naoyuki Fujimori
- Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Tadanobu Nagaya
- Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Michiharu Komatsu
- Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Eiji Tanaka
- Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
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32
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Modulation of Gut Microbiota by Lonicera caerulea L. Berry Polyphenols in a Mouse Model of Fatty Liver Induced by High Fat Diet. Molecules 2018; 23:molecules23123213. [PMID: 30563142 PMCID: PMC6321169 DOI: 10.3390/molecules23123213] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 11/20/2018] [Accepted: 11/27/2018] [Indexed: 12/18/2022] Open
Abstract
Polyphenols from the Lonicera caerulea L. berry have shown protective effects on experimental non-alcoholic fatty liver disease (NAFLD) in our previous studies. As endotoxins from gut bacteria are considered to be the major trigger of inflammation in NAFLD, this study aims to clarify the regulatory effects of L. caerulea L. berry polyphenols (LCBP) on gut microbiota in a high fat diet (HFD)-induced mouse model. C57BL/6N mice were fed with a normal diet, HFD, or HFD containing 0.5–1% of LCBP for 45 days. The results revealed that supplementation with LCBP decreased significantly the levels of IL-2, IL-6, MCP-1, and TNF-α in serum, as well as endotoxin levels in both serum and liver in HFD-fed mice. Fecal microbiota characterization by high throughput 16S rRNA gene sequencing revealed that a HFD increased the Firmicutes/Bacteroidetes ratio, and LCBP reduced this ratio by increasing the relative abundance of Bacteroides,Parabacteroides, and another two undefined bacterial genera belonging to the order of Bacteroidales and family of Rikenellaceae, and also by decreasing the relative abundance of six bacterial genera belonging to the phylum Firmicutes, including Staphylococcus, Lactobacillus, Ruminococcus, and Oscillospira. These data demonstrated that LCBP potentially attenuated inflammation in NAFLD through modulation of gut microbiota, especially the ratio of Firmicutes to Bacteroidetes.
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33
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Komatsu M, Tanaka N, Kimura T, Fujimori N, Sano K, Horiuchi A, Sugiura A, Yamazaki T, Shibata S, Joshita S, Umemura T, Matsumoto A, Tanaka E. Miglitol attenuates non-alcoholic steatohepatitis in diabetic patients. Hepatol Res 2018; 48:1092-1098. [PMID: 29935004 DOI: 10.1111/hepr.13223] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Revised: 06/03/2018] [Accepted: 06/16/2018] [Indexed: 12/13/2022]
Abstract
AIM Postprandial hyperglycemia is frequently accompanied by non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH). Although α-glucosidase inhibitors (αGIs) can slow glucose absorption from the intestine and suppress the surge of circulating glucose concentration after meals, it remains unclear whether αGIs are also beneficial for NASH. The aim of this prospective study was to examine the efficacy and safety of miglitol, a typical αGI, for NASH. METHODS Seventeen patients with histologically confirmed NASH and hemoglobin A1c (HbA1c) >6.5% were treated with miglitol (150 mg/day) for 12 months. The changes in clinical parameters and liver histology were analyzed. RESULTS All patients completed the 12-month miglitol treatment course with no severe adverse events. The treatment significantly decreased body mass index, serum alanine aminotransferase levels, and HbA1c (all P < 0.001). Post-treatment liver biopsy of 11 patients revealed significant improvements in steatosis (from 2.2 ± 0.6 to 1.5 ± 0.7, P = 0.001), lobular inflammation (from 1.8 ± 0.8 to 1.3 ± 0.5, P = 0.014), portal inflammation scores (from 0.6 ± 0.5 to 0.1 ± 0.3, P = 0.025), and NAFLD activity score (from 5.5 ± 1.5 to 3.9 ± 1.4, P = 0.012). Fibrosis and hepatocyte ballooning scores were unchanged. CONCLUSIONS Miglitol appears to safely ameliorate NASH activity by attenuation of steatosis and lobular/portal inflammation. Appropriately powered controlled trials are warranted to validate our results.
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Affiliation(s)
- Michiharu Komatsu
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Naoki Tanaka
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Japan.,International Research Center for Agricultural Food Industry, Shinshu University, Matsumoto, Japan
| | - Takefumi Kimura
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Naoyuki Fujimori
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Kenji Sano
- Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan
| | - Akira Horiuchi
- Digestive Disease Center, Showa Inan General Hospital, Komagane, Japan
| | - Ayumi Sugiura
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Tomoo Yamazaki
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Soichiro Shibata
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Satoru Joshita
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Takeji Umemura
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Akihiro Matsumoto
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Eiji Tanaka
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
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34
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Schuster S, Cabrera D, Arrese M, Feldstein AE. Triggering and resolution of inflammation in NASH. Nat Rev Gastroenterol Hepatol 2018; 15:349-364. [PMID: 29740166 DOI: 10.1038/s41575-018-0009-6] [Citation(s) in RCA: 616] [Impact Index Per Article: 88.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Nonalcoholic steatohepatitis (NASH) is considered the progressive form of nonalcoholic fatty liver disease (NAFLD) and is characterized by liver steatosis, inflammation, hepatocellular injury and different degrees of fibrosis. A central issue in this field relates to the identification of those factors that trigger inflammation, thus fuelling the transition from nonalcoholic fatty liver to NASH. These triggers of liver inflammation might have their origins outside the liver (such as in adipose tissue or the gut) as well as inside the organ (for instance, lipotoxicity, innate immune responses, cell death pathways, mitochondrial dysfunction and endoplasmic reticulum stress), both of which contribute to NASH development. In this Review, we summarize the currently available information on the key upstream triggers of inflammation in NASH. We further delineate the mechanisms by which liver inflammation is resolved and the implications of a defective pro-resolution process. A better knowledge of these mechanisms should help to design targeted therapies able to halt or reverse disease progression.
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Affiliation(s)
- Susanne Schuster
- Department of Pediatrics, University of California, San Diego, CA, USA
| | - Daniel Cabrera
- Department of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,Departamento de Ciencias Químicas y Biológicas, Facultad de Salud, Universidad Bernardo O Higgins, Santiago, Chile
| | - Marco Arrese
- Department of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,Centre for Aging and Regeneration (CARE), Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Ariel E Feldstein
- Department of Pediatrics, University of California, San Diego, CA, USA.
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35
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Kimura T, Tanaka N, Fujimori N, Sugiura A, Yamazaki T, Joshita S, Komatsu M, Umemura T, Matsumoto A, Tanaka E. Mild drinking habit is a risk factor for hepatocarcinogenesis in non-alcoholic fatty liver disease with advanced fibrosis. World J Gastroenterol 2018; 24:1440-1450. [PMID: 29632425 PMCID: PMC5889824 DOI: 10.3748/wjg.v24.i13.1440] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 03/03/2018] [Accepted: 03/10/2018] [Indexed: 02/06/2023] Open
Abstract
AIM The impact of mild drinking habit (less than 20 g/d of ethanol) on the clinical course of non-alcoholic fatty liver disease (NAFLD) has not been determined. We examined the influence of a mild drinking habit on liver carcinogenesis from NAFLD.
METHODS A total of 301 patients who had been diagnosed as having NAFLD by liver biopsy between 2003 and 2016 [median age: 56 years, 45% male, 56% with non-alcoholic steatohepatitis, 26% with advanced fibrosis (F3-4)] were divided into the mild drinking group with ethanol consumption of less than 20 g/d (mild drinking group, n = 93) and the non-drinking group (n = 208). Clinicopathological features at the time of liver biopsy and factors related to hepatocellular carcinoma (HCC) occurrence were compared between the groups.
RESULTS We observed significant differences in male prevalence (P = 0.01), platelet count (P = 0.04), and gamma-glutamyl transpeptidase (P = 0.02) between the test groups. Over 6 years of observation, the HCC appearance rate was significantly higher in the mild drinking group (6.5% vs 1.4%, P = 0.02). Multivariate survival analysis using Cox’s regression model revealed that hepatic advanced fibrosis (F3-4) (P < 0.01, risk ratio: 11.60), diabetes mellitus (P < 0.01, risk ratio: 89.50), and serum triglyceride (P = 0.04, risk ratio: 0.98) were factors significantly related to HCC in all NAFLD patients, while the effect of a drinking habit was marginal (P = 0.07, risk ratio: 4.43). In patients with advanced fibrosis (F3-4), however, a drinking habit (P = 0.04, risk ratio: 4.83), alpha-fetoprotein (P = 0.01, risk ratio: 1.23), and diabetes mellitus (P = 0.03, risk ratio: 12.00) were identified as significant contributors to HCC occurrence.
CONCLUSION A mild drinking habit appears to be a risk factor for hepatocarcinogenesis in NAFLD patients, especially those with advanced fibrosis.
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Affiliation(s)
- Takefumi Kimura
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Naoki Tanaka
- Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, Matsumoto 390-8621, Japan
- Research Center for Agricultural Food Industry, Shinshu University, Matsumoto 390-8621, Japan
| | - Naoyuki Fujimori
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Ayumi Sugiura
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Tomoo Yamazaki
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Satoru Joshita
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Michiharu Komatsu
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Takeji Umemura
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Akihiro Matsumoto
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Eiji Tanaka
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
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36
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Fujimori N, Umemura T, Kimura T, Tanaka N, Sugiura A, Yamazaki T, Joshita S, Komatsu M, Usami Y, Sano K, Igarashi K, Matsumoto A, Tanaka E. Serum autotaxin levels are correlated with hepatic fibrosis and ballooning in patients with non-alcoholic fatty liver disease. World J Gastroenterol 2018; 24:1239-1249. [PMID: 29568204 PMCID: PMC5859226 DOI: 10.3748/wjg.v24.i11.1239] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Revised: 02/10/2018] [Accepted: 03/03/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To examine the relationship between serum autotaxin (ATX) concentrations and clinicopathological findings in non-alcoholic fatty liver disease (NAFLD) patients.
METHODS One hundred eighty-six NAFLD patients who had undergone liver biopsy between 2008 and 2017 were retrospectively enrolled. Serum samples were collected at the time of biopsy and ATX was measured by enzyme immunoassays. Sera obtained from 160 healthy, non-obese individuals were used as controls. Histological findings were graded according to an NAFLD scoring system and correlations with serum ATX were calculated by Spearman’s test. Diagnostic accuracy was evaluated using the area under the receiver operating characteristic curve (AUC). Cut-off values were identified by the Youden index, and the nearest clinically applicable value to the cutoff was considered the optimal threshold for clinical convenience.
RESULTS Serum ATX levels were significantly higher in NAFLD patients than in controls (0.86 mg/L vs 0.76 mg/L, P < 0.001) and correlated significantly with ballooning score and fibrosis stage (r = 0.36, P < 0.001 and r = 0.45, P < 0.001, respectively). Such tendencies were stronger in female patients. There were no remarkable relationships between ATX and serum alanine aminotransferase, lipid profiles, or steatosis scores. The AUC values of ATX for predicting the presence of fibrosis (≥ F1), significant fibrosis (≥ F2), severe fibrosis (≥ F3), and cirrhosis (F4), were all more than 0.70 in respective analyses.
CONCLUSION Serum ATX levels may at least partially reflect histological severity in NAFLD.
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Affiliation(s)
- Naoyuki Fujimori
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Takeji Umemura
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Takefumi Kimura
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Naoki Tanaka
- Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, Matsumoto, Japan, and Research Center for Agricultural Food Industry, Shinshu University, Matsumoto, 390-8621, Japan
| | - Ayumi Sugiura
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Tomoo Yamazaki
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Satoru Joshita
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Michiharu Komatsu
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Yoko Usami
- Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto 390-8621, Japan
| | - Kenji Sano
- Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto 390-8621, Japan
| | - Koji Igarashi
- Bioscience Division, TOSOH Corporation, Kanagawa 252-1123, Japan
| | - Akihiro Matsumoto
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Eiji Tanaka
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
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Valenti L, Romeo S. Editorial: new insights into the relationship between the intestine and non-alcoholic fatty liver-is "fatty gut" involved in disease progression? Aliment Pharmacol Ther 2017; 46:377-378. [PMID: 28677287 PMCID: PMC5519939 DOI: 10.1111/apt.14154] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- L. Valenti
- Department of Pathophysiology and TransplantationUniversità degli Studi di MilanoMilanItaly,Internal Medicine and Metabolic DiseasesFondazione IRCCS Ca’ Granda Ospedale Policlinico MilanoMilanItaly
| | - S. Romeo
- Institute of MedicineSahlgrenska AcademyUniversity of GothenburgGothenburgSweden,Clinical Nutrition UnitDepartment of Medical and Surgical SciencesUniversity Magna GraeciaCatanzaroItaly,Cardiology DepartmentSahlgrenska University HospitalGothenburgSweden
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Tanaka N, Aoyama T, Kimura S, Gonzalez FJ. Targeting nuclear receptors for the treatment of fatty liver disease. Pharmacol Ther 2017; 179:142-157. [PMID: 28546081 DOI: 10.1016/j.pharmthera.2017.05.011] [Citation(s) in RCA: 166] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Ligand-activated nuclear receptors, including peroxisome proliferator-activated receptor alpha (PPARα), pregnane X receptor, and constitutive androstane receptor, were first identified as key regulators of the responses against chemical toxicants. However, numerous studies using mouse disease models and human samples have revealed critical roles for these receptors and others, such as PPARβ/δ, PPARγ, farnesoid X receptor (FXR), and liver X receptor (LXR), in maintaining nutrient/energy homeostasis in part through modulation of the gut-liver-adipose axis. Recently, disorders associated with disrupted nutrient/energy homeostasis, e.g., obesity, metabolic syndrome, and non-alcoholic fatty liver disease (NAFLD), are increasing worldwide. Notably, in NAFLD, a progressive subtype exists, designated as non-alcoholic steatohepatitis (NASH) that is characterized by typical histological features resembling alcoholic steatohepatitis (ASH), and NASH/ASH are recognized as major causes of hepatitis virus-unrelated liver cirrhosis and hepatocellular carcinoma. Since hepatic steatosis is basically caused by an imbalance between fat/energy influx and utilization, abnormal signaling of these nuclear receptors contribute to the pathogenesis of fatty liver disease. Standard therapeutic interventions have not been fully established for fatty liver disease, but some new agents that activate or inhibit nuclear receptor signaling have shown promise as possible therapeutic targets. In this review, we summarize recent findings on the roles of nuclear receptors in fatty liver disease and discuss future perspectives to develop promising pharmacological strategies targeting nuclear receptors for NAFLD/NASH.
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Affiliation(s)
- Naoki Tanaka
- Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, Matsumoto, Nagano, Japan.
| | - Toshifumi Aoyama
- Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, Matsumoto, Nagano, Japan
| | - Shioko Kimura
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Frank J Gonzalez
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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