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Baumert B, Maretti-Mira A, Walker D, Li Z, Stratakis N, Wang H, Zhao Y, Fischer F, Jia Q, Valvi D, Bartell S, Chen J, Inge T, Ryder J, Jenkins T, Sisley S, Xanthakos S, Kleiner D, Kohli R, Rock S, Eckel S, Merrill ML, Aung M, Salomon M, McConnell R, Goodrich J, Conti D, Golden-Mason L, Chatzi L. Integrated Spheroid-to-Population Framework for Evaluating PFHpA-Associated Metabolic Dysfunction and Steatotic Liver Disease. RESEARCH SQUARE 2025:rs.3.rs-5960979. [PMID: 40092438 PMCID: PMC11908348 DOI: 10.21203/rs.3.rs-5960979/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/19/2025]
Abstract
The rising prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), particularly among pediatric populations, requires identification of modifiable risk factors to control disease progression. Per- and polyfluoroalkyl substances (PFAS) have emerged as potential contributors to liver damage; however, their role in the etiology of MASLD remains underexplored. This study aimed to bridge the gap between human epidemiological data and in vitro experimental findings to elucidate the effect of perfluoroheptanoic acid (PFHpA), a short chain, unregulated PFAS congener on MASLD development. Our analysis of the Teen-LABS cohort, a national multi-site study on obese adolescents undergoing bariatric surgery, revealed that doubling of PFHpA plasma levels was associated with an 80% increase in MASLD risk (OR, 1.8; 95% CI: 1.3-2.5) based on liver biospies. To further investigate the underlying mechanisms, we used 3D human liver spheroids and single-cell transcriptomics to assess the effect of PFHpA on hepatic metabolism. Integrative analysis identified dysregulation of common pathways in both human and spheroid models, particularly those involved in innate immunity, inflammation, and lipid metabolism. We applied the latent unknown clustering with integrated data (LUCID) model to assess associations between PFHpA exposure, multiomic signatures, and MASLD risk. Our results identified a proteome profile with significantly higher odds of MASLD (OR = 7.1), whereas a distinct metabolome profile was associated with lower odds (OR = 0.51), highlighting the critical role of protein dysregulation in disease pathogenesis. A translational framework was applied to uncover the molecular mechanisms of PFAS-induced MASLD in a cohort of obese adolescents. Identifying key molecular mechanisms for PFAS-induced MASLD can guide the development of targeted prevention and treatment.
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Vaittinen M, Ilha M, Sehgal R, Lankinen MA, Ågren J, Käkelä P, Virtanen KA, Laakso M, Schwab U, Pihlajamäki J. Modification in mitochondrial function is associated with the FADS1 variant and its interaction with alpha-linolenic acid-enriched diet-An exploratory study. J Lipid Res 2024; 65:100638. [PMID: 39218219 PMCID: PMC11459653 DOI: 10.1016/j.jlr.2024.100638] [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: 01/17/2024] [Revised: 08/16/2024] [Accepted: 08/21/2024] [Indexed: 09/04/2024] Open
Abstract
Fatty acid desaturase (FADS1) variant-rs174550 strongly regulates polyunsaturated fatty acid (PUFA) biosynthesis. Additionally, the FADS1 is related to mitochondrial function. Thus, we investigated whether changes in mitochondrial function are associated with the genetic variation in FADS1 (rs174550) in human adipocytes isolated from individuals consuming diets enriched with either dietary alpha-linolenic (ALA) or linoleic acid (LA). Two cohorts of men homozygous for the genotype of FADS1 (rs174550) were studied: FADSDIET2 dietary intervention study with ALA- and LA-enriched diets and Kuopio Obesity Surgery study (KOBS), respectively. We could demonstrate that differentiated human adipose-derived stromal cells from subjects with the TT genotype had higher mitochondrial metabolism compared with subjects with the CC genotype of FADS1-rs174550 in the FADSDIET2. Responses to PUFA-enriched diets differed between the genotypes of FADS1-rs174550, showing that ALA, but not LA, -enriched diet stimulated mitochondrial metabolism more in subjects with the CC genotype when compared with subjects with the TT genotype. ALA, but not LA, proportion in plasma phospholipid fraction correlated positively with adipose tissue mitochondrial-DNA amount in subjects with the CC genotype of FADS1-rs174550 in the KOBS. These findings demonstrate that the FADS1-rs174550 is associated with modification in mitochondrial function in human adipocytes. Additionally, subjects with the CC genotype, when compared with the TT genotype, benefit more from the ALA-enriched diet, leading to enhanced energy metabolism in human adipocytes. Altogether, the FADS1-rs174550 could be a genetic marker to identify subjects who are most suitable to receive dietary PUFA supplementation, establishing also a personalized therapeutic strategy to improve mitochondrial function in metabolic diseases.
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Affiliation(s)
- Maija Vaittinen
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.
| | - Mariana Ilha
- Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA
| | - Ratika Sehgal
- Department of Experimental Diabetology, German Institute of Human Nutrition (DIfE), Potsdam, Germany
| | - Maria A Lankinen
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - Jyrki Ågren
- Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland
| | - Pirjo Käkelä
- Department of Surgery, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
| | - Kirsi A Virtanen
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; Turku PET Centre, Turku University Hospital, Turku, Finland
| | - Markku Laakso
- Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland; Department of Medicine, Kuopio University Hospital, Kuopio, Finland
| | - Ursula Schwab
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; Department of Medicine, Endocrinology, and Clinical Nutrition Kuopio University Hospital, Kuopio, Finland
| | - Jussi Pihlajamäki
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; Department of Medicine, Endocrinology, and Clinical Nutrition Kuopio University Hospital, Kuopio, Finland
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Ullah A, Singla RK, Batool Z, Cao D, Shen B. Pro- and anti-inflammatory cytokines are the game-changers in childhood obesity-associated metabolic disorders (diabetes and non-alcoholic fatty liver diseases). Rev Endocr Metab Disord 2024; 25:783-803. [PMID: 38709387 DOI: 10.1007/s11154-024-09884-y] [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] [Accepted: 05/01/2024] [Indexed: 05/07/2024]
Abstract
Childhood obesity is a chronic inflammatory epidemic that affects children worldwide. Obesity affects approximately 1 in 5 children worldwide. Obesity in children can worsen weight gain and raise the risk of obesity-related comorbidities like diabetes and non-alcoholic fatty liver disease (NAFLD). It can also negatively impact the quality of life for these children. Obesity disrupts immune system function, influencing cytokine (interleukins) balance and expression levels, adipokines, and innate and adaptive immune cells. The altered expression of immune system mediators, including interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-17 (IL-17), interleukin-18 (IL-18), transforming growth factor (TGF), tumor necrosis factor (TNF), and others, caused inflammation, progression, and the development of pediatric obesity and linked illnesses such as diabetes and NAFLD. Furthermore, anti-inflammatory cytokines, including interleukin-2 (IL-2), have been shown to have anti-diabetes and IL-1 receptor antagonist (IL-1Ra) anti-diabetic and pro-NAFLFD properties, and interleukin-10 (IL-10) has been shown to have a dual role in managing diabetes and anti-NAFLD. In light of the substantial increase in childhood obesity-associated disorders such as diabetes and NAFLD and the absence of an effective pharmaceutical intervention to inhibit immune modulation factors, it is critical to consider the alteration of immune system components as a preventive and therapeutic approach. Thus, the current review focuses on the most recent information regarding the influence of pro- and anti-inflammatory cytokines (interleukins) and their molecular mechanisms on pediatric obesity-associated disorders (diabetes and NAFLD). Furthermore, we discussed the current therapeutic clinical trials in childhood obesity-associated diseases, diabetes, and NAFLD.
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Affiliation(s)
- Amin Ullah
- Department of Abdominal Oncology, Cancer Center of West China Hospital and Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Rajeev K Singla
- Department of Abdominal Oncology, Cancer Center of West China Hospital and Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
- School of Pharmaceutical Sciences, Lovely Professional University, 144411, Phagwara, Punjab, India
| | - Zahra Batool
- Department of Abdominal Oncology, Cancer Center of West China Hospital and Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Dan Cao
- Department of Abdominal Oncology, Cancer Center of West China Hospital and Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Bairong Shen
- Department of Abdominal Oncology, Cancer Center of West China Hospital and Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China.
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4
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Matilainen J, Berg V, Vaittinen M, Impola U, Mustonen AM, Männistö V, Malinen M, Luukkonen V, Rosso N, Turunen T, Käkelä P, Palmisano S, Arasu UT, Sihvo SP, Aaltonen N, Härkönen K, Caddeo A, Kaminska D, Pajukanta P, Kaikkonen MU, Tiribelli C, Käkelä R, Laitinen S, Pihlajamäki J, Nieminen P, Rilla K. Increased secretion of adipocyte-derived extracellular vesicles is associated with adipose tissue inflammation and the mobilization of excess lipid in human obesity. J Transl Med 2024; 22:623. [PMID: 38965596 PMCID: PMC11225216 DOI: 10.1186/s12967-024-05249-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 04/28/2024] [Indexed: 07/06/2024] Open
Abstract
BACKGROUND Obesity is a worldwide epidemic characterized by adipose tissue (AT) inflammation. AT is also a source of extracellular vesicles (EVs) that have recently been implicated in disorders related to metabolic syndrome. However, our understanding of mechanistic aspect of obesity's impact on EV secretion from human AT remains limited. METHODS We investigated EVs from human Simpson Golabi Behmel Syndrome (SGBS) adipocytes, and from AT as well as plasma of subjects undergoing bariatric surgery. SGBS cells were treated with TNFα, palmitic acid, and eicosapentaenoic acid. Various analyses, including nanoparticle tracking analysis, electron microscopy, high-resolution confocal microscopy, and gas chromatography-mass spectrometry, were utilized to study EVs. Plasma EVs were analyzed with imaging flow cytometry. RESULTS EVs from mature SGBS cells differed significantly in size and quantity compared to preadipocytes, disagreeing with previous findings in mouse adipocytes and indicating that adipogenesis promotes EV secretion in human adipocytes. Inflammatory stimuli also induced EV secretion, and altered EV fatty acid (FA) profiles more than those of cells, suggesting the role of EVs as rapid responders to metabolic shifts. Visceral AT (VAT) exhibited higher EV secretion compared to subcutaneous AT (SAT), with VAT EV counts positively correlating with plasma triacylglycerol (TAG) levels. Notably, the plasma EVs of subjects with obesity contained a higher number of adiponectin-positive EVs than those of lean subjects, further demonstrating higher AT EV secretion in obesity. Moreover, plasma EV counts of people with obesity positively correlated with body mass index and TNF expression in SAT, connecting increased EV secretion with AT expansion and inflammation. Finally, EVs from SGBS adipocytes and AT contained TAGs, and EV secretion increased despite signs of less active lipolytic pathways, indicating that AT EVs could be involved in the mobilization of excess lipids into circulation. CONCLUSIONS We are the first to provide detailed FA profiles of human AT EVs. We report that AT EV secretion increases in human obesity, implicating their role in TAG transport and association with adverse metabolic parameters, thereby emphasizing their role in metabolic disorders. These findings promote our understanding of the roles that EVs play in human AT biology and metabolic disorders.
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Affiliation(s)
- Johanna Matilainen
- Faculty of Health Sciences, School of Medicine, Institute of Biomedicine, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland.
| | - Viivi Berg
- Faculty of Health Sciences, School of Medicine, Institute of Biomedicine, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland
- Faculty of Science, Forestry and Technology, Department of Technical Physics, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland
| | - Maija Vaittinen
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - Ulla Impola
- Finnish Red Cross Blood Service, Helsinki, Finland
| | - Anne-Mari Mustonen
- Faculty of Health Sciences, School of Medicine, Institute of Biomedicine, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland
- Faculty of Science, Forestry and Technology, Department of Environmental and Biological Sciences, University of Eastern Finland, Joensuu, Finland
| | - Ville Männistö
- Kuopio University Hospital, Kuopio, Finland
- Faculty of Health Sciences, School of Medicine, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland
| | - Marjo Malinen
- Faculty of Science, Forestry and Technology, Department of Environmental and Biological Sciences, University of Eastern Finland, Joensuu, Finland
- Department of Forestry and Environmental Engineering, South-Eastern Finland University of Applied Sciences, Kouvola, Finland
| | - Veera Luukkonen
- Faculty of Health Sciences, School of Medicine, Institute of Biomedicine, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland
| | - Natalia Rosso
- Metabolic Liver Disease Unit, Centro Studi Fegato, Fondazione Italiana Fegato, SS14 Km 163.5 Area Science Park Basovizza, Trieste, Italy
| | - Tanja Turunen
- Faculty of Health Sciences, School of Medicine, Institute of Biomedicine, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland
| | - Pirjo Käkelä
- Kuopio University Hospital, Kuopio, Finland
- Faculty of Health Sciences, School of Medicine, Institute of Clinical Medicine, Department of Surgery, University of Eastern Finland, Kuopio, Finland
| | - Silvia Palmisano
- Surgical Clinic Division, Cattinara Hospital, Trieste, Italy
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - Uma Thanigai Arasu
- Faculty of Health Sciences, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Sanna P Sihvo
- Faculty of Biological and Environmental Sciences, Molecular and Integrative Biosciences Research Programme, University of Helsinki, Helsinki, Finland
- Helsinki Institute of Life Science (HiLIFE), Helsinki University Lipidomics Unit (HiLIPID), Biocenter Finland, Helsinki, Finland
| | - Niina Aaltonen
- Faculty of Health Sciences, School of Medicine, Institute of Biomedicine, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland
| | - Kai Härkönen
- Faculty of Health Sciences, School of Medicine, Institute of Biomedicine, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland
| | - Andrea Caddeo
- Department of Molecular and Clinical Medicine, Institute of Medicine, Wallenberg Laboratory, University of Gothenburg, Sahlgrenska Academy, Gothenburg, Sweden
| | - Dorota Kaminska
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
- Department of Medicine, Division of Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Päivi Pajukanta
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
- Institute for Precision Health, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Minna U Kaikkonen
- Faculty of Health Sciences, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Claudio Tiribelli
- Metabolic Liver Disease Unit, Centro Studi Fegato, Fondazione Italiana Fegato, SS14 Km 163.5 Area Science Park Basovizza, Trieste, Italy
| | - Reijo Käkelä
- Faculty of Biological and Environmental Sciences, Molecular and Integrative Biosciences Research Programme, University of Helsinki, Helsinki, Finland
- Helsinki Institute of Life Science (HiLIFE), Helsinki University Lipidomics Unit (HiLIPID), Biocenter Finland, Helsinki, Finland
| | | | - Jussi Pihlajamäki
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
- Endocrinology and Clinical Nutrition, Kuopio University Hospital, Kuopio, Finland
| | - Petteri Nieminen
- Faculty of Health Sciences, School of Medicine, Institute of Biomedicine, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland
| | - Kirsi Rilla
- Faculty of Health Sciences, School of Medicine, Institute of Biomedicine, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland
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Jain H, Kumar A, Almousa S, Mishra S, Langsten KL, Kim S, Sharma M, Su Y, Singh S, Kerr BA, Deep G. Characterisation of LPS+ bacterial extracellular vesicles along the gut-hepatic portal vein-liver axis. J Extracell Vesicles 2024; 13:e12474. [PMID: 39001704 PMCID: PMC11245684 DOI: 10.1002/jev2.12474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Accepted: 06/10/2024] [Indexed: 07/15/2024] Open
Abstract
Gut microbiome dysbiosis is a major contributing factor to several pathological conditions. However, the mechanistic understanding of the communication between gut microbiota and extra-intestinal organs remains largely elusive. Extracellular vesicles (EVs), secreted by almost every form of life, including bacteria, could play a critical role in this inter-kingdom crosstalk and are the focus of present study. Here, we present a novel approach for isolating lipopolysaccharide (LPS)+ bacterial extracellular vesicles (bEVLPS) from complex biological samples, including faeces, plasma and the liver from lean and diet-induced obese (DIO) mice. bEVLPS were extensively characterised using nanoparticle tracking analyses, immunogold labelling coupled with transmission electron microscopy, flow cytometry, super-resolution microscopy and 16S sequencing. In liver tissues, the protein expressions of TLR4 and a few macrophage-specific biomarkers were assessed by immunohistochemistry, and the gene expressions of inflammation-related cytokines and their receptors (n = 89 genes) were measured using a PCR array. Faecal samples from DIO mice revealed a remarkably lower concentration of total EVs but a significantly higher percentage of LPS+ EVs. Interestingly, DIO faecal bEVLPS showed a higher abundance of Proteobacteria by 16S sequencing. Importantly, in DIO mice, a higher number of total EVs and bEVLPS consistently entered the hepatic portal vein and subsequently reached the liver, associated with increased expression of TLR4, macrophage markers (F4/80, CD86 and CD206), cytokines and receptors (Il1rn, Ccr1, Cxcl10, Il2rg and Ccr2). Furthermore, a portion of bEVLPS escaped liver and entered the peripheral circulation. In conclusion, bEV could be the key mediator orchestrating various well-established biological effects induced by gut bacteria on distant organs.
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Affiliation(s)
- Heetanshi Jain
- Department of Cancer BiologyWake Forest University School of MedicineWinston‐SalemNorth CarolinaUSA
| | - Ashish Kumar
- Department of Cancer BiologyWake Forest University School of MedicineWinston‐SalemNorth CarolinaUSA
| | - Sameh Almousa
- Department of Cancer BiologyWake Forest University School of MedicineWinston‐SalemNorth CarolinaUSA
| | - Shalini Mishra
- Department of Cancer BiologyWake Forest University School of MedicineWinston‐SalemNorth CarolinaUSA
| | - Kendall L. Langsten
- Department of Cancer BiologyWake Forest University School of MedicineWinston‐SalemNorth CarolinaUSA
| | - Susy Kim
- Department of Cancer BiologyWake Forest University School of MedicineWinston‐SalemNorth CarolinaUSA
| | - Mitu Sharma
- Department of Cancer BiologyWake Forest University School of MedicineWinston‐SalemNorth CarolinaUSA
| | - Yixin Su
- Department of Cancer BiologyWake Forest University School of MedicineWinston‐SalemNorth CarolinaUSA
| | - Sangeeta Singh
- Department of Cancer BiologyWake Forest University School of MedicineWinston‐SalemNorth CarolinaUSA
| | - Bethany A. Kerr
- Department of Cancer BiologyWake Forest University School of MedicineWinston‐SalemNorth CarolinaUSA
- Atrium Health Wake Forest Baptist Comprehensive Cancer CenterWinston‐SalemNorth CarolinaUSA
| | - Gagan Deep
- Department of Cancer BiologyWake Forest University School of MedicineWinston‐SalemNorth CarolinaUSA
- Atrium Health Wake Forest Baptist Comprehensive Cancer CenterWinston‐SalemNorth CarolinaUSA
- Department of Internal Medicine‐Gerontology and Geriatric MedicineWake Forest University School of MedicineWinston‐SalemNorth CarolinaUSA
- Sticht Center for Healthy Aging and Alzheimer's PreventionWake Forest University School of MedicineWinston‐SalemNorth CarolinaUSA
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6
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Meyer M, Schwärzler J, Jukic A, Tilg H. Innate Immunity and MASLD. Biomolecules 2024; 14:476. [PMID: 38672492 PMCID: PMC11048298 DOI: 10.3390/biom14040476] [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: 03/20/2024] [Revised: 04/08/2024] [Accepted: 04/11/2024] [Indexed: 04/28/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most common liver disease worldwide in recent years. MASLD commonly presents as simple hepatic steatosis, but ~25% of patients develop liver inflammation, progressive fibrosis, liver cirrhosis and related hepatocellular carcinoma. Liver inflammation and the degree of fibrosis are key determinants of the prognosis. The pathophysiology of liver inflammation is incompletely understood and involves diverse factors and specifically innate and adaptive immune responses. More specifically, diverse mediators of innate immunity such as proinflammatory cytokines, adipokines, inflammasomes and various cell types like mononuclear cells, macrophages and natural killer cells are involved in directing the inflammatory process in MASLD. The activation of innate immunity is driven by various factors including excess lipids and lipotoxicity, insulin resistance and molecular patterns derived from gut commensals. Targeting pathways of innate immunity might therefore appear as an attractive therapeutic strategy in the future management of MASLD and possibly its complications.
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Affiliation(s)
| | | | | | - Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University Innsbruck, 6020 Innsbruck, Austria; (M.M.); (A.J.)
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7
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Lu H. Inflammatory liver diseases and susceptibility to sepsis. Clin Sci (Lond) 2024; 138:435-487. [PMID: 38571396 DOI: 10.1042/cs20230522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Revised: 01/09/2024] [Accepted: 03/12/2024] [Indexed: 04/05/2024]
Abstract
Patients with inflammatory liver diseases, particularly alcohol-associated liver disease and metabolic dysfunction-associated fatty liver disease (MAFLD), have higher incidence of infections and mortality rate due to sepsis. The current focus in the development of drugs for MAFLD is the resolution of non-alcoholic steatohepatitis and prevention of progression to cirrhosis. In patients with cirrhosis or alcoholic hepatitis, sepsis is a major cause of death. As the metabolic center and a key immune tissue, liver is the guardian, modifier, and target of sepsis. Septic patients with liver dysfunction have the highest mortality rate compared with other organ dysfunctions. In addition to maintaining metabolic homeostasis, the liver produces and secretes hepatokines and acute phase proteins (APPs) essential in tissue protection, immunomodulation, and coagulation. Inflammatory liver diseases cause profound metabolic disorder and impairment of energy metabolism, liver regeneration, and production/secretion of APPs and hepatokines. Herein, the author reviews the roles of (1) disorders in the metabolism of glucose, fatty acids, ketone bodies, and amino acids as well as the clearance of ammonia and lactate in the pathogenesis of inflammatory liver diseases and sepsis; (2) cytokines/chemokines in inflammatory liver diseases and sepsis; (3) APPs and hepatokines in the protection against tissue injury and infections; and (4) major nuclear receptors/signaling pathways underlying the metabolic disorders and tissue injuries as well as the major drug targets for inflammatory liver diseases and sepsis. Approaches that focus on the liver dysfunction and regeneration will not only treat inflammatory liver diseases but also prevent the development of severe infections and sepsis.
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Affiliation(s)
- Hong Lu
- Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY 13210, U.S.A
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8
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Rafaqat S, Gluscevic S, Mercantepe F, Rafaqat S, Klisic A. Interleukins: Pathogenesis in Non-Alcoholic Fatty Liver Disease. Metabolites 2024; 14:153. [PMID: 38535313 PMCID: PMC10972081 DOI: 10.3390/metabo14030153] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 02/23/2024] [Accepted: 03/01/2024] [Indexed: 07/26/2024] Open
Abstract
Inflammatory cytokines have been implicated as crucial contributors to the onset and progression of non-alcoholic fatty liver disease (NAFLD). The exact mechanisms by which interleukins (ILs) contribute to NAFLD may vary, and ongoing research is aimed at understanding the specific roles of different ILs in the pathogenesis of this condition. In addition, variations in environmental factors and genetics in each individual can influence the onset and/or progression of NAFLD. The lack of clinical studies related to the potential therapeutic properties of IL-1 inhibitors currently does not allow us to conclude their validity as a therapeutic option, although preclinical studies show promising results. Further studies are needed to elucidate their beneficial properties in NAFLD treatment.
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Affiliation(s)
- Saira Rafaqat
- Department of Zoology, Lahore College for Women University, Lahore 54600, Pakistan
| | - Sanja Gluscevic
- Clinical Center of Montenegro, Department for Neurology, 81000 Podgorica, Montenegro
| | - Filiz Mercantepe
- Department of Endocrinology and Metabolism, Faculty of Medicine, Recep Tayyip Erdogan University, 53010 Rize, Turkey
| | - Sana Rafaqat
- Department of Biotechnology (Human Genetics), Lahore College for Women University, Lahore 54600, Pakistan
| | - Aleksandra Klisic
- Faculty of Medicine, University of Montenegro, 81000 Podgorica, Montenegro
- Center for Laboratory Diagnostics, Primary Health Care Center, 81000 Podgorica, Montenegro
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9
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Gu J, Xu J, Jiao A, Gao Z, Zhang C, Cai N, Xia S, Li J, Wang Z, Chen G, Liu X, Chen Y. The levels of IL1RN is a factor influencing the onset of rheumatoid arthritis in non-alcoholic fatty liver disease. Int Immunopharmacol 2024; 128:111528. [PMID: 38241845 DOI: 10.1016/j.intimp.2024.111528] [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: 08/17/2023] [Revised: 01/07/2024] [Accepted: 01/07/2024] [Indexed: 01/21/2024]
Abstract
With the improvement of global dietary conditions, non-alcoholic fatty liver disease (NAFLD) has gradually become prevalent. As the number of NAFLD patients increases, the coexistence of diseases associated with it has come into focus. In this study, based on immune phenotypes, intercellular communication activities, and clinical manifestations of NAFLD patients, IL1RN was identified as a central pro-inflammatory factor. Subsequently, potential downstream biological pathways of IL1RN in liver tissues and various cell types were enriched to describe its functions. Transcription factors Nfkb1, Jun, and Sp1, significantly associated with these functions, were also enriched. Functional studies of IL1RN suggest its potential to trigger autoimmune diseases. Given this, Mendelian randomization analysis was used to explore the causal relationship between NAFLD and various autoimmune diseases, with IL1RN considered as an intermediary introduced into Mendelian randomization studies. The results indicate that IL1RN and its partially related proteins play a certain mediating role in the process of NAFLD inducing rheumatoid arthritis (RA). Finally, additional research results suggest that intrahepatic ALT levels may influence IL1RN levels, possibly through amino acid metabolism.
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Affiliation(s)
- Jinghua Gu
- First Clinical Medical College, Anhui Medical University, Hefei 230032, China; School of Life Sciences, Anhui Medical University, Hefei 230032, China.
| | - Jiansheng Xu
- First Clinical Medical College, Anhui Medical University, Hefei 230032, China
| | - Annan Jiao
- First Affiliated Hospital, Anhui Medical University, Hefei 230032, China
| | - Zongxuan Gao
- First Clinical Medical College, Anhui Medical University, Hefei 230032, China
| | - Chen Zhang
- First Clinical Medical College, Anhui Medical University, Hefei 230032, China
| | - Ningning Cai
- First Clinical Medical College, Anhui Medical University, Hefei 230032, China
| | - Siyuan Xia
- Second Clinical Medical College, Anhui Medical University, Hefei 230032, China
| | - Jianyang Li
- First Clinical Medical College, Anhui Medical University, Hefei 230032, China
| | - Zihao Wang
- School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Guoqing Chen
- First Clinical Medical College, Anhui Medical University, Hefei 230032, China
| | - Xiaoying Liu
- School of Life Sciences, Anhui Medical University, Hefei 230032, China.
| | - Yang Chen
- First Affiliated Hospital, Anhui Medical University, Hefei 230032, China.
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10
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Chen D, Zhang Y, Zhou Y, Liu Y. Association between circulating biomarkers and non-alcoholic fatty liver disease: An integrative Mendelian randomization study of European ancestry. Nutr Metab Cardiovasc Dis 2024; 34:404-417. [PMID: 37973425 DOI: 10.1016/j.numecd.2023.09.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Revised: 09/18/2023] [Accepted: 09/19/2023] [Indexed: 11/19/2023]
Abstract
BACKGROUND AND AIM Circulating biomarkers provide potential diagnostic or prognostic information on disease presentation, progression or both. Early detection of circulating risk biomarkers is critical for non-alcoholic fatty liver disease (NAFLD) prevention. We aimed to systematically assess the potential causal relationship of genetically predicted 60 circulatory biomarkers with NAFLD using a two-sample Mendelian randomization (MR) design. METHODS AND RESULTS We extracted instrumental variables for 60 circulating biomarkers, and obtained genome-wide association data for NAFLD from 3 sources [(including Anstee, FinnGen and UK Biobank (N ranges: 19264-377988)] among individuals of European ancestry. Our primary method was inverse-variance weighted (IVW) MR, with a series of additional and sensitivity analyses to test the hypothesis of MR. MR results showed that genetically predicted higher density lipoprotein-cholesterol (odds ratio (OR) = 0.86, 95% confidence interval (CI): 0.77-0.96) and vitamin D (OR = 0.39, 95% CI: 0.19-0.78) levels decreased the risk of NAFLD, whereas genetically predicted higher alanine (OR = 1.68, 95% CI: 1.21-2.33), histidine (OR = 1.21, 95% CI: 1.00-1.46), lactate (OR = 2.64, 95% CI: 1.09-6.39), triglycerides (OR = 1.16, 95% CI: 1.05-1.13), ferritin (OR = 1.17, 95% CI: 1.01-1.37), serum iron (OR = 1.23, 95% CI: 1.07-1.41) and transferrin saturation (OR = 1.16, 95% CI: 1.05-1.29), component 4 (OR = 1.10, 95% CI: 1.01-1.20), interleukin-1 receptor antagonist (OR = 1.12, 95% CI: 1.04-1.21) and interleukin-6 (OR = 1.62, 95% CI: 1.14-2.30) levels increased the risk of NAFLD. CONCLUSIONS The findings might aid in elucidating the underlying processes of these causal relationships and provide strong evidence for focusing on high-risk populations and the therapeutic management of specific biomarkers.
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Affiliation(s)
- Dongze Chen
- State Key Laboratory of Molecular Oncology, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Genetics, Peking University Cancer Hospital & Institute, Beijing 100142, China.
| | - Yali Zhang
- Department of Occupational and Environmental Health Sciences, School of Public Health, Peking University, Beijing 100083, China.
| | - Yi Zhou
- Shenzhen Health Development Research and Data Management Center, Shenzhen, China.
| | - Yuyang Liu
- Shenzhen Health Development Research and Data Management Center, Shenzhen, China.
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11
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Liu J, Hu S, Chen L, Daly C, Prada Medina CA, Richardson TG, Traylor M, Dempster NJ, Mbasu R, Monfeuga T, Vujkovic M, Tsao PS, Lynch JA, Voight BF, Chang KM, Million VA, Cobbold JF, Tomlinson JW, van Duijn CM, Howson JMM. Profiling the genome and proteome of metabolic dysfunction-associated steatotic liver disease identifies potential therapeutic targets. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.11.30.23299247. [PMID: 38076879 PMCID: PMC10705663 DOI: 10.1101/2023.11.30.23299247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/21/2023]
Abstract
BACKGROUND & AIMS Metabolic dysfunction-associated steatotic liver disease (MASLD) affects over 25% of the population and currently has no effective treatments. Plasma proteins with causal evidence may represent promising drug targets. We aimed to identify plasma proteins in the causal pathway of MASLD and explore their interaction with obesity. METHODS We analysed 2,941 plasma proteins in 43,978 European participants from UK Biobank. We performed genome-wide association study (GWAS) for all MASLD-associated proteins and created the largest MASLD GWAS (109,885 cases/1,014,923 controls). We performed Mendelian Randomization (MR) and integrated proteins and their encoding genes in MASLD ranges to identify candidate causal proteins. We then validated them through independent replication, exome sequencing, liver imaging, bulk and single-cell gene expression, liver biopsies, pathway, and phenome-wide data. We explored the role of obesity by MR and multivariable MR across proteins, body mass index, and MASLD. RESULTS We found 929 proteins associated with MASLD, reported five novel genetic loci associated with MASLD, and identified 17 candidate MASLD protein targets. We identified four novel targets for MASLD (CD33, GRHPR, HMOX2, and SCG3), provided protein evidence supporting roles of AHCY, FCGR2B, ORM1, and RBKS in MASLD, and validated nine previously known targets. We found that CD33, FCGR2B, ORM1, RBKS, and SCG3 mediated the association of obesity and MASLD, and HMOX2, ORM1, and RBKS had effect on MASLD independent of obesity. CONCLUSIONS This study identified new protein targets in the causal pathway of MASLD, providing new insights into the multi-omics architecture and pathophysiology of MASLD. These findings advise further therapeutic interventions for MASLD.
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Affiliation(s)
- Jun Liu
- Nuffield Department of Population Health, University of Oxford, Oxford, UK
- Genetics Centre-of-Excellence, Novo Nordisk Research Centre Oxford, Oxford, UK
| | - Sile Hu
- Genetics Centre-of-Excellence, Novo Nordisk Research Centre Oxford, Oxford, UK
| | - Lingyan Chen
- Genetics Centre-of-Excellence, Novo Nordisk Research Centre Oxford, Oxford, UK
| | - Charlotte Daly
- Department of Discovery Technology and Genomics, Novo Nordisk Research Centre Oxford, Oxford, UK
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK
| | | | - Tom G Richardson
- Genetics Centre-of-Excellence, Novo Nordisk Research Centre Oxford, Oxford, UK
- MRC Integrative Epidemiology Unit (IEU), Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Matthew Traylor
- Genetics Centre-of-Excellence, Novo Nordisk Research Centre Oxford, Oxford, UK
| | - Niall J Dempster
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK
| | - Richard Mbasu
- Department of Discovery Technology and Genomics, Novo Nordisk Research Centre Oxford, Oxford, UK
| | - Thomas Monfeuga
- AI & Digital Research, Research & Early Development, Novo Nordisk Research Centre Oxford, UK
| | - Marijana Vujkovic
- Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Philip S Tsao
- VA Palo Alto Health Care System, Palo Alto, CA, USA
- Department of Cardiovascular Medicine, School of Medicine, Stanford University, Stanford, CA, USA
| | - Julie A Lynch
- VA Informatics and Computing Infrastructure, VA Salt Lake City Health Care System, Salt Lake City, Utah, USA
- Department of Internal Medicine, School of Medicine, University of Utah, Salt Lake City, Utah, USA
| | - Benjamin F Voight
- Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Kyong-Mi Chang
- Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - V A Million
- Nuffield Department of Population Health, University of Oxford, Oxford, UK
- Genetics Centre-of-Excellence, Novo Nordisk Research Centre Oxford, Oxford, UK
- Department of Discovery Technology and Genomics, Novo Nordisk Research Centre Oxford, Oxford, UK
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK
- AI & Digital Research, Research & Early Development, Novo Nordisk Research Centre Oxford, UK
- MRC Integrative Epidemiology Unit (IEU), Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
- Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- VA Palo Alto Health Care System, Palo Alto, CA, USA
- Department of Cardiovascular Medicine, School of Medicine, Stanford University, Stanford, CA, USA
- VA Informatics and Computing Infrastructure, VA Salt Lake City Health Care System, Salt Lake City, Utah, USA
- Department of Internal Medicine, School of Medicine, University of Utah, Salt Lake City, Utah, USA
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust and the University of Oxford, Oxford, UK
- Translational Gastroenterology Unit, University of Oxford, Oxford, UK
| | - Jeremy F Cobbold
- NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust and the University of Oxford, Oxford, UK
- Translational Gastroenterology Unit, University of Oxford, Oxford, UK
| | - Jeremy W Tomlinson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK
- NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust and the University of Oxford, Oxford, UK
| | | | - Joanna M M Howson
- Genetics Centre-of-Excellence, Novo Nordisk Research Centre Oxford, Oxford, UK
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12
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Anwar I, Ashfaq UA. Impact of Nanotechnology on Differentiation and Augmentation of Stem Cells for Liver Therapy. Crit Rev Ther Drug Carrier Syst 2023; 40:89-116. [PMID: 37585310 DOI: 10.1615/critrevtherdrugcarriersyst.2023042400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/18/2023]
Abstract
The liver is one of the crucial organs of the body that performs hundreds of chemical reactions needed by the body to survive. It is also the largest gland of the body. The liver has multiple functions, including the synthesis of chemicals, metabolism of nutrients, and removal of toxins. It also acts as a storage unit. The liver has a unique ability to regenerate itself, but it can lead to permanent damage if the injury is beyond recovery. The only possible treatment of severe liver damage is liver transplant which is a costly procedure and has several other drawbacks. Therefore, attention has been shifted towards the use of stem cells that have shown the ability to differentiate into hepatocytes. Among the numerous kinds of stem cells (SCs), the mesenchymal stem cells (MSCs) are the most famous. Various studies suggest that an MSC transplant can repair liver function, improve the signs and symptoms, and increase the chances of survival. This review discusses the impact of combining stem cell therapy with nanotechnology. By integrating stem cell science and nanotechnology, the information about stem cell differentiation and regulation will increase, resulting in a better comprehension of stem cell-based treatment strategies. The augmentation of SCs with nanoparticles has been shown to boost the effect of stem cell-based therapy. Also, the function of green nanoparticles in liver therapies is discussed.
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Affiliation(s)
- Ifrah Anwar
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad, Faisalabad, Pakistan
| | - Usman Ali Ashfaq
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad, Faisalabad, Pakistan
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13
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Yang F, Ni B, Lian Q, Qiu X, He Y, Zhang Q, Zou X, He F, Chen W. Key genes associated with non-alcoholic fatty liver disease and hepatocellular carcinoma with metabolic risk factors. Front Genet 2023; 14:1066410. [PMID: 36950134 PMCID: PMC10025510 DOI: 10.3389/fgene.2023.1066410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 02/21/2023] [Indexed: 03/08/2023] Open
Abstract
Background: Hepatocellular carcinoma (HCC) has become the world's primary cause of cancer death. Obesity, hyperglycemia, and dyslipidemia are all illnesses that are part of the metabolic syndrome. In recent years, this risk factor has become increasingly recognized as a contributing factor to HCC. Around the world, non-alcoholic fatty liver disease (NAFLD) is on the rise, especially in western countries. In the past, the exact pathogenesis of NAFLD that progressed to metabolic risk factors (MFRs)-associated HCC has not been fully understood. Methods: Two groups of the GEO dataset (including normal/NAFLD and HCC with MFRs) were used to analyze differential expression. Differentially expressed genes of HCC were verified by overlapping in TCGA. In addition, functional enrichment analysis, modular analysis, Receiver Operating Characteristic (ROC) analysis, LASSO analysis, and Genes with key survival characteristics were analyzed. Results: We identified six hub genes (FABP5, SCD, CCL20, AGPAT9(GPAT3), PLIN1, and IL1RN) that may be closely related to NAFLD and HCC with MFRs. We constructed survival and prognosis gene markers based on FABP5, CCL20, AGPAT9(GPAT3), PLIN1, and IL1RN.This gene signature has shown good diagnostic accuracy in both NAFLD and HCC and in predicting HCC overall survival rates. Conclusion: As a result of the findings of this study, there is some guiding significance for the diagnosis and treatment of liver disease associated with NAFLD progression.
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Affiliation(s)
- Fan Yang
- Department of Infectious Diseases, The First People’s Hospital of Kashi, The Kashi Affiliated Hospital, Sun Yat-Sen University, Kashi, China
- Biotherapy Centre, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Postdoctoral Research Station, Xinjiang Medical University, Ürümqi, China
| | - Beibei Ni
- Cell-Gene Therapy Translational Medicine Research Centre, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Qinghai Lian
- Cell-Gene Therapy Translational Medicine Research Centre, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xiusheng Qiu
- Cell-Gene Therapy Translational Medicine Research Centre, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yizhan He
- Biotherapy Centre, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Qi Zhang
- Department of Infectious Diseases, The First People’s Hospital of Kashi, The Kashi Affiliated Hospital, Sun Yat-Sen University, Kashi, China
- Biotherapy Centre, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xiaoguang Zou
- Department of Infectious Diseases, The First People’s Hospital of Kashi, The Kashi Affiliated Hospital, Sun Yat-Sen University, Kashi, China
- *Correspondence: Xiaoguang Zou, ; Fangping He, ; Wenjie Chen,
| | - Fangping He
- Department of Hepatobiliary and Pancreatic Surgery, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, Guangdong, China
- *Correspondence: Xiaoguang Zou, ; Fangping He, ; Wenjie Chen,
| | - Wenjie Chen
- Biotherapy Centre, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Cell-Gene Therapy Translational Medicine Research Centre, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- *Correspondence: Xiaoguang Zou, ; Fangping He, ; Wenjie Chen,
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14
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Xiang L, Li X, Luo Y, Zhou B, Liu Y, Li Y, Wu D, Jia L, Zhu PW, Zheng MH, Wang H, Lu Y. A multi-omic landscape of steatosis-to-NASH progression. LIFE METABOLISM 2022; 1:242-257. [PMID: 39872077 PMCID: PMC11749464 DOI: 10.1093/lifemeta/loac034] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 09/20/2022] [Accepted: 11/16/2022] [Indexed: 01/29/2025]
Abstract
Nonalcoholic steatohepatitis (NASH) has emerged as a major cause of liver failure and hepatocellular carcinoma. Investigation into the molecular mechanisms that underlie steatosis-to-NASH progression is key to understanding the development of NASH pathophysiology. Here, we present comprehensive multi-omic profiles of preclinical animal models to identify genes, non-coding RNAs, proteins, and plasma metabolites involved in this progression. In particular, by transcriptomics analysis, we identified Growth Differentiation Factor 3 (GDF3) as a candidate noninvasive biomarker in NASH. Plasma GDF3 levels are associated with hepatic pathological features in patients with NASH, and differences in these levels provide a high diagnostic accuracy of NASH diagnosis (AUROC = 0.90; 95% confidence interval: 0.85-0.95) with a good sensitivity (90.7%) and specificity (86.4%). In addition, by developing integrated proteomic-metabolomic datasets and performing a subsequent pharmacological intervention in a mouse model of NASH, we show that ferroptosis may be a potential target to treat NASH. Moreover, by using competing endogenous RNAs network analysis, we found that several miRNAs, including miR-582-5p and miR-292a-3p, and lncRNAs, including XLOC-085738 and XLOC-041531, are associated with steatosis-to-NASH progression. Collectively, our data provide a valuable resource into the molecular characterization of NASH progression, leading to the novel insight that GDF3 may be a potential noninvasive diagnostic biomarker for NASH while further showing that ferroptosis is a therapeutic target for the disease.
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Affiliation(s)
- Liping Xiang
- Department of Endocrinology and Metabolism, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiaoyan Li
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yunchen Luo
- Department of Endocrinology and Metabolism, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bing Zhou
- Department of Endocrinology and Metabolism, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuejun Liu
- Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yao Li
- Department of Laboratory Animal Science, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Duojiao Wu
- Zhongshan Hospital Institute of Clinical Science, Fudan University, Shanghai Institute of Clinical Bioinformatics, Shanghai, China
| | - Lijing Jia
- Department of Endocrinology, The Second Clinical Medical College, Jinan University (Shenzhen People’s Hospital), Shenzhen, China
| | - Pei-Wu Zhu
- Department of Laboratory Medicine, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Ming-Hua Zheng
- MAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Hua Wang
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yan Lu
- Institute of Metabolism and Regenerative Medicine, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
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15
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Meng LC, Zheng JY, Qiu YH, Zheng L, Zheng JY, Liu YQ, Miao XL, Lu XY. Salvianolic acid B ameliorates non-alcoholic fatty liver disease by inhibiting hepatic lipid accumulation and NLRP3 inflammasome in ob/ob mice. Int Immunopharmacol 2022; 111:109099. [PMID: 35932615 DOI: 10.1016/j.intimp.2022.109099] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Revised: 07/19/2022] [Accepted: 07/25/2022] [Indexed: 12/12/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) has high occurrence in the global world, which poses serious threats to human health. Salvianolic acid B (SalB), an extract of the root of Salvia miltiorrhiza, has the protective effect on metabolic homeostasis. However, the mechanism is still unknown. In this study, we used ob/ob mice, a model of NAFLD, to explore the hepatoprotective effects of SalB. The results showed that SalB significantly reduced the body weights and liver weights, and ameliorated plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), hepatic free fatty acid (FFA), total cholesterol (TC) levels, and hepatic TG and TC levels in ob/ob mice. SalB reduced the number of lipid droplets and inhibited hepatic lipogenesis by regulating peroxisome proliferator-activated receptor gamma (PPARγ), fatty acid synthase (FASN), stearoyl-Co A desaturase 1 (SCD1), and cluster of differentiation 36 (CD36). Compared to ob/ob mice, the lower expressions of the pro-inflammatory cytokines, such as interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and F4/80, were observed after SalB treatment. Importantly, SalB treatment inhibited the activation of NLRP3 inflammasome and reduced the severity of liver inflammation. Our findings suggested that SalB improved NAFLD pathology in ob/ob mice by reducing hepatic lipid accumulation and NLRP3 inflammasome activation, which might be the potential hepatoprotective mechanism of SalB.
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Affiliation(s)
- Ling-Cui Meng
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jia-Yi Zheng
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yu-Hui Qiu
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Li Zheng
- The Department of Clinical Laboratory, The Fifth People's Hospital of Zhuhai, Zhuhai, China
| | | | | | | | - Xin-Yi Lu
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China; Biological Resource Centre, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China; Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research.
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16
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Arelaki S, Koletsa T, Sinakos E, Papadopoulos V, Arvanitakis K, Skendros P, Akriviadis E, Ritis K, Germanidis G, Hytiroglou P. Neutrophil extracellular traps enriched with IL-1β and IL-17A participate in the hepatic inflammatory process of patients with non-alcoholic steatohepatitis. Virchows Arch 2022; 481:455-465. [PMID: 35503185 DOI: 10.1007/s00428-022-03330-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 04/18/2022] [Accepted: 04/24/2022] [Indexed: 10/18/2022]
Abstract
Neutrophil extracellular traps (NETs) are implicated in the pathogenesis of various non-infectious inflammatory and thrombotic diseases. We investigated the presence and possible associations of NETs with various histopathologic parameters in patients with non-alcoholic steatohepatitis (NASH). We retrospectively assessed 20 liver biopsy specimens from patients with non-alcoholic fatty liver disease (NAFLD), including 17 specimens with NASH, and 14 control specimens. NETs were identified with confocal microscopy as extracellular structures with co-localization of neutrophil elastase (NE) and citrullinated histone-3. Interleukin-1β (IL-1β) and IL-17A were assessed with the same methodology. Histologic features of NAFLD were semi-quantitatively evaluated, and correlated with presence of NETs, neutrophil density, and platelet density/aggregates (assessed by immunohistochemistry for NE and CD42b, respectively). NETs were identified in 94.1% (16/17) of the NASH biopsy specimens; they were absent from all other NAFLD and control specimens. The presence of NETs was strongly correlated with steatosis (p = 0.003), ballooning degeneration (p < 0.001), lobular inflammation (p < 0.001), portal inflammation (p < 0.001), NAS score (p = 0.001), stage (p = 0.001), and diagnosis of NASH (p < 0.001). NETs were decorated with IL-1β and IL-17A. Platelet aggregates were much larger in NASH specimens, as compared to controls. In conclusion, NETs are implicated in the pathogenesis of NASH. Their associations with inflammation, ballooning degeneration (a hallmark of NASH), and stage emphasize their role in the disease process. In this setting, NETs provide a vehicle for IL-1β and IL-17A. In addition, platelet aggregation in hepatic sinusoids implies a role for thromboinflammation in NASH, and may explain the low peripheral blood platelet counts reported in patients with NASH.
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Affiliation(s)
- Stella Arelaki
- Department of Pathology, Aristotle University School of Medicine, 54006, Thessaloniki, Greece.,Laboratory of Molecular Hematology, Department of Medicine, Democritus University of Thrace, Alexandroupolis, Greece.,National Center for Tumor Diseases, Heidelberg, Germany
| | - Triantafyllia Koletsa
- Department of Pathology, Aristotle University School of Medicine, 54006, Thessaloniki, Greece
| | - Emmanuil Sinakos
- Fourth Department of Internal Medicine, Aristotle University School of Medicine, "Hippokration" General Hospital, Thessaloniki, Greece
| | | | - Konstantinos Arvanitakis
- First Department of Internal Medicine, Aristotle University School of Medicine, AHEPA University Hospital, 54636, Thessaloniki, Greece.,Basic and Translational Research Unit, Special Unit for Biomedical Research and Education (SUBRE), School of Medicine, Aristotle University, Thessaloniki, Greece
| | - Panagiotis Skendros
- Laboratory of Molecular Hematology, Department of Medicine, Democritus University of Thrace, Alexandroupolis, Greece.,First Department of Internal Medicine, Democritus University of Thrace, University Hospital of Alexandroupolis, Alexandroupolis, Greece
| | - Evangelos Akriviadis
- Fourth Department of Internal Medicine, Aristotle University School of Medicine, "Hippokration" General Hospital, Thessaloniki, Greece
| | - Konstantinos Ritis
- Laboratory of Molecular Hematology, Department of Medicine, Democritus University of Thrace, Alexandroupolis, Greece.,First Department of Internal Medicine, Democritus University of Thrace, University Hospital of Alexandroupolis, Alexandroupolis, Greece
| | - Georgios Germanidis
- First Department of Internal Medicine, Aristotle University School of Medicine, AHEPA University Hospital, 54636, Thessaloniki, Greece. .,Basic and Translational Research Unit, Special Unit for Biomedical Research and Education (SUBRE), School of Medicine, Aristotle University, Thessaloniki, Greece.
| | - Prodromos Hytiroglou
- Department of Pathology, Aristotle University School of Medicine, 54006, Thessaloniki, Greece.
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17
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Franko JJ, Vu MM, Parsons ME, Conner JR, Lammers DT, Ieronimakis N, Reynolds GD, Eckert MJ, Bingham JR. Adenosine, lidocaine, and magnesium for attenuating ischemia reperfusion injury from resuscitative endovascular balloon occlusion of the aorta in a porcine model. J Trauma Acute Care Surg 2022; 92:631-639. [PMID: 34840271 DOI: 10.1097/ta.0000000000003482] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
BACKGROUND Minimally invasive resuscitative endovascular balloon occlusion of the aorta (REBOA) following noncompressible hemorrhage results in significant ischemia reperfusion injury (IRI). Adverse outcomes from IRI include organ dysfunction and can result in profound hemodynamic and molecular compromise. We hypothesized that adenosine, lidocaine, and magnesium (ALM) attenuates organ injury and inflammation responses following REBOA IRI in a porcine model of hemorrhage. METHODS Animals underwent a 20% controlled hemorrhage followed by 45 minutes of supraceliac balloon occlusion. They were randomized into two groups: control (n = 9) and ALM intervention (n = 9) to include a posthemorrhage, pre-REBOA bolus (200 mL of 3% NaCl ALM) followed by a continuous drip (2 mL/kg per hour of 0.9% NaCl ALM) during the 4-hour resuscitative period. Primary outcomes included hemodynamic parameters, gene expression of inflammatory signaling molecules, and plasma concentrations of select cytokines and chemokines. RESULTS The ALM cohort demonstrated a significant reduction in cardiac output and cardiac index. Plasma concentrations of interleukin 2 and interleukin 10 were significantly lower 3 hours post-REBOA in animals treated with ALM versus vehicle. Interleukin 4 levels in plasma were also lower with ALM at 3 and 4 hours post-REBOA (p < 0.05). Liver expression of IL1RN, MTOR, and LAMP3 messenger RNA was significantly lower with ALM as compared with the vehicle. No significant difference in large bowel gene expression was observed between treatments. CONCLUSION In a porcine model of hemorrhage, ALM treatment mitigated inflammatory responses early during post-REBOA resuscitation. Our findings suggest that ALM use with trauma may reduce inflammatory injury and improve outcomes related to REBOA utilization.
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Affiliation(s)
- Jace J Franko
- From the Department of Surgery (J.J.F., M.M.V., M.E.P., J.R.C., D.T.L., N.I., G.D.R., J.R.B.), Madigan Army Medical Center, Tacoma, Washington; and Department of Surgery (M.J.E.), University of North Carolina Medical Center, Chapel Hill, North Carolina
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18
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Frühbeck G, Catalán V, Ramírez B, Valentí V, Becerril S, Rodríguez A, Moncada R, Baixauli J, Silva C, Escalada J, Gómez-Ambrosi J. Serum Levels of IL-1 RA Increase with Obesity and Type 2 Diabetes in Relation to Adipose Tissue Dysfunction and are Reduced After Bariatric Surgery in Parallel to Adiposity. J Inflamm Res 2022; 15:1331-1345. [PMID: 35237063 PMCID: PMC8884708 DOI: 10.2147/jir.s354095] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 02/15/2022] [Indexed: 12/22/2022] Open
Abstract
Background Excess adiposity leads to a dysfunctional adipose tissue that contributes to the development of obesity-associated comorbidities such as type 2 diabetes (T2D). Interleukin-1 receptor antagonist (IL-1RA) is a naturally occurring antagonist of the IL-1 receptor with anti-inflammatory properties. The aim of the present study was to compare the circulating concentrations of IL-1RA and its mRNA expression in visceral adipose tissue (VAT) in subjects with normal weight (NW), obesity with normoglycemia (OB-NG), or obesity with impaired glucose tolerance or T2D (OB-IGT&T2D) and to analyze the effect of changes in body fat percentage (BF%) on IL-1RA levels. Methods Serum concentrations of IL-1RA were measured in 156 volunteers. Expression of IL1RN mRNA in VAT obtained from 36 individuals was determined. In addition, the concentrations of IL-1RA were measured before and after weight gain as well as weight loss following a dietetic program or Roux-en-Y gastric bypass (RYGB). Results Serum levels of IL-1RA were significantly increased in individuals with obesity, being further increased in the OB-IGT&T2D group (NW 440 ± 316, OB-NG 899 ± 562, OB-IGT&T2D 1265 ± 739 pg/mL; P<0.001) and associated with markers of inflammation and fatty liver. IL1RN mRNA expression in VAT was significantly increased in the OB-IGT&T2D group and correlated in the global cohort with the mRNA expression of SPP1, CCL2, CD68, and MMP9. Levels of IL-1RA were not modified after modest changes in BF%, but RYGB-induced weight loss significantly decreased IL-1RA concentrations from 1233 ± 1009 to 660 ± 538 pg/mL (P<0.001). Conclusion Serum IL-1RA concentrations are increased in patients with obesity being further elevated in obesity-associated IGT and T2D in association with markers of adipose tissue dysfunction. The mRNA expression of IL1RN is markedly increased in VAT of subjects with obesity and T2D in relation with genes involved in macrophage recruitment, inflammation and matrix remodeling. Serum IL-1RA concentrations are reduced when a notable amount of BF% is loss. Measurement of IL-1RA is an excellent biomarker of adipose tissue dysfunction in obesity-associated metabolic alterations.
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Affiliation(s)
- Gema Frühbeck
- Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain
- Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IDISNA), Pamplona, Spain
- Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, Pamplona, Spain
| | - Victoria Catalán
- Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain
- Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IDISNA), Pamplona, Spain
| | - Beatriz Ramírez
- Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain
- Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IDISNA), Pamplona, Spain
| | - Víctor Valentí
- Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IDISNA), Pamplona, Spain
- Department of Surgery, Clínica Universidad de Navarra, Pamplona, Spain
| | - Sara Becerril
- Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain
- Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IDISNA), Pamplona, Spain
| | - Amaia Rodríguez
- Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain
- Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IDISNA), Pamplona, Spain
| | - Rafael Moncada
- Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IDISNA), Pamplona, Spain
- Department of Anesthesia, Clínica Universidad de Navarra, Pamplona, Spain
| | - Jorge Baixauli
- Department of Surgery, Clínica Universidad de Navarra, Pamplona, Spain
| | - Camilo Silva
- Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IDISNA), Pamplona, Spain
- Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, Pamplona, Spain
| | - Javier Escalada
- Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain
- Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, Pamplona, Spain
| | - Javier Gómez-Ambrosi
- Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain
- Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IDISNA), Pamplona, Spain
- Correspondence: Javier Gómez-Ambrosi, Metabolic Research Laboratory, Clínica Universidad de Navarra, Irunlarrea 1, Pamplona, 31008, Spain, Tel +34 948 425600 (ext. 806567), Email
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Vaittinen M, Lankinen MA, Käkelä P, Ågren J, Wheelock CE, Laakso M, Schwab U, Pihlajamäki J. The FADS1 genotypes modify the effect of linoleic acid-enriched diet on adipose tissue inflammation via pro-inflammatory eicosanoid metabolism. Eur J Nutr 2022; 61:3707-3718. [PMID: 35701670 PMCID: PMC9464166 DOI: 10.1007/s00394-022-02922-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 05/24/2022] [Indexed: 01/08/2023]
Abstract
PURPOSE Fatty acid desaturase (FADS) variants associate with fatty acid (FA) and adipose tissue (AT) metabolism and inflammation. Thus, the role of FADS1 variants in the regulation of dietary linoleic acid (LA)-induced effects on AT inflammation was investigated. METHODS Subjects homozygotes for the TT and CC genotypes of the FADS1-rs174550 (TT, n = 25 and CC, n = 28) or -rs174547 (TT, n = 42 and CC, n = 28), were either recruited from the METabolic Syndrome In Men cohort to participate in an intervention with LA-enriched diet (FADSDIET) or from the Kuopio Obesity Surgery (KOBS) study. GC and LC-MS for plasma FA proportions and eicosanoid concentrations and AT gene expression for AT inflammatory score (AT-InSc) was determined. RESULTS We observed a diet-genotype interaction between LA-enriched diet and AT-InSc in the FADSDIET. In the KOBS study, interleukin (IL)1 beta mRNA expression in AT was increased in subjects with the TT genotype and highest LA proportion. In the FADSDIET, n-6/LA proportions correlated positively with AT-InSc in those with the TT genotype but not with the CC genotype after LA-enriched diet. Specifically, LA- and AA-derived pro-inflammatory eicosanoids related to CYP450/sEH-pathways correlated positively with AT-InSc in those with the TT genotype, whereas in those with the CC genotype, the negative correlations between pro-inflammatory eicosanoids and AT-InSc related to COX/LOX-pathways. CONCLUSIONS LA-enriched diet increases inflammatory AT gene expression in subjects with the TT genotype, while CC genotype could play a protective role against LA-induced AT inflammation. Overall, the FADS1 variant could modify the dietary LA-induced effects on AT inflammation through the differential biosynthesis of AA-derived eicosanoids.
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Affiliation(s)
- Maija Vaittinen
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70210, Kuopio, Finland.
| | - Maria A. Lankinen
- grid.9668.10000 0001 0726 2490Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70210 Kuopio, Finland
| | - Pirjo Käkelä
- grid.9668.10000 0001 0726 2490Department of Surgery, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
| | - Jyrki Ågren
- grid.9668.10000 0001 0726 2490Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland
| | - Craig E. Wheelock
- grid.4714.60000 0004 1937 0626Division of Physiological Chemistry 2, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
| | - Markku Laakso
- grid.9668.10000 0001 0726 2490Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland ,grid.410705.70000 0004 0628 207XDepartment of Medicine, Kuopio University Hospital, Kuopio, Finland
| | - Ursula Schwab
- grid.9668.10000 0001 0726 2490Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70210 Kuopio, Finland ,grid.410705.70000 0004 0628 207XDepartment of Medicine, Endocrinology, and Clinical Nutrition, Kuopio University Hospital, Kuopio, Finland
| | - Jussi Pihlajamäki
- grid.9668.10000 0001 0726 2490Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70210 Kuopio, Finland ,grid.410705.70000 0004 0628 207XDepartment of Medicine, Endocrinology, and Clinical Nutrition, Kuopio University Hospital, Kuopio, Finland
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Portincasa P, Bonfrate L, Khalil M, Angelis MD, Calabrese FM, D’Amato M, Wang DQH, Di Ciaula A. Intestinal Barrier and Permeability in Health, Obesity and NAFLD. Biomedicines 2021; 10:83. [PMID: 35052763 PMCID: PMC8773010 DOI: 10.3390/biomedicines10010083] [Citation(s) in RCA: 96] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 12/20/2021] [Accepted: 12/28/2021] [Indexed: 02/07/2023] Open
Abstract
The largest surface of the human body exposed to the external environment is the gut. At this level, the intestinal barrier includes luminal microbes, the mucin layer, gastrointestinal motility and secretion, enterocytes, immune cells, gut vascular barrier, and liver barrier. A healthy intestinal barrier is characterized by the selective permeability of nutrients, metabolites, water, and bacterial products, and processes are governed by cellular, neural, immune, and hormonal factors. Disrupted gut permeability (leaky gut syndrome) can represent a predisposing or aggravating condition in obesity and the metabolically associated liver steatosis (nonalcoholic fatty liver disease, NAFLD). In what follows, we describe the morphological-functional features of the intestinal barrier, the role of major modifiers of the intestinal barrier, and discuss the recent evidence pointing to the key role of intestinal permeability in obesity/NAFLD.
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Affiliation(s)
- Piero Portincasa
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (L.B.); (M.K.); (A.D.C.)
| | - Leonilde Bonfrate
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (L.B.); (M.K.); (A.D.C.)
| | - Mohamad Khalil
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (L.B.); (M.K.); (A.D.C.)
- Department of Soil, Plant and Food Sciences, University of Bari Aldo Moro, Via Amendola 165/a, 70126 Bari, Italy; (M.D.A.); (F.M.C.)
| | - Maria De Angelis
- Department of Soil, Plant and Food Sciences, University of Bari Aldo Moro, Via Amendola 165/a, 70126 Bari, Italy; (M.D.A.); (F.M.C.)
| | - Francesco Maria Calabrese
- Department of Soil, Plant and Food Sciences, University of Bari Aldo Moro, Via Amendola 165/a, 70126 Bari, Italy; (M.D.A.); (F.M.C.)
| | - Mauro D’Amato
- Gastrointestinal Genetics Lab, CIC bioGUNE-BRTA, 48160 Derio, Spain;
- Ikerbasque, Basque Foundation for Science, 48009 Bilbao, Spain
| | - David Q.-H. Wang
- Department of Medicine and Genetics, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, New York, NY 10461, USA;
| | - Agostino Di Ciaula
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (L.B.); (M.K.); (A.D.C.)
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21
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Ma HL, Chen SD, Zheng KI, Yu Y, Wang XX, Tang LJ, Li G, Rios RS, Huang OY, Zheng XY, Xu RA, Targher G, Byrne CD, Wang XD, Chen YP, Zheng MH. TA allele of rs2070673 in the CYP2E1 gene is associated with lobular inflammation and nonalcoholic steatohepatitis in patients with biopsy-proven nonalcoholic fatty liver disease. J Gastroenterol Hepatol 2021; 36:2925-2934. [PMID: 34031913 DOI: 10.1111/jgh.15554] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 05/10/2021] [Accepted: 05/21/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM Cytochrome P450 2E1 (CYP2E1) plays a role in lipid metabolism, and by increasing hepatic oxidative stress and inflammation, the upregulation of CYP2E1 is involved in development of nonalcoholic steatohepatitis (NASH). We aimed to explore the relationship between CYP2E1-333A>T (rs2070673) and the histological severity of nonalcoholic fatty liver disease (NAFLD). METHODS We studied 438 patients with biopsy-proven NAFLD. NASH was defined as NAFLD Activity Score ≥ 5 with existence of steatosis, ballooning, and lobular inflammation. CYP2E1-333A>T (rs2070673) was genotyped by matrix-assisted laser desorption ionization-time of flight mass spectrometry. Serum cytokines related to inflammation were measured by the Bio-plex 200 system to investigate possible mediating factors involved in the process. RESULTS The TA genotype of rs2070673 had a higher prevalence of moderate/severe lobular inflammation (27.6% vs 20.3% vs 13.3%, P < 0.01) and NASH (55.7% vs 42.4% vs 40.5%, P < 0.01) compared with the AA and TT genotypes, respectively. In multivariable regression modeling, the heterozygote state TA was associated with moderate/severe lobular inflammation (adjusted odds ratio: 2.31, 95% confidence interval 1.41-3.78, P < 0.01) or NASH (adjusted odds ratio: 1.82, 95% confidence interval 1.22-2.69, P < 0.01), independently of age, sex, common metabolic risk factors, and presence of liver fibrosis. Compared with no-NASH, NASH patients had significantly higher levels of serum interleukin-1 receptor antagonist, interleukin-18, and interferon-inducible protein-10 (IP-10), whereas only IP-10 was increased with the rs2070673 TA variant (P = 0.01). Mediation analysis showed that IP-10 was responsible for ~60% of the association between the rs2070672 and NASH. CONCLUSIONS The TA allele of rs2070673 is strongly associated with lobular inflammation and NASH, and this effect appears to be largely mediated by serum IP-10 levels.
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Affiliation(s)
- Hong-Lei Ma
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Sui-Dan Chen
- Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Kenneth I Zheng
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yue Yu
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xin-Xin Wang
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Liang-Jie Tang
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Gang Li
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Rafael S Rios
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Ou-Yang Huang
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiao-Yong Zheng
- Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Ren-Ai Xu
- Department of Pharmacy, Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Christopher D Byrne
- Southampton National Institute for Health Research Biomedical Research Centre, University Hospital Southampton, Southampton General Hospital, Southampton, UK
| | - Xiao-Dong Wang
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.,Institute of Hepatology, Wenzhou Medical University, Wenzhou, China.,Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China
| | - Yong-Ping Chen
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.,Institute of Hepatology, Wenzhou Medical University, Wenzhou, China.,Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China
| | - Ming-Hua Zheng
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.,Institute of Hepatology, Wenzhou Medical University, Wenzhou, China.,Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China
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Nawrot M, Peschard S, Lestavel S, Staels B. Intestine-liver crosstalk in Type 2 Diabetes and non-alcoholic fatty liver disease. Metabolism 2021; 123:154844. [PMID: 34343577 DOI: 10.1016/j.metabol.2021.154844] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 07/28/2021] [Accepted: 07/29/2021] [Indexed: 02/08/2023]
Abstract
Type 2 diabetes (T2D) and Non-Alcoholic Fatty Liver Disease (NAFLD) are pathologies whose prevalence continues to increase worldwide. Both diseases are precipitated by an excessive caloric intake, which promotes insulin resistance and fatty liver. The role of the intestine and its crosstalk with the liver in the development of these metabolic diseases is receiving increasing attention. Alterations in diet-intestinal microbiota interactions lead to the dysregulation of intestinal functions, resulting in altered metabolite and energy substrate production and increased intestinal permeability. Connected through the portal circulation, these changes in intestinal functions impact the liver and other metabolic organs, such as visceral adipose tissue, hence participating in the development of insulin resistance, and worsening T2D and NAFLD. Thus, targeting the intestine may be an efficient therapeutic approach to cure T2D and NAFLD. In this review, we will first introduce the signaling pathways linking T2D and NAFLD. Next, we will address the role of the gut-liver crosstalk in the development of T2D and NAFLD, with a particular focus on the gut microbiota and the molecular pathways behind the increased intestinal permeability and inflammation. Finally, we will summarize the therapeutic strategies which target the gut and its functions and are currently used or under development to treat T2D and NAFLD.
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Affiliation(s)
- Margaux Nawrot
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000 Lille, France
| | - Simon Peschard
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000 Lille, France
| | - Sophie Lestavel
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000 Lille, France
| | - Bart Staels
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000 Lille, France.
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23
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Gil-Gómez A, Brescia P, Rescigno M, Romero-Gómez M. Gut-Liver Axis in Nonalcoholic Fatty Liver Disease: the Impact of the Metagenome, End Products, and the Epithelial and Vascular Barriers. Semin Liver Dis 2021; 41:191-205. [PMID: 34107545 DOI: 10.1055/s-0041-1723752] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a systemic, dynamic, heterogeneous, and multiaxis entity, the pathogenesis of which is still uncertain. The gut-liver axis is regulated and stabilized by a complex network encompassing a metabolic, immune, and neuroendocrine cross-talk between the gut, the microbiota, and the liver. Changes in the gut-liver axis affect the metabolism of lipids and carbohydrates in the hepatocytes, and they impact the balance of inflammatory mediators and cause metabolic deregulation, promoting NAFLD and its progression to nonalcoholic steatohepatitis. Moreover, the microbiota and its metabolites can play direct and indirect roles in gut barrier function and fibrosis development. In this review, we will highlight findings from the recent literature focusing on the gut-liver axis and its relation to NAFLD. Finally, we will discuss the impact of technical issues, design bias, and other limitations on current knowledge of the gut microbiota in the context of NAFLD.
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Affiliation(s)
- Antonio Gil-Gómez
- SeLiver Group at Institute of Biomedicine of Seville (IBiS), Virgen del Rocio University Hospital/CSIC/University of Seville, Seville, Spain.,Hepatic and Digestive Diseases Networking Biomedical Research Centre (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Paola Brescia
- Humanitas Clinical and Research Center - IRCCS, Rozzano, Milan, Italy
| | - Maria Rescigno
- Humanitas Clinical and Research Center - IRCCS, Rozzano, Milan, Italy
| | - Manuel Romero-Gómez
- SeLiver Group at Institute of Biomedicine of Seville (IBiS), Virgen del Rocio University Hospital/CSIC/University of Seville, Seville, Spain.,Hepatic and Digestive Diseases Networking Biomedical Research Centre (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.,UCM Digestive Diseases, Virgen del Rocío University Hospital, Seville, Spain
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24
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Albhaisi S, Sanyal AJ. Does Nonalcoholic Fatty Liver Disease Increase the Risk for Extrahepatic Malignancies? Clin Liver Dis (Hoboken) 2021; 17:215-219. [PMID: 33868668 PMCID: PMC8043706 DOI: 10.1002/cld.1029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 08/02/2020] [Accepted: 08/15/2020] [Indexed: 02/04/2023] Open
Affiliation(s)
- Somaya Albhaisi
- Department of Internal MedicineVirginia Commonwealth UniversityRichmondVA
| | - Arun J. Sanyal
- Division of Gastroenterology, Hepatology and NutritionDepartment of Internal MedicineVirginia Commonwealth UniversityRichmondVA
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Lambrecht J, Tacke F. Controversies and Opportunities in the Use of Inflammatory Markers for Diagnosis or Risk Prediction in Fatty Liver Disease. Front Immunol 2021; 11:634409. [PMID: 33633748 PMCID: PMC7900147 DOI: 10.3389/fimmu.2020.634409] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Accepted: 12/29/2020] [Indexed: 12/12/2022] Open
Abstract
In the Western society, non-alcoholic fatty liver disease (NAFLD), characterized by the excessive accumulation of fat in the liver, represents the most common cause of chronic liver disease. If left untreated, approximately 15%-20% of patients with NAFLD will progress to non-alcoholic steatohepatitis (NASH), in which lobular inflammation, hepatocyte ballooning and fibrogenesis further contribute to a distorted liver architecture and function. NASH initiation has significant effects on liver-related mortality, as even the presence of early stage fibrosis increases the chances of adverse patient outcome. Therefore, adequate diagnostic tools for NASH are needed, to ensure that relevant therapeutic actions can be taken as soon as necessary. To date, the diagnostic gold standard remains the invasive liver biopsy, which is associated with several drawbacks such as high financial costs, procedural risks, and inter/intra-observer variability in histology analysis. As liver inflammation is a major hallmark of disease progression, inflammation-related circulating markers may represent an interesting source of non-invasive biomarkers for NAFLD/NASH. Examples for such markers include cytokines, chemokines or shed receptors from immune cells, circulating exosomes related to inflammation, and changing proportions of peripheral blood mononuclear cell (PBMC) subtypes. This review aims at documenting and critically discussing the utility of such novel inflammatory markers for NAFLD/NASH-diagnosis, patient stratification and risk prediction.
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Affiliation(s)
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany
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Jin Y, Wang H, Yi K, Lv S, Hu H, Li M, Tao Y. Applications of Nanobiomaterials in the Therapy and Imaging of Acute Liver Failure. NANO-MICRO LETTERS 2020; 13:25. [PMID: 34138224 PMCID: PMC8187515 DOI: 10.1007/s40820-020-00550-x] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 10/22/2020] [Indexed: 05/02/2023]
Abstract
This review focuses on the therapeutic mechanisms, targeting strategies of various nanomaterials in acute liver failure, and recent advances of diverse nanomaterials for acute liver failure therapy, diagnosis, and imaging. This review provides an outlook on the applications of nanomaterials, especially on the new horizons in acute liver failure therapy, and inspires broader interests across various disciplines. Acute liver failure (ALF), a fatal clinical disease featured with overwhelming hepatocyte necrosis, is a grand challenge in global health. However, a satisfactory therapeutic option for curing ALF is still absent, other than liver transplantation. Nanobiomaterials are currently being developed for the diagnosis and treatment of ALF. The liver can sequester most of nanoparticles from blood circulation, which becomes an intrinsic superiority for nanobiomaterials targeting hepatic diseases. Nanobiomaterials can enhance the bioavailability of free drugs, thereby significantly improving the therapeutic effects in ALF. Nanobiomaterials can also increase the liver accumulation of therapeutic agents and enable more effective targeting of the liver or specific liver cells. In addition, stimuli-responsive, optical, or magnetic nanomaterials exhibit great potential in the therapeutical, diagnostic, and imaging applications in ALF. Therefore, therapeutic agents in combination with nanobiomaterials increase the specificity of ALF therapy, diminish adverse systemic effects, and offer a multifunctional theranostic platform. Nanobiomaterial holds excellent significance and prospects in ALF theranostics. In this review, we summarize the therapeutic mechanisms and targeting strategies of various nanobiomaterials in ALF. We highlight recent developments of diverse nanomedicines for ALF therapy, diagnosis, and imaging. Furthermore, the challenges and future perspectives in the theranostics of ALF are also discussed.
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Affiliation(s)
- Yuanyuan Jin
- Laboratory of Biomaterials and Translational Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, People's Republic of China
| | - Haixia Wang
- Laboratory of Biomaterials and Translational Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, People's Republic of China
| | - Ke Yi
- Laboratory of Biomaterials and Translational Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, People's Republic of China
| | - Shixian Lv
- Department of Bioengineering, University of Washington, Seattle, WA, 98195, USA
| | - Hanze Hu
- Department of Biomedical Engineering, Columbia University, New York, NY, 10027, USA
| | - Mingqiang Li
- Laboratory of Biomaterials and Translational Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, People's Republic of China.
| | - Yu Tao
- Laboratory of Biomaterials and Translational Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, People's Republic of China.
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Kuchay MS, Choudhary NS, Mishra SK. Pathophysiological mechanisms underlying MAFLD. Diabetes Metab Syndr 2020; 14:1875-1887. [PMID: 32998095 DOI: 10.1016/j.dsx.2020.09.026] [Citation(s) in RCA: 94] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Revised: 09/21/2020] [Accepted: 09/23/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS The pathophysiology underlying metabolic associated fatty liver disease (MAFLD) involves a multitude of interlinked processes, including insulin resistance (IR) underlying the metabolic syndrome, lipotoxicity attributable to the accumulation of toxic lipid species, infiltration of proinflammatory cells causing hepatic injury and ultimately leading to hepatic stellate cell (HSC) activation and fibrogenesis. The proximal processes, such as IR, lipid overload and lipotoxicity are relatively well established, but the downstream molecular mechanisms, such as inflammatory processes, hepatocyte lipoapoptosis, and fibrogenesis are incompletely understood. METHODS A literature search was performed with Medline (PubMed), Scopus and Google Scholar electronic databases till June 2020, using relevant keywords (nonalcoholic fatty liver disease; metabolic associated fatty liver disease; nonalcoholic steatohepatitis; NASH pathogenesis) to extract relevant studies describing pathogenesis of MAFLD/MASH. RESULTS Several studies have reported new concepts underlying pathophysiology of MAFLD. Activation of HSCs is the common final pathway for diverse signals from damaged hepatocytes and proinflammatory cells. Activated HSCs then secrete excess extracellular matrix (ECM) which accumulates and impairs structure and function of the liver. TAZ (a transcriptional regulator), hedgehog (HH) ligands, transforming growth factor-β (TGF-β), bone morphogenetic protein 8B (BMP8B) and osteopontin play important roles in activating these HSCs. Dysfunctional gut microbiome, dysregulated bile acid metabolism, endogenous alcohol production, and intestinal fructose handling, modify individual susceptibility to MASH. CONCLUSIONS Newer concepts of pathophysiology underlying MASH, such as TAZ/Ihh pathway, extracellular vesicles, microRNA, dysfunctional gut microbiome and intestinal fructose handling present promising targets for the development of therapeutic agents.
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Affiliation(s)
- Mohammad Shafi Kuchay
- Division of Endocrinology and Metabolism, Medanta the Medicity Hospital, Gurugram, 122001, Haryana, India.
| | - Narendra Singh Choudhary
- Institute of Digestive and Hepatobiliary Sciences, Medanta-The Medicity Hospital, Gurugram, 122001, Haryana, India
| | - Sunil Kumar Mishra
- Division of Endocrinology and Metabolism, Medanta the Medicity Hospital, Gurugram, 122001, Haryana, India
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Adams LA, Chan WK. Noninvasive Tests in the Assessment of NASH and NAFLD Fibrosis: Now and Into the Future. Semin Liver Dis 2020; 40:331-338. [PMID: 32526784 DOI: 10.1055/s-0040-1713006] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Noninvasive serum and imaging methods offer accessible, accurate, and safe assessment of fibrosis severity in nonalcoholic fatty liver disease. In contrast, current serum and imaging methods for the prediction of nonalcoholic steatohepatitis are not sufficiently accurate for routine clinical use. Serum fibrosis markers that incorporate direct measures of fibrogenesis (for example, hyaluronic acid) or fibrinolysis are generally more accurate than biomarkers not incorporating direct measures of fibrogenesis. Elastography methods are more accurate than serum markers for fibrosis assessment and particularly for the determination of cirrhosis, but have a significant failure and/or unreliability rate in obese individuals. To overcome this, combining serum and elastography methods in a sequential manner minimizes indeterminate results and maintains accuracy. The accuracy of current noninvasive methods for monitoring fibrosis response to treatment are limited; however, new tools derived from "omic" methodologies offer promise for the future.
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Affiliation(s)
- Leon A Adams
- Medical School, Faculty of Medicine and Health Sciences, The University of Western Australia, Nedlands, Western Australia, Australia.,Department of Hepatology, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia
| | - Wah-Kheong Chan
- Department of Medicine, Gastroenterology and Hepatology Unit, University of Malaysia, Kuala Lumpur, Malaysia
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Knorr J, Wree A, Tacke F, Feldstein AE. The NLRP3 Inflammasome in Alcoholic and Nonalcoholic Steatohepatitis. Semin Liver Dis 2020; 40:298-306. [PMID: 32526788 DOI: 10.1055/s-0040-1708540] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Nonalcoholic steatohepatitis (NASH) and alcoholic hepatitis (ASH) are advanced forms of fatty liver diseases that are associated with a high morbidity and mortality worldwide. Patients with ASH or NASH are more susceptible to the progression of fibrosis and cirrhosis up to the development of hepatocellular carcinoma. Currently, there are limited medical therapies available. Accompanied by the asymptomatic disease progression, the demand for liver transplants is high. This review provides an overview about the growing evidence for a central role of NLR family pyrin domain containing 3 (NLRP3) inflammasome, a multiprotein complex that acts as a central driver of inflammation via activation of caspase 1, maturation and release of pro-inflammatory cytokines including interleukin-1β, and trigger of inflammatory pyroptotic cell death in both NASH and ASH. We also discuss potential therapeutic approaches targeting NLRP3 inflammasome and related upstream and downstream pathways to develop prognostic biomarkers and medical treatments for both liver diseases.
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Affiliation(s)
- Jana Knorr
- Department of Hepatology and Gastroenterology, Charité Campus Mitte and Campus Virchow Clinic, Charité University Medicine, Berlin, Germany
| | - Alexander Wree
- Department of Hepatology and Gastroenterology, Charité Campus Mitte and Campus Virchow Clinic, Charité University Medicine, Berlin, Germany.,Department of Pediatric Gastroenterology, University of California, San Diego (UCSD), San Diego, California and Rady Children's Hospital, San Diego, California
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité Campus Mitte and Campus Virchow Clinic, Charité University Medicine, Berlin, Germany
| | - Ariel E Feldstein
- Department of Pediatric Gastroenterology, University of California, San Diego (UCSD), San Diego, California and Rady Children's Hospital, San Diego, California
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Katsarou A, Moustakas II, Pyrina I, Lembessis P, Koutsilieris M, Chatzigeorgiou A. Metabolic inflammation as an instigator of fibrosis during non-alcoholic fatty liver disease. World J Gastroenterol 2020; 26:1993-2011. [PMID: 32536770 PMCID: PMC7267690 DOI: 10.3748/wjg.v26.i17.1993] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 04/09/2020] [Accepted: 04/20/2020] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive storage of fatty acids in the form of triglycerides in hepatocytes. It is most prevalent in western countries and includes a wide range of clinical and histopathological findings, namely from simple steatosis to steatohepatitis and fibrosis, which may lead to cirrhosis and hepatocellular cancer. The key event for the transition from steatosis to fibrosis is the activation of quiescent hepatic stellate cells (qHSC) and their differentiation to myofibroblasts. Pattern recognition receptors (PRRs), expressed by a plethora of immune cells, serve as essential components of the innate immune system whose function is to stimulate phagocytosis and mediate inflammation upon binding to them of various molecules released from damaged, apoptotic and necrotic cells. The activation of PRRs on hepatocytes, Kupffer cells, the resident macrophages of the liver, and other immune cells results in the production of proinflammatory cytokines and chemokines, as well as profibrotic factors in the liver microenvironment leading to qHSC activation and subsequent fibrogenesis. Thus, elucidation of the inflammatory pathways associated with the pathogenesis and progression of NAFLD may lead to a better understanding of its pathophysiology and new therapeutic approaches.
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Affiliation(s)
- Angeliki Katsarou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
- 251 Hellenic Airforce General Hospital, Athens 11525, Greece
| | - Ioannis I Moustakas
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Iryna Pyrina
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine Carl Gustav Carus of TU Dresden, Dresden 01307, Germany
| | - Panagiotis Lembessis
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Michael Koutsilieris
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Antonios Chatzigeorgiou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine Carl Gustav Carus of TU Dresden, Dresden 01307, Germany.
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Tilg H, Effenberger M, Adolph TE. A role for IL-1 inhibitors in the treatment of non-alcoholic fatty liver disease (NAFLD)? Expert Opin Investig Drugs 2019; 29:103-106. [PMID: 31615278 DOI: 10.1080/13543784.2020.1681397] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Maria Effenberger
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Timon E Adolph
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria
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Tilg H, Zmora N, Adolph TE, Elinav E. The intestinal microbiota fuelling metabolic inflammation. Nat Rev Immunol 2019; 20:40-54. [DOI: 10.1038/s41577-019-0198-4] [Citation(s) in RCA: 377] [Impact Index Per Article: 62.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/05/2019] [Indexed: 02/06/2023]
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Puris E, Pasanen M, Ranta VP, Gynther M, Petsalo A, Käkelä P, Männistö V, Pihlajamäki J. Laparoscopic Roux-en-Y gastric bypass surgery influenced pharmacokinetics of several drugs given as a cocktail with the highest impact observed for CYP1A2, CYP2C8 and CYP2E1 substrates. Basic Clin Pharmacol Toxicol 2019; 125:123-132. [PMID: 30916845 DOI: 10.1111/bcpt.13234] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2019] [Accepted: 02/26/2019] [Indexed: 12/15/2022]
Abstract
There is a lack of information about the changes in drug pharmacokinetics and cytochrome P450 (CYP) metabolism after bariatric surgery. Here, we investigated the effects of laparoscopic Roux-en-Y gastric bypass (LRYGB) surgery on pharmacokinetics of nine drugs given simultaneously which may reveal changes in the activities of the main CYPs. Eight obese subjects undergoing LRYGB received an oral cocktail containing nine drugs, substrates of various CYPs: melatonin (CYP1A2), nicotine (CYP2A6), bupropion (CYP2B6), repaglinide (CYP2C8), losartan (CYP2C9), omeprazole (CYP2C19/CYP3A4), dextromethorphan (CYP2D6), chlorzoxazone (CYP2E1) and midazolam (CYP3A). The 6-hours pharmacokinetic profiles in serum and urine of each drug or corresponding metabolite as well as their metabolic ratios were compared before surgery with those at a median 1 year later. LRYGB exerted variable effects on the pharmacokinetics of these drugs. The geometric mean AUC0-6 (90% confidence interval) of melatonin, bupropion, repaglinide, chlorzoxazone and midazolam after LRYGB was 27 (19%-41%), 54 (43%-67%), 44 (29%-66%), 160 (129%-197%) and 74 (62%-90%) of the pre-surgery values, respectively. The pharmacokinetics of losartan, omeprazole and dextromethorphan did not change in response to surgery. Nicotine was not detected in serum, while geometric mean of AUC0-6 of its metabolite, cotinine, increased by 1.7 times after surgery. There were 3.6- and 1.3-fold increases in the AUC ratios of 6-hydroxymelatonin/melatonin and hydroxybupropion/bupropion, respectively. The cocktail revealed multiple pharmacokinetic changes occurring after LRYGB with the greatest effects observed for CYP1A2, CYP2C8 and CYP2E1 substrates. Future studies should be focused on CYP1A2, CYP2A6, CYP2C8 and CYP2B6 to clarify the changes in activities of these enzymes after LRYGB.
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Affiliation(s)
- Elena Puris
- School of Pharmacy, University of Eastern Finland, Kuopio, Finland
| | - Markku Pasanen
- School of Pharmacy, University of Eastern Finland, Kuopio, Finland
| | - Veli-Pekka Ranta
- School of Pharmacy, University of Eastern Finland, Kuopio, Finland
| | - Mikko Gynther
- School of Pharmacy, University of Eastern Finland, Kuopio, Finland
| | | | - Pirjo Käkelä
- Institute of Clinical Medicine, Surgery, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
| | - Ville Männistö
- Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
| | - Jussi Pihlajamäki
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.,Institute of Medicine and Clinical Nutrition, Kuopio University Hospital, Kuopio, Finland
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Interleukin-1 Receptor Antagonist Modulates Liver Inflammation and Fibrosis in Mice in a Model-Dependent Manner. Int J Mol Sci 2019; 20:ijms20061295. [PMID: 30875826 PMCID: PMC6471711 DOI: 10.3390/ijms20061295] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Revised: 03/04/2019] [Accepted: 03/06/2019] [Indexed: 12/19/2022] Open
Abstract
Background: Interleukin-1 (IL-1)β and IL-1 receptor antagonist (IL-1Ra) have been proposed as important mediators during chronic liver diseases. We aimed to determine whether the modulation of IL-1β signaling with IL-1Ra impacts on liver fibrosis. Methods: We assessed the effects of IL-1β on human hepatic stellate cells (HSC) and in mouse models of liver fibrosis induced by bile duct ligation (BDL) or carbon tetrachloride treatment (CCl-4). Results: Human HSCs treated with IL-1β had increased IL-1β, IL-1Ra, and MMP-9 expressions in vitro. HSCs treated with IL-1β had reduced α-smooth muscle actin expression. These effects were all prevented by IL-1Ra treatment. In the BDL model, liver fibrosis and Kuppfer cell numbers were increased in IL-1Ra KO mice compared to wild type mice and wild type mice treated with IL-1Ra. In contrast, after CCl-4 treatment, fibrosis, HSC and Kupffer cell numbers were decreased in IL-1Ra KO mice compared to the other groups. IL-1Ra treatment provided a modest protective effect in the BDL model and was pro-fibrotic in the CCl-4 model. Conclusions: We demonstrated bivalent effects of IL-1Ra during liver fibrosis in mice. IL-1Ra was detrimental in the CCl-4 model, whereas it was protective in the BDL model. Altogether these data suggest that blocking IL-1-mediated inflammation may be beneficial only in selective liver fibrotic disease.
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Grabherr F, Grander C, Effenberger M, Adolph TE, Tilg H. Gut Dysfunction and Non-alcoholic Fatty Liver Disease. Front Endocrinol (Lausanne) 2019; 10:611. [PMID: 31555219 PMCID: PMC6742694 DOI: 10.3389/fendo.2019.00611] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Accepted: 08/22/2019] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has emerged as one of the leading liver diseases worldwide. NAFLD is characterized by hepatic steatosis and may progress to an inflammatory condition termed non-alcoholic steatohepatitis (NASH), liver cirrhosis, and hepatocellular carcinoma. It became evident in the last years that NAFLD pathophysiology is complex and involves diverse immunological and metabolic pathways. An association between intestinal signals (e.g., derived from the gut microbiota) and the development of obesity and its metabolic consequences such as NAFLD are increasingly recognized. Pre-clinical studies have shown that germ-free mice are protected against obesity and hepatic steatosis. Several human studies from the past years have demonstrated that NAFLD contains a disease-specific gut microbiome signature. Controlled studies propose that certain bacteria with rather pro-inflammatory features such as Proteobacteria or Escherichia coli are dominantly present in these patients. In contrast, rather protective bacteria such as Faecalibacterium prausnitzii are decreased in NAFLD patients. Furthermore, various bacterial metabolites and microbiota-generated secondary bile acids are involved in NAFLD-associated metabolic dysfunction. Although these findings are exciting, research currently lack evidence that interference at the level of the gut microbiome is beneficial for these diseases. Further preclinical and clinical studies are needed to advance this aspect of NAFLD research and to support the notion that the intestinal microbiota is indeed of major relevance in this disorder.
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Abstract
BACKGROUND AND AIMS Different bariatric procedures have been associated with variable weight loss and decrease in serum levels of lipids and lipoproteins. This variation could be partly related to the length of the small intestinal bypass. We evaluated the association of the small intestinal length with the non-alcoholic fatty liver disease (NAFLD) at baseline and with lipid metabolism before and after laparoscopic Roux-en-Y gastric bypass (LRYGB). METHODS Seventy consecutive morbidly obese patients were recruited to this prospective study. A standard 60-cm biliopancreatic limb (BPL) and 120-cm alimentary limb (AL) was performed, and thereafter, the common channel (CC) length was measured during elective LRYGB. Histological analysis of liver biopsy to diagnose NAFLD was performed. The mRNA expression of genes participating in the cholesterol and fatty acid metabolism in the liver was analyzed. RESULTS Female sex (p = 0.006), serum triglycerides (TG, p = 0.016), serum alanine aminotransferase (ALT, p = 0.007), and liver steatosis (p = 0.001) associated with the small intestinal length (BPL + AL + CC) at baseline. Association remained significant between levels of serum TG and CC length (p = 0.048) at 1-year follow-up. Liver mRNA expression of genes regulating cholesterol synthesis and bile metabolism did not associate with the baseline small intestinal length. CONCLUSIONS Our findings support the suggestions that small intestinal length regulates TG metabolism before and after LRYGB. Therefore, modification of the length of bypassed small intestine based on measured total small intestinal length could optimize the outcomes of the elective LRYGB.
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Intke C, Korpelainen S, Hämäläinen S, Vänskä M, Koivula I, Jantunen E, Pulkki K, Juutilainen A. Interleukin-1 receptor antagonist as a biomarker of sepsis in neutropenic haematological patients. Eur J Haematol 2018; 101:691-698. [PMID: 30099772 DOI: 10.1111/ejh.13161] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Revised: 08/04/2018] [Accepted: 08/06/2018] [Indexed: 12/26/2022]
Abstract
OBJECTIVE The study aim was to compare the performance of interleukin-1 receptor antagonist (IL-1Ra) to C-reactive protein (CRP) and procalcitonin (PCT) in early prediction of the clinical course of febrile neutropenia. METHODS The study population consisted of 86 consecutive patients with febrile neutropenia who received intensive chemotherapy for haematological malignancy between November 2009 and November 2012 at the adult haematology ward of Kuopio University Hospital. Twenty-three (27%) patients had acute myeloid leukaemia and 63 (73%) patients were autologous stem cell transplant recipients. IL-1Ra, CRP and procalcitonin were measured at the onset of fever (d0), on day 1 (d1) and on day 2 (d2). RESULTS Eight patients developed severe sepsis, including three patients with septic shock. Eighteen patients had bacteraemia. After the onset of febrile neutropenia Youden´s indices (with their 95% confidence intervals) to identify severe sepsis were for IL-1Ra on d0 0.57 (0.20-0.71) and on d1 0.65 (0.28-0.78), for CRP on d0 0.41 (0.04-0.61) and on d1 0.47 (0.11-0.67) and for PCT on d0 0.39 (0.05-0.66) and on d1 0.52 (0.18-0.76). CONCLUSIONS In haematological patients, IL-1Ra has a comparable capacity with CRP and PCT to predict severe sepsis at the early stages of febrile neutropenia.
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Affiliation(s)
- Carina Intke
- Department of Medicine, Kuopio University Hospital, Kuopio, Finland
| | - Sini Korpelainen
- Institute of Clinical Medicine/Internal Medicine, University of Eastern Finland, Kuopio, Finland
| | - Sari Hämäläinen
- Department of Medicine, Kuopio University Hospital, Kuopio, Finland
| | - Matti Vänskä
- Department of Internal Medicine, Tampere University Hospital, Tampere, Finland
| | - Irma Koivula
- Department of Medicine, Kuopio University Hospital, Kuopio, Finland
| | - Esa Jantunen
- Department of Medicine, Kuopio University Hospital, Kuopio, Finland
- Institute of Clinical Medicine/Internal Medicine, University of Eastern Finland, Kuopio, Finland
- Siun Sote - Hospital District of North Carelia, Joensuu, Finland
| | - Kari Pulkki
- Eastern Finland Laboratory Centre, Kuopio, Finland
- Laboratory Division, Turku University Central Hospital and Department of Clinical Chemistry, Faculty of Medicine, University of Turku, Turku, Finland
| | - Auni Juutilainen
- Department of Medicine, Kuopio University Hospital, Kuopio, Finland
- Institute of Clinical Medicine/Internal Medicine, University of Eastern Finland, Kuopio, Finland
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WITHDRAWN: Cytokines and fatty liver diseases. LIVER RESEARCH 2018. [DOI: 10.1016/j.livres.2018.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Abstract
Background and aims: Non-alcoholic fatty liver disease (NAFLD) associates with low levels of serum plant sterols in cross-sectional studies. In addition, it has been suggested that the hepatic sterol transport mechanisms are altered in NAFLD. Therefore, we investigated the association between serum, liver and bile plant sterols and sitostanol with NAFLD. Methods: Out of the 138 individuals (age: 46.3 ± 8.9, body mass index: 43.3 ± 6.9 kg/m², 28% men and 72% women), 44 could be histologically categorized to have normal liver, and 94 to have NAFLD. Within the NAFLD group, 28 had simple steatosis and 27 had non-alcoholic steatohepatitis. Plant sterols and sitostanol were measured from serum (n=138), liver (n=38), and bile (n=41). The mRNA expression of genes regulating liver sterol metabolism and inflammation was measured (n=102). Results: Liver and bile sitostanol ratios to cholesterol were higher in those with NAFLD compared to those with histologically normal liver (all P<0.022). Furthermore, liver sitostanol to cholesterol ratio correlated positively with histological steatosis and lobular inflammation (rs > 0.407, P<0.01 for both). In contrast, liver sitosterol to cholesterol ratio correlated negatively with steatosis (rs = −0.392, P=0.015) and lobular inflammation (rs = −0.395, P=0.014). Transcriptomics analysis revealed suggestive correlations between serum plant sterol levels and mRNA expression. Conclusion: Our study showed that liver and bile sitostanol ratios to cholesterol associated positively and liver sitosterol ratio to cholesterol associated negatively with liver steatosis and inflammation in obese individuals with NAFLD..
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Ramírez-López G, Morán-Villota S, Mendoza-Carrera F, Portilla-de Buen E, Valles-Sánchez V, Castro-Martínez XH, Sánchez-Corona J, Salmerón J. Metabolic and genetic markers' associations with elevated levels of alanine aminotransferase in adolescents. J Pediatr Endocrinol Metab 2018; 31:407-414. [PMID: 29584615 DOI: 10.1515/jpem-2017-0217] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Accepted: 01/22/2018] [Indexed: 01/07/2023]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease in adolescents, is a feature of metabolic syndrome (MetS). Obesity and insulin resistance (IR) are risk factors for NAFLD, as well as inflammation-related genetic markers. The relationship between metabolic or inflammation-related genetic markers and alanine aminotransferase (ALT) is not fully understood. We examined the relationship of MetS, metabolic and inflammation-related genetic markers with elevated ALT in adolescents. METHODS A total of 674 adolescents participated in a cross-sectional study in Guadalajara, Mexico. Elevated ALT (>40 IU/L), a surrogate marker of NAFLD, and MetS (International Diabetes Federation definition) were evaluated. Obesity, IR, lipids, C-reactive protein (CRP) and genetic markers (TNFA-308G>A, CRP+1444C>T, IL1RN and IL6-597/-572/-174 haplotype) were evaluated. Multivariate logistic regression was performed. RESULTS Elevated ALT was observed in 3% and 14.1% (total and obese, respectively) of the adolescents. Obesity (odds ratio [OR], 5.86; 95% confidence interval [95% CI], 1.16-25.89), insulin (OR, 8.51; 95% CI, 2.61-27.71), IR (OR, 9.10; 95% CI, 2.82-29.38), total cholesterol (TC) (OR, 3.67; 95% CI, 1.25-10.72), low-density lipoprotein-cholesterol (LDL-C) (OR, 3.06; 95% CI, 1.06-8.33), non-high-density lipoprotein-cholesterol (HDL-C) (OR, 3.88; 95% CI, 1.27-11.90) and IL1RN (OR, 4.64; 95% CI, 1.10-19.53) were associated with elevated ALT. Among males, ≥2 MetS criteria were associated with elevated ALT (OR, 4.22; 95% CI, 1.14-15.71). CONCLUSIONS Obesity, insulin, IR, high TC, high LDL-C, high non-HDL-C and IL1RN polymorphism were associated with elevated ALT. Among males, ≥2 MetS criteria were associated with elevated ALT. There is an urgent need to reduce obesity and IR in adolescents to prevent NAFLD.
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Affiliation(s)
- Guadalupe Ramírez-López
- Adolescent Epidemiological and Health Services Research Unit, Mexican Institute of Social Security, Av. Tonalá 121, Tonalá, Jalisco, 45400, México
| | - Segundo Morán-Villota
- Laboratory of Gastrohepatology Research, Pediatric Hospital, XXI Century Medical Center, Mexican Institute of Social Security, Mexico City, Mexico
| | - Francisco Mendoza-Carrera
- Molecular Medicine Division, Western Biomedical Research Center, Mexican Institute of Social Security, Guadalajara, Jalisco, Mexico
| | - Eliseo Portilla-de Buen
- Surgical Research Division, Western Biomedical Research Center, Mexican Institute of Social Security, Guadalajara, Jalisco, Mexico
| | - Victoria Valles-Sánchez
- Department of Endocrinology, National Institute of Medical Science and Nutrition "Salvador Zubirán", Mexico City, Mexico
| | - Xochitl H Castro-Martínez
- Molecular Medicine Division, Western Biomedical Research Center, Mexican Institute of Social Security, Guadalajara, Jalisco, Mexico
| | - José Sánchez-Corona
- Molecular Medicine Division, Western Biomedical Research Center, Mexican Institute of Social Security, Guadalajara, Jalisco, Mexico
| | - Jorge Salmerón
- Academic Unit in Epidemiological Research, Research Center on Policies, Population and Health, School of Medicine, National Autonomous University of Mexico, Mexico City, Mexico
- Center for Population Health Research, National Institute of Public Health, Cuernavaca, Morelos, Mexico
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Li YW, Zhang C, Sheng QJ, Bai H, Ding Y, Dou XG. Mesenchymal stem cells rescue acute hepatic failure by polarizing M2 macrophages. World J Gastroenterol 2017; 23:7978-7988. [PMID: 29259373 PMCID: PMC5725292 DOI: 10.3748/wjg.v23.i45.7978] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Revised: 10/01/2017] [Accepted: 11/01/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate whether M1 or M2 polarization contributes to the therapeutic effects of mesenchymal stem cells (MSCs) in acute hepatic failure (AHF).
METHODS MSCs were transfused into rats with AHF induced by D-galactosamine (DGalN). The therapeutic effects of MSCs were evaluated based on survival rate and hepatocyte proliferation and apoptosis. Hepatocyte regeneration capacity was evaluated by the expression of the hepatic progenitor surface marker epithelial cell adhesion molecule (EpCAM). Macrophage polarization was analyzed by M1 markers [CD68, tumor necrosis factor alpha (TNF-α), interferon-γ (IFN-γ), inducible nitric oxide synthase (INOS)] and M2 markers [CD163, interleukin (IL)-4, IL-10, arginase-1 (Arg-1)] in the survival and death groups after MSC transplantation.
RESULTS The survival rate in the MSC-treated group was increased compared with the DPBS-treated control group (37.5% vs 10%). MSC treatment protected rats with AHF by reducing apoptotic hepatocytes and promoting hepatocyte regeneration. Immunohistochemical analysis showed that MSC treatment significantly increased the expression of EpCAM compared with the control groups (P < 0.001). Expression of EpCAM in the survival group was significantly up-regulated compared with the death group after MSC transplantation (P = 0.003). Transplantation of MSCs significantly improved the expression of CD163 and increased the gene expression of IL-10 and Arg-1 in the survival group. IL-4 concentrations were significantly increased compared to the death group after MSC transplantation (88.51 ± 24.51 pg/mL vs 34.61 ± 6.6 pg/mL, P < 0.001). In contrast, macrophages showed strong expression of CD68, TNF-α, and INOS in the death group. The concentration of IFN-γ was significantly increased compared to the survival group after MSC transplantation (542.11 ± 51.59 pg/mL vs 104.07 ± 42.80 pg/mL, P < 0.001).
CONCLUSION M2 polarization contributes to the therapeutic effects of MSCs in AHF by altering levels of anti-inflammatory and pro-inflammatory factors.
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Affiliation(s)
- Yan-Wei Li
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang 110022, Liaoning Province, China
| | - Chong Zhang
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang 110022, Liaoning Province, China
| | - Qiu-Ju Sheng
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang 110022, Liaoning Province, China
| | - Han Bai
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang 110022, Liaoning Province, China
| | - Yang Ding
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang 110022, Liaoning Province, China
| | - Xiao-Guang Dou
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang 110022, Liaoning Province, China
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Drori A, Rotnemer-Golinkin D, Avni S, Drori A, Danay O, Levanon D, Tam J, Zolotarev L, Ilan Y. Attenuating the rate of total body fat accumulation and alleviating liver damage by oral administration of vitamin D-enriched edible mushrooms in a diet-induced obesity murine model is mediated by an anti-inflammatory paradigm shift. BMC Gastroenterol 2017; 17:130. [PMID: 29179679 PMCID: PMC5704499 DOI: 10.1186/s12876-017-0688-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Accepted: 11/17/2017] [Indexed: 02/08/2023] Open
Abstract
Background Hypovitaminosis D is associated with many features of the metabolic syndrome, including non-alcoholic fatty liver disease. Vitamin D-enriched mushrooms extracts exert a synergistic anti-inflammatory effect. The aim of the present study is to determine the immunomodulatory effect of oral administration of vitamin D-enriched mushrooms extracts on high-fat diet (HFD) animal model of non-alcoholic steatohepatitis (NASH). Methods C57BL/6 mice on HFD were orally administered with vitamin D supplement, Lentinula edodes (LE) mushrooms extract, or vitamin D-enriched mushrooms extract for 25 weeks. Mice were studied for the effect of the treatment on the immune system, liver functions and histology, insulin resistance and lipid profile. Results Treatment with vitamin D-enriched LE extracts was associated with significant attenuation of the rate of total body fat accumulation, along with a decrease in hepatic fat content as measured by an EchoMRI. Significant alleviation of liver damage manifested by a marked decrease in ALT, and AST serum levels (from 900 and 1021 U/L in the control group to 313 and 340; 294 and 292; and 366 and 321 U/L for ALT and AST, in Vit D, LE and LE + Vit D treated groups, respectively). A corresponding effect on hepatocyte ballooning were also noted. A significant decrease in serum triglycerides (from 103 to 75, 69 and 72 mg/dL), total cholesterol (from 267 to 160, 157 and 184 mg/dL), and LDL cholesterol (from 193 mg/dL to 133, 115 and 124 mg/dL) along with an increase in the HDL/LDL ratio, and improved glucose levels were documented. These beneficial effects were associated with a systemic immunomodulatory effect associated with an increased CD4/CD8 lymphocyte ratio (from 1.38 in the control group to 1.69, 1.71 and 1.63), and a pro- to an anti-inflammatory cytokine shift. Conclusions Oral administration of vitamin-D enriched mushrooms extracts exerts an immune modulatory hepato-protective effect in NASH model.
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Affiliation(s)
- A Drori
- Gastroenterology and Liver Units, Department of Medicine, Hadassah-Hebrew University Medical Center, P.O.B 12000, -91120, Jerusalem, IL, Israel
| | - D Rotnemer-Golinkin
- Gastroenterology and Liver Units, Department of Medicine, Hadassah-Hebrew University Medical Center, P.O.B 12000, -91120, Jerusalem, IL, Israel
| | - S Avni
- Migal, Galilee Research Institute, Kiryat Shmona, Israel
| | - A Drori
- Obesity and Metabolism Laboratory, The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - O Danay
- Migal, Galilee Research Institute, Kiryat Shmona, Israel
| | - D Levanon
- Migal, Galilee Research Institute, Kiryat Shmona, Israel
| | - J Tam
- Obesity and Metabolism Laboratory, The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - L Zolotarev
- Gastroenterology and Liver Units, Department of Medicine, Hadassah-Hebrew University Medical Center, P.O.B 12000, -91120, Jerusalem, IL, Israel
| | - Y Ilan
- Gastroenterology and Liver Units, Department of Medicine, Hadassah-Hebrew University Medical Center, P.O.B 12000, -91120, Jerusalem, IL, Israel.
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Neuvonen M, Tarkiainen EK, Tornio A, Hirvensalo P, Tapaninen T, Paile-Hyvärinen M, Itkonen MK, Holmberg MT, Kärjä V, Männistö VT, Neuvonen PJ, Pihlajamäki J, Backman JT, Niemi M. Effects of Genetic Variants on Carboxylesterase 1 Gene Expression, and Clopidogrel Pharmacokinetics and Antiplatelet Effects. Basic Clin Pharmacol Toxicol 2017; 122:341-345. [DOI: 10.1111/bcpt.12916] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Accepted: 09/25/2017] [Indexed: 01/27/2023]
Affiliation(s)
- Mikko Neuvonen
- Department of Clinical Pharmacology; University of Helsinki and Helsinki University Hospital; Helsinki Finland
| | - E. Katriina Tarkiainen
- Department of Clinical Pharmacology; University of Helsinki and Helsinki University Hospital; Helsinki Finland
| | - Aleksi Tornio
- Department of Clinical Pharmacology; University of Helsinki and Helsinki University Hospital; Helsinki Finland
| | - Päivi Hirvensalo
- Department of Clinical Pharmacology; University of Helsinki and Helsinki University Hospital; Helsinki Finland
| | - Tuija Tapaninen
- Department of Clinical Pharmacology; University of Helsinki and Helsinki University Hospital; Helsinki Finland
| | - Maria Paile-Hyvärinen
- Department of Clinical Pharmacology; University of Helsinki and Helsinki University Hospital; Helsinki Finland
| | - Matti K. Itkonen
- Department of Clinical Pharmacology; University of Helsinki and Helsinki University Hospital; Helsinki Finland
| | - Mikko T. Holmberg
- Department of Clinical Pharmacology; University of Helsinki and Helsinki University Hospital; Helsinki Finland
| | - Vesa Kärjä
- Department of Pathology; Kuopio University Hospital; Kuopio Finland
| | - Ville T. Männistö
- Department of Medicine; University of Eastern Finland; Kuopio Finland
| | - Pertti J. Neuvonen
- Department of Clinical Pharmacology; University of Helsinki and Helsinki University Hospital; Helsinki Finland
| | - Jussi Pihlajamäki
- Department of Public Health and Clinical Nutrition; University of Eastern Finland; Kuopio Finland
- Clinical Nutrition and Obesity Center; Kuopio University Hospital; Kuopio Finland
| | - Janne T. Backman
- Department of Clinical Pharmacology; University of Helsinki and Helsinki University Hospital; Helsinki Finland
| | - Mikko Niemi
- Department of Clinical Pharmacology; University of Helsinki and Helsinki University Hospital; Helsinki Finland
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45
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Hirvensalo P, Tornio A, Neuvonen M, Tapaninen T, Paile-Hyvärinen M, Kärjä V, Männistö VT, Pihlajamäki J, Backman JT, Niemi M. Comprehensive Pharmacogenomic Study Reveals an Important Role of UGT1A3 in Montelukast Pharmacokinetics. Clin Pharmacol Ther 2017; 104:158-168. [PMID: 28940478 PMCID: PMC6033076 DOI: 10.1002/cpt.891] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Revised: 09/01/2017] [Accepted: 09/19/2017] [Indexed: 12/17/2022]
Abstract
To identify the genetic basis of interindividual variability in montelukast exposure, we determined its pharmacokinetics and sequenced 379 pharmacokinetic genes in 191 healthy volunteers. An intronic single nucleotide variation (SNV), strongly linked with UGT1A3*2, associated with reduced area under the plasma concentration–time curve (AUC0‐∞) of montelukast (by 18% per copy of the minor allele; P = 1.83 × 10−10). UGT1A3*2 was associated with increased AUC0‐∞ of montelukast acyl‐glucuronide M1 and decreased AUC0‐∞ of hydroxymetabolites M5R, M5S, and M6 (P < 10−9). Furthermore, SNVs in SLCO1B1 and ABCC9 were associated with the AUC0‐∞ of M1 and M5R, respectively. In addition, a candidate gene analysis suggested that CYP2C8 and ABCC9 SNVs also affect the AUC0‐∞ of montelukast. The found UGT1A3 and ABCC9 variants associated with increased expression of the respective genes in human liver samples. Montelukast and its hydroxymetabolites were glucuronidated by UGT1A3 in vitro. These results indicate that UGT1A3 plays an important role in montelukast pharmacokinetics, especially in UGT1A3*2 carriers.
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Affiliation(s)
- Päivi Hirvensalo
- Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Aleksi Tornio
- Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Mikko Neuvonen
- Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Tuija Tapaninen
- Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Maria Paile-Hyvärinen
- Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Vesa Kärjä
- Department of Pathology, Kuopio University Hospital, Kuopio, Finland
| | - Ville T Männistö
- Department of Medicine, University of Eastern Finland, Kuopio, Finland
| | - Jussi Pihlajamäki
- Department of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.,Clinical Nutrition and Obesity Center, Kuopio University Hospital, Kuopio, Finland
| | - Janne T Backman
- Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Mikko Niemi
- Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
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46
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Adams LA, Anstee QM, Tilg H, Targher G. Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases. Gut 2017; 66:1138-1153. [PMID: 28314735 DOI: 10.1136/gutjnl-2017-313884] [Citation(s) in RCA: 776] [Impact Index Per Article: 97.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Revised: 02/14/2017] [Accepted: 02/16/2017] [Indexed: 02/07/2023]
Abstract
Key physiological functions of the liver, including glucose and lipid metabolism, become disturbed in the setting of non-alcoholic fatty liver disease (NAFLD) and may be associated with a systemic inflammatory 'milieu' initiated in part by liver-secreted cytokines and molecules. Consequently, the pathophysiological effects of NAFLD extend beyond the liver with a large body of clinical evidence demonstrating NAFLD to be independently associated with both prevalent and incident cardiovascular disease (CVD), chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM). The magnitude of risk of developing these extrahepatic diseases parallels the underlying severity of NAFLD, such that patients with non-alcoholic steatohepatitis (NASH) appear to be at greater risk of incident CVD, CKD and T2DM than those with simple steatosis. Other modifiers of risk may include genetic variants (eg, patatin-like phospholipase domain-containing 3 and trans-membrane 6 superfamily member 2 polymorphisms), visceral adipose tissue accumulation, dietary intake and the gut microbiome. Emerging data also suggest that NAFLD may be a risk factor for colonic neoplasia and reduced bone mineral density, especially among men. Importantly, improvement/resolution of NAFLD is associated with a reduced incidence of T2DM and improved kidney function, adding weight to causality and suggesting liver focused treatments may reduce risk of extrahepatic complications. Awareness of these associations is important for the clinicians such that CVD risk factor management, screening for T2DM and CKD are part of the routine management of patients with NAFLD.
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Affiliation(s)
- Leon A Adams
- School of Medicine and Pharmacology, The University of Western Australia, Nedlands, Western Australia, Australia
| | - Quentin M Anstee
- Faculty of Medical Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK.,Liver Unit, Newcastle Upon Tyne Hospitals NHS Trust, Freeman Hospital, Newcastle upon Tyne, UK
| | - Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Hepatology & Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Giovanni Targher
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
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Vaittinen M, Männistö V, Käkelä P, Ågren J, Tiainen M, Schwab U, Pihlajamäki J. Interorgan cross talk between fatty acid metabolism, tissue inflammation, and FADS2 genotype in humans with obesity. Obesity (Silver Spring) 2017; 25:545-552. [PMID: 28145068 DOI: 10.1002/oby.21753] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Revised: 11/21/2016] [Accepted: 11/28/2016] [Indexed: 12/25/2022]
Abstract
OBJECTIVE Fatty acid (FA) composition affects obesity-associated low-grade inflammation. It has been shown that the fatty acid desaturase (FADS) 2 gene polymorphism associates with FA metabolism and adipose tissue (AT) inflammation. This study aimed to investigate the relationship between FA metabolism and inflammation in different tissues and the possible interorgan cross talk. METHODS Cross-sectional baseline data from 155 individuals with obesity (both male and female) participating in the Roux-en-Y gastric bypass operation in the ongoing Kuopio Obesity Surgery Study were used. Gas chromatograph for FA composition, liver histology, and targeted RNA expression for gene expression profile were performed. RESULTS It was demonstrated that the saturated fatty acid (SFA) proportion in AT correlated positively with inflammation in subcutaneous AT (SAT) and visceral AT (VAT) but not in the liver, while the monounsaturated fatty acid (MUFA) proportion in SAT and VAT correlated negatively with AT inflammation. Notably, there was a positive correlation between AT n-6 polyunsaturated fatty acids (PUFAs), but not AT SFAs or MUFAs, and liver inflammation. This correlation was modified by the FADS2 genotype. CONCLUSIONS The AT FA profile relates with AT inflammation. Additionally, there seems to be a complex interaction, partly regulated by the FADS2 genotype, regulating the interaction between FAs in AT and liver inflammation.
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Affiliation(s)
- Maija Vaittinen
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
- Turku PET Centre, Turku University Hospital, Finland
| | - Ville Männistö
- Departments of Medicine, University of Eastern Finland and Kuopio University Hospital, Finland
| | - Pirjo Käkelä
- Department of Surgery, University of Eastern Finland and Kuopio University Hospital, Finland
| | - Jyrki Ågren
- Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
| | - Mika Tiainen
- School of Pharmacy, University of Eastern Finland, Kuopio, Finland
| | - Ursula Schwab
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
- Clinical Nutrition and Obesity Center, Kuopio University Hospital, Kuopio, Finland
| | - Jussi Pihlajamäki
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
- Clinical Nutrition and Obesity Center, Kuopio University Hospital, Kuopio, Finland
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Kim JW, Yun H, Choi SJ, Lee SH, Park S, Lim CW, Lee K, Kim B. Evaluating the Influence of Side Stream Cigarette Smoke at an Early Stage of Non-Alcoholic Steatohepatitis Progression in Mice. Toxicol Res 2017; 33:31-41. [PMID: 28133511 PMCID: PMC5266378 DOI: 10.5487/tr.2017.33.1.031] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Accepted: 11/23/2016] [Indexed: 12/29/2022] Open
Abstract
Side stream cigarette smoke (SSCS) is known to be as harmful and hazardous to human health as is active smoking. In this study, we investigated the relationship between the exposure to SSCS and its stimulatory and subacute effects on the progression of non-alcoholic steatohepatitis (NASH). A methionine and choline-deficient plus high fat (MCDHF) diet was administered to C57BL/6 mice for 6 weeks. During the first three weeks of MCDHF diet feeding, each diet group was exposed to SSCS (0, 20, 40 μg/L) or fresh air for 2 hrs per day and 5 days per week. Additional experiments were performed by increasing the concentration (0, 30, 60 μg/L) and exposure time (6 hours per day) of SSCS. According to histopathologic analysis and serum levels of Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST), there were no differences in hepatic fat deposition, fibrosis, apoptosis or liver damage in MCDHF-fed mice based on SSCS exposure. There were also no differences in the expression of inflammation-, oxidative stress- or fibrosis-related genes between MCDHF-fed mice with or without SSCS exposure. Therefore, it is concluded that SSCS with current exposure amounts does not have additive detrimental effects on the early stage of NASH.
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Affiliation(s)
- Jong Won Kim
- Biosafety Research Institute and Laboratory of Pathology (BK21 Plus Program), College of Veterinary Medicine, Chonbuk National University, Iksan, Korea
| | - Hyejin Yun
- Biosafety Research Institute and Laboratory of Pathology (BK21 Plus Program), College of Veterinary Medicine, Chonbuk National University, Iksan, Korea
| | - Seong-Jin Choi
- Inhalation Toxicology Center, Jeonbuk Department of Inhalation Research, Korea Institute of Toxicology, Jeongeup, Korea
| | - Sang-Hyub Lee
- Inhalation Toxicology Center, Jeonbuk Department of Inhalation Research, Korea Institute of Toxicology, Jeongeup, Korea
| | - Surim Park
- Biosafety Research Institute and Laboratory of Pathology (BK21 Plus Program), College of Veterinary Medicine, Chonbuk National University, Iksan, Korea
| | - Chae Woong Lim
- Biosafety Research Institute and Laboratory of Pathology (BK21 Plus Program), College of Veterinary Medicine, Chonbuk National University, Iksan, Korea
| | - Kyuhong Lee
- Inhalation Toxicology Center, Jeonbuk Department of Inhalation Research, Korea Institute of Toxicology, Jeongeup, Korea
| | - Bumseok Kim
- Biosafety Research Institute and Laboratory of Pathology (BK21 Plus Program), College of Veterinary Medicine, Chonbuk National University, Iksan, Korea
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Laakso M, Kuusisto J, Stančáková A, Kuulasmaa T, Pajukanta P, Lusis AJ, Collins FS, Mohlke KL, Boehnke M. The Metabolic Syndrome in Men study: a resource for studies of metabolic and cardiovascular diseases. J Lipid Res 2017; 58:481-493. [PMID: 28119442 DOI: 10.1194/jlr.o072629] [Citation(s) in RCA: 130] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Revised: 01/15/2017] [Indexed: 12/30/2022] Open
Abstract
The Metabolic Syndrome in Men (METSIM) study is a population-based study including 10,197 Finnish men examined in 2005-2010. The aim of the study is to investigate nongenetic and genetic factors associated with the risk of T2D and CVD, and with cardiovascular risk factors. The protocol includes a detailed phenotyping of the participants, an oral glucose tolerance test, fasting laboratory measurements including proton NMR measurements, mass spectometry metabolomics, adipose tissue biopsies from 1,400 participants, and a stool sample. In our ongoing follow-up study, we have, to date, reexamined 6,496 participants. Extensive genotyping and exome sequencing have been performed for essentially all METSIM participants, and >2,000 METSIM participants have been whole-genome sequenced. We have identified several nongenetic markers associated with the development of diabetes and cardiovascular events, and participated in several genetic association studies to identify gene variants associated with diabetes, hyperglycemia, and cardiovascular risk factors. The generation of a phenotype and genotype resource in the METSIM study allows us to proceed toward a "systems genetics" approach, which includes statistical methods to quantitate and integrate intermediate phenotypes, such as transcript, protein, or metabolite levels, to provide a global view of the molecular architecture of complex traits.
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Affiliation(s)
- Markku Laakso
- Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland .,Department of Medicine, Kuopio University Hospital, Kuopio, Finland
| | - Johanna Kuusisto
- Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland.,Department of Medicine, Kuopio University Hospital, Kuopio, Finland
| | - Alena Stančáková
- Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland
| | - Teemu Kuulasmaa
- Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland
| | - Päivi Pajukanta
- Departments of Human Genetics David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA.,Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA
| | - Aldons J Lusis
- Departments of Human Genetics David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA.,Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA
| | - Francis S Collins
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD
| | - Karen L Mohlke
- Department of Genetics, University of North Carolina, Chapel Hill, NC
| | - Michael Boehnke
- Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI
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50
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Walenbergh SMA, Houben T, Rensen SS, Bieghs V, Hendrikx T, van Gorp PJ, Oligschlaeger Y, Jeurissen MLJ, Gijbels MJJ, Buurman WA, Vreugdenhil ACE, Greve JWM, Plat J, Hofker MH, Kalhan S, Pihlajamäki J, Lindsey P, Koek GH, Shiri-Sverdlov R. Plasma cathepsin D correlates with histological classifications of fatty liver disease in adults and responds to intervention. Sci Rep 2016; 6:38278. [PMID: 27922112 PMCID: PMC5138820 DOI: 10.1038/srep38278] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Accepted: 10/25/2016] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is characterized by liver lipid accumulation and inflammation. The mechanisms that trigger hepatic inflammation are poorly understood and subsequently, no specific non-invasive markers exist. We previously demonstrated a reduction in the plasma lysosomal enzyme, cathepsin D (CatD), in children with NASH compared to children without NASH. Recent studies have raised the concept that non-alcoholic fatty liver disease (NAFLD) in adults is distinct from children due to a different histological pattern in the liver. Yet, the link between plasma CatD to adult NASH was not examined. In the current manuscript, we investigated whether plasma CatD in adults correlates with NASH development and regression. Biopsies were histologically evaluated for inflammation and NAFLD in three complementary cohorts of adults (total n = 248). CatD and alanine aminotransferase (ALT) were measured in plasma. Opposite to our previous observations with childhood NASH, we observed increased levels of plasma CatD in patients with NASH compared to adults without hepatic inflammation. Furthermore, after surgical intervention, we found a reduction of plasma CatD compared to baseline. Our observations highlight a distinct pathophysiology between NASH in children and adults. The observation that plasma CatD correlated with NASH development and regression is promising for NASH diagnosis.
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Affiliation(s)
- Sofie M A Walenbergh
- Molecular Genetics, General Surgery, Paediatrics, Pathology, Population Genetics, Human Biology, Maastricht University Medical Centre, 6200MD, Maastricht, The Netherlands
| | - Tom Houben
- Molecular Genetics, General Surgery, Paediatrics, Pathology, Population Genetics, Human Biology, Maastricht University Medical Centre, 6200MD, Maastricht, The Netherlands
| | - Sander S Rensen
- Molecular Genetics, General Surgery, Paediatrics, Pathology, Population Genetics, Human Biology, Maastricht University Medical Centre, 6200MD, Maastricht, The Netherlands
| | - Veerle Bieghs
- Molecular Genetics, General Surgery, Paediatrics, Pathology, Population Genetics, Human Biology, Maastricht University Medical Centre, 6200MD, Maastricht, The Netherlands
| | - Tim Hendrikx
- Molecular Genetics, General Surgery, Paediatrics, Pathology, Population Genetics, Human Biology, Maastricht University Medical Centre, 6200MD, Maastricht, The Netherlands
| | - Patrick J van Gorp
- Molecular Genetics, General Surgery, Paediatrics, Pathology, Population Genetics, Human Biology, Maastricht University Medical Centre, 6200MD, Maastricht, The Netherlands
| | - Yvonne Oligschlaeger
- Molecular Genetics, General Surgery, Paediatrics, Pathology, Population Genetics, Human Biology, Maastricht University Medical Centre, 6200MD, Maastricht, The Netherlands
| | - Mike L J Jeurissen
- Molecular Genetics, General Surgery, Paediatrics, Pathology, Population Genetics, Human Biology, Maastricht University Medical Centre, 6200MD, Maastricht, The Netherlands
| | - Marion J J Gijbels
- Molecular Genetics, General Surgery, Paediatrics, Pathology, Population Genetics, Human Biology, Maastricht University Medical Centre, 6200MD, Maastricht, The Netherlands
| | - Wim A Buurman
- Molecular Genetics, General Surgery, Paediatrics, Pathology, Population Genetics, Human Biology, Maastricht University Medical Centre, 6200MD, Maastricht, The Netherlands
| | - Anita C E Vreugdenhil
- Molecular Genetics, General Surgery, Paediatrics, Pathology, Population Genetics, Human Biology, Maastricht University Medical Centre, 6200MD, Maastricht, The Netherlands
| | - Jan Willem M Greve
- Surgery, Atrium Medical Center Parkstad, 6419PC, Heerlen, The Netherlands
| | - Jogchum Plat
- Molecular Genetics, General Surgery, Paediatrics, Pathology, Population Genetics, Human Biology, Maastricht University Medical Centre, 6200MD, Maastricht, The Netherlands
| | - Marten H Hofker
- Pathology and Medical Biology, Molecular Genetics, Medical Biology Section, University Medical Center Groningen, 9713GZ, Groningen, The Netherlands
| | - Satish Kalhan
- Pathobiology, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, USA
| | - Jussi Pihlajamäki
- Clinical Nutrition, University of Eastern Finland, FI-70211 Kuopio, Finland.,Clinical Nutrition and Obesity Center, Kuopio University Hospital, FI-70211 Kuopio, Finland
| | - Patrick Lindsey
- Molecular Genetics, General Surgery, Paediatrics, Pathology, Population Genetics, Human Biology, Maastricht University Medical Centre, 6200MD, Maastricht, The Netherlands
| | - Ger H Koek
- Internal Medicine, Division of Gastroenterology and Hepatology, Maastricht University Medical Centre, 6200MD, Maastricht, The Netherlands
| | - Ronit Shiri-Sverdlov
- Molecular Genetics, General Surgery, Paediatrics, Pathology, Population Genetics, Human Biology, Maastricht University Medical Centre, 6200MD, Maastricht, The Netherlands
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