المؤلفون: Remmerie, Anneleen, Martens, Liesbet, Scott, Charlotte

المصدر: FRONTIERS IN ENDOCRINOLOGY ; ISSN: 1664-2392

مصطلحات موضوعية: Biology and Life Sciences, Medicine and Health Sciences, NONALCOHOLIC STEATOHEPATITIS, LOCAL PROLIFERATION, HEPATIC RECRUITMENT, ADIPOCYTE DEATH, SPI-C, CELLS, INFLAMMATION, DEPLETION, NICHE, POLARIZATION, macrophages, adipose tissue, non-alcoholic fatty liver disease (NAFLD), single-cell, heterogeneity, liver, NASH (non-alcoholic steatohepatitis)

الوصف: The increasing prevalence of obesity is accompanied by a rising incidence in metabolic syndrome and related pathologies such as non-alcoholic fatty liver disease. Macrophages are hypothesized to play central roles in these diseases, through their role as inflammatory mediators and as such are thought to be potential targets for future therapies. Recently, single cell technologies have revealed significant heterogeneity within the macrophage pool in both liver and adipose tissue in obesity. Thus current efforts are focused on dissecting this heterogeneity and understanding the distinct functions of the individual subsets. In this review, we discuss the current knowledge regarding macrophage heterogeneity, ontogeny and functions in the context of obese adipose tissue and fatty liver disease and attempt to align the distinct populations described to date.

وصف الملف: text/plain

العلاقة: https://biblio.ugent.be/publication/8672783Test; http://hdl.handle.net/1854/LU-8672783Test; http://dx.doi.org/10.3389/fendo.2020.00259Test; https://biblio.ugent.be/publication/8672783/file/8672784Test

الإتاحة: https://doi.org/10.3389/fendo.2020.00259Test
https://biblio.ugent.be/publication/8672783Test
http://hdl.handle.net/1854/LU-8672783Test
https://biblio.ugent.be/publication/8672783/file/8672784Test

المؤلفون: Hans-Peter Hammes, Elena Heidenreich, Peter P. Nawroth, Martina U. Muckenthaler, Sandro Altamura, Thomas Fleming, Andrea Schlotterer, Katja Müdder, Ruiyue Qiu

المصدر: Molecular Metabolism, Vol 51, Iss, Pp 101235-(2021)
Molecular Metabolism

مصطلحات موضوعية: 0301 basic medicine, Blood Glucose, Male, DR, diabetic retinopathy, Hepcidin, medicine.disease_cause, Mice, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, MetS, Metabolic Syndrome, Internal medicine, biology, Fpn, Ferroportin, Fatty liver, Liver, DIOS, dysmetabolic iron overload syndrome, CRP, C-reactive protein, Receptors, Leptin, HH, hereditary hemochromatosis, Original Article, IRP, Iron Regulatory Protein, medicine.medical_specialty, Iron Overload, Iron, 030209 endocrinology & metabolism, Mice, Transgenic, IR, Insulin Resistance, SEM, standard error of the mean, 03 medical and health sciences, Insulin resistance, ROS, reactive oxygen species, NASH, Non Alcoholic Steatohepatitis, NAFLD, medicine, Animals, Humans, Molecular Biology, business.industry, NTBI, Non Transferrin Bound Iron, Cell Biology, medicine.disease, RC31-1245, IRS1, Db/db Mouse, Disease Models, Animal, Oxidative Stress, 030104 developmental biology, Endocrinology, Diabetes Mellitus, Type 2, biology.protein, NAFLD, Non Alcoholic Fatty Liver Disease, Lipid Peroxidation, Steatosis, Metabolic syndrome, business, Oxidative stress, IRE, Iron Responsive Element, T2DM, Type 2 Diabetes Mellitus

الوصف: Objective The molecular pathogenesis of late complications associated with type 2 diabetes mellitus (T2DM) is not yet fully understood. While high glucose levels indicated by increased HbA1c only poorly explain disease progression and late complications, a pro-inflammatory status, oxidative stress, and reactive metabolites generated by metabolic processes were postulated to be involved. Individuals with metabolic syndrome (MetS) frequently progress to T2DM, whereby 70% of patients with T2DM show non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of MetS, and insulin resistance (IR). Epidemiological studies have shown that T2DM and steatosis are associated with alterations in iron metabolism and hepatic iron accumulation. Excess free iron triggers oxidative stress and a switch towards a macrophage pro-inflammatory status. However, so far it remains unclear whether hepatic iron accumulation plays a causative role in the generation of IR and T2DM or whether it is merely a manifestation of altered hepatic metabolism. To address this open question, we generated and characterized a mouse model of T2DM with IR, steatosis, and iron overload. Methods Leprdb/db mice hallmarked by T2DM, IR and steatosis were crossed with Fpnwt/C326S mice with systemic iron overload to generate Leprdb/db/Fpnwt/C326S mice. The resulting progeny was characterized for major diabetic and iron-related parameters. Results We demonstrated that features associated with T2DM in Leprdb/db mice, such as obesity, steatosis, or IR, reduce the degree of tissue iron overload in Fpnwt/C326S mice, suggesting an ‘iron resistance’ phenotype. Conversely, we observed increased serum iron levels that strongly exceeded those in the iron-overloaded Fpnwt/C326S mice. Increased hepatic iron levels induced oxidative stress and lipid peroxidation and aggravated IR, as indicated by diminished IRS1 phosphorylation and AKT activation. Additionally, in the liver, we observed gene response patterns indicative of de novo lipogenesis and increased gluconeogenesis as well as elevated free glucose levels. Finally, we showed that iron overload in Leprdb/db/Fpnwt/C326S mice enhances microvascular complications observed in retinopathy, suggesting that iron accumulation can enhance diabetic late complications associated with the liver and the eye. Conclusion Taken together, our data show that iron causes the worsening of symptoms associated with the MetS and T2DM. These findings imply that iron depletion strategies together with anti-diabetic drugs may ameliorate IR and diabetic late complications.
Highlights • T2DM causes an iron resistance phenotype. • Iron affects hepatic insulin resistance. • Systemic iron accumulation aggravates diabetic pericyte loss.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::746ad7abfa625d87337f2502f8e59462Test
http://www.sciencedirect.com/science/article/pii/S2212877821000806Test

المؤلفون: Julie Rodriguez, Nathalie M. Delzenne, Christelle Knudsen, Audrey M. Neyrinck, Martin Beaumont, Laure B. Bindels

المساهمون: UCL - SSS/LDRI - Louvain Drug Research Institute, Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université Catholique de Louvain = Catholic University of Louvain (UCL), Génétique Physiologie et Systèmes d'Elevage (GenPhySE ), École nationale supérieure agronomique de Toulouse [ENSAT]-Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Wallonia (FOOD4GUT project) 1318148 / EU 613979 MyNewGut FP7-609398

المصدر: The Proceedings of the Nutrition Society, Vol. 78, no. 3, p. 319-328 (2019)
Proceedings of the Nutrition Society
Proceedings of the Nutrition Society, Cambridge University Press (CUP), 2019, 78 (3), pp.319-328. ⟨10.1017/S0029665118002756⟩

مصطلحات موضوعية: GLP glucagon-like peptide, 0301 basic medicine, non-alcoholic fatty liver desease, Medicine (miscellaneous), Gut flora, Bioinformatics, Mice, GPR G protein-coupled receptors, 0302 clinical medicine, NASH non-alcoholic steatohepatitis, Non-alcoholic Fatty Liver Disease, Nutrition and Dietetics, Fatty liver, 3. Good health, Liver, NAFLD non-alcoholic fatty liver disease, prebiotic, ALT alanine aminotransferase, 030211 gastroenterology & hepatology, medicine.symptom, ITF inulin-type fructans, [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], Inflammation, Gut microbiota, Biology, digestive system, 03 medical and health sciences, BA bile acid, medicine, Animals, Humans, gut microbiota, Host (biology), Probiotics, FXR farnesoid X receptor, AST aspartate aminotransferase, Metabolism, medicine.disease, biology.organism_classification, Obesity, Gastrointestinal Microbiome, Disease Models, Animal, Prebiotics, 030104 developmental biology, AhR aryl hydrocarbon receptor, inflammation, LPS lipopolysaccharides, Farnesoid X receptor, Energy Metabolism, Function (biology), Non-alcoholic fatty liver disease

الوصف: This review presents mechanistic studies performed in vitro and in animal models, as well as data obtained in patients that contribute to a better understanding of the impact of nutrients interacting with the gut microbiota on metabolic and behavioural alterations linked to obesity. The gut microbiota composition and function are altered in several pathological conditions including obesity and related diseases i.e. non-alcoholic fatty liver diseases (NAFLD). The gut–liver axis is clearly influenced by alterations of the gut barrier that drives inflammation. In addition, recent papers propose that specific metabolites issued from the metabolic cooperation between the gut microbes and host enzymes, modulate inflammation and gene expression in the liver. This review illustrates how dietary intervention with prebiotics or probiotics influences host energy metabolism and inflammation. Indeed, intervention studies are currently underway in obese and NAFLD patients to unravel the relevance of the changes in gut microbiota composition in the management of metabolic and behavioural disorders by nutrients interacting with the gut microbiota. In conclusion, diet is among the main triggers of NAFLD and the gut microbiota is modified accordingly, underlining the importance of the concomitant study of the nutrients and microbial impact on liver health and metabolism, in order to propose innovative, clinically relevant, therapeutic approaches.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::18e56d9d5d0ddd04fa33e558922e0d67Test
https://doi.org/10.1017/s0029665118002756Test

المؤلفون: Carrie E. McCurdy, Kenneth N. Maclean, Paul Kievit, Bryan C. Bergman, Rachel C. Janssen, Peter R. Baker, Christopher M. Mulligan, Tyler Dean, Diana L. Takahashi, Travis Nemkov, Kjersti Aagaard, Hua Jiang, Stephanie R. Wesolowski, Angelo D'Alessandro, Jacob E. Friedman

المصدر: Molecular Metabolism, Vol 18, Iss, Pp 25-41 (2018)
Molecular Metabolism

مصطلحات موضوعية: 0301 basic medicine, Steatosis, VIP, variable importance in projection, Hypoxemia, AUC, area under the curve, PC, phosphatidylcholine, 0302 clinical medicine, WSD, Western-style diet, Non-alcoholic Fatty Liver Disease, Pregnancy, Fetal programming, Hyperlipidemia, DAG, diacylglyceride, VLDL, very low-density lipoprotein, Hypoxia, 2. Zero hunger, TG, triglyceride, NEFA, non-esterified fatty acid, NHP, non-human primate, Fatty liver, 3. Good health, Liver, Lipotoxicity, CON, control, OB-WSD, Western-style diet induced obesity group, IV-GTT, intravenous glucose tolerance test, Prenatal Exposure Delayed Effects, Original Article, Female, Diet, Healthy, PLS-DA, partial least squares discriminant analysis, TCA, tricarboxylic acid cycle, NAFLD, non-alcoholic fatty liver disease, lcsh:Internal medicine, medicine.medical_specialty, Offspring, NASH, non-alcoholic steatohepatitis, Citric Acid Cycle, Metabolomic, 030209 endocrinology & metabolism, DNL, de novo lipogenesis, TBARs, thiobarbituric acid reactive substances, OB-DR, diet reversal group, 03 medical and health sciences, Fetus, Internal medicine, medicine, TBARS, Animals, Obesity, AA, amino acid, lcsh:RC31-1245, Molecular Biology, Triglycerides, business.industry, Gluconeogenesis, Maternal Nutritional Physiological Phenomena, Cell Biology, medicine.disease, Oxidative Stress, 030104 developmental biology, Endocrinology, Diet, Western, Macaca, business

الوصف: Objective Non-alcoholic fatty liver disease (NAFLD) risk begins in utero in offspring of obese mothers. A critical unmet need in this field is to understand the pathways and biomarkers underlying fetal hepatic lipotoxicity and whether maternal dietary intervention during pregnancy is an effective countermeasure. Methods We utilized a well-established non-human primate model of chronic, maternal, Western-style diet induced obesity (OB-WSD) compared with mothers on a healthy control diet (CON) or a subset of OB-WSD mothers switched to the CON diet (diet reversal; OB-DR) prior to and for the duration of the next pregnancy. Fetuses were studied in the early 3rd trimester. Results Fetuses from OB-WSD mothers had higher circulating triglycerides (TGs) and lower arterial oxygenation suggesting hypoxemia, compared with fetuses from CON and OB-DR mothers. Hepatic TG content, oxidative stress (TBARs), and de novo lipogenic genes were increased in fetuses from OB-WSD compared with CON mothers. Fetuses from OB-DR mothers had lower lipogenic gene expression and TBARs yet persistently higher TGs. Metabolomic profiling of fetal liver and serum (umbilical artery) revealed distinct separation of CON and OB-WSD groups, and an intermediate phenotype in fetuses from OB-DR mothers. Pathway analysis identified decreased tricarboxylic acid cycle intermediates, increased amino acid (AA) metabolism and byproducts, and increased gluconeogenesis, suggesting an increased reliance on AA metabolism to meet energy needs in the liver of fetuses from OB-WSD mothers. Components in collagen synthesis, including serum protein 5-hydroxylysine and hepatic lysine and proline, were positively correlated with hepatic TGs and TBARs, suggesting early signs of fibrosis in livers from the OB-WSD group. Importantly, hepatic gluconeogenic and arginine related intermediates and serum levels of lactate, pyruvate, several AAs, and nucleotide intermediates were normalized in the OB-DR group. However, hepatic levels of CDP-choline and total ceramide levels remained high in fetuses from OB-DR mothers. Conclusions Our data provide new metabolic evidence that, in addition to fetal hepatic steatosis, maternal WSD creates fetal hypoxemia and increases utilization of AAs for energy production and early activation of gluconeogenic pathways in the fetal liver. When combined with hyperlipidemia and limited antioxidant activity, the fetus suffers from hepatic oxidative stress and altered intracellular metabolism which can be improved with maternal diet intervention. Our data reinforce the concept that multiple “first hits” occur in the fetus prior to development of obesity and demonstrate new biomarkers with potential clinical implications for monitoring NAFLD risk in offspring.
Graphical abstract Image 1
Highlights • Maternal WSD increases fetal hypoxemia and utilization of AAs for gluconeogenesis. • Maternal WSD increases fetal oxidative stress and precursors to liver fibrosis. • Carnosine and l-proline uniquely correlated with fetal TG and oxidative stress. • Fetal TGs were correlated with fetal arterial oxygen saturation. • Diet reversal in obese WSD mothers prevents fetal hypoxemia and oxidative stress.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b06dccd8288a52f01636dbe7fd72ba0fTest
https://doi.org/10.1016/j.molmet.2018.09.008Test

المؤلفون: Saeko Takami, Kazue Honma, Toshinao Goda, Kaho Oshima

المصدر: Metabolism Open
Metabolism Open, Vol 7, Iss, Pp 100043-(2020)

مصطلحات موضوعية: medicine.medical_specialty, NAFLD, non-alcoholic fatty liver disease, Antioxidant, medicine.medical_treatment, NaB, sodium butyrate, NASH, non-alcoholic steatohepatitis, HDAC, histone deacetylase, Butyrate, SCFAs, short-chain fatty acids, lcsh:Physiology, lcsh:Biochemistry, chemistry.chemical_compound, ROS, reactive oxygen species, Internal medicine, medicine, Ingestion, lcsh:QD415-436, Non-alcoholic steatohepatitis (NASH), Beta oxidation, Fatty acid synthesis, lcsh:QP1-981, Sodium butyrate, Lipid metabolism, General Medicine, medicine.disease, Original Research Paper, Endocrinology, chemistry, Liver, Steatohepatitis

الوصف: Background: Rapid influx of energy caused by fasting/refeeding repeatedly enhances fatty acid synthesis leading to triacylglycerol accumulation and production of reactive oxygen species (ROS), increasing the risk of non-alcoholic steatohepatitis (NASH). Previous studies have reported that the ingestion of butyrate is effective at preventing hepatic disorders, which are accompanied by fat accumulation and inflammation. The aim of this study is to reveal the mechanism of action of butyrate, and thus we investigated the effects of dietary butyrate on the expressions of antioxidant enzymes in the livers of rats during refeeding following fasting. Methods: Thirty-seven male rats were divided into six groups (6–7 animals per group): non-fasting, fasting, refeeding with a high sucrose diet as control for 12 or 24 h, and refeeding with a high sucrose diet containing 5% sodium butyrate (NaB) for 12 or 24 h. All groups except the non-fasting group were fasted for 72 h before refeeding. Statistical analysis was conducted among 4 refeeding groups (refeeding with the control diet for 12 or 24 h, and refeeding with a diet containing NaB for 12 or 24 h). Results: Supplementation with NaB significantly reduced (p

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f140eed2a39d2d480edbe3bc327e8656Test
https://pubmed.ncbi.nlm.nih.gov/32812944Test

المؤلفون: Anneleen Remmerie, Liesbet Martens, Charlotte L. Scott

المصدر: Frontiers in Endocrinology
FRONTIERS IN ENDOCRINOLOGY
Frontiers in Endocrinology, Vol 11 (2020)

مصطلحات موضوعية: 0301 basic medicine, POLARIZATION, Endocrinology, Diabetes and Metabolism, ADIPOCYTE DEATH, Adipose tissue, 030209 endocrinology & metabolism, Inflammation, Context (language use), Disease, Review, Biology, liver, lcsh:Diseases of the endocrine glands. Clinical endocrinology, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, INFLAMMATION, Non-alcoholic Fatty Liver Disease, LOCAL PROLIFERATION, medicine, Medicine and Health Sciences, Macrophage, Animals, Humans, NASH (non-alcoholic steatohepatitis), Obesity, Metabolic Syndrome, lcsh:RC648-665, NONALCOHOLIC STEATOHEPATITIS, HEPATIC RECRUITMENT, Macrophages, Fatty liver, NICHE, Biology and Life Sciences, single-cell, medicine.disease, macrophages, adipose tissue, 030104 developmental biology, Immunology, CELLS, Metabolic syndrome, medicine.symptom, DEPLETION, Inflammation Mediators, heterogeneity, SPI-C, non-alcoholic fatty liver disease (NAFLD)

الوصف: The increasing prevalence of obesity is accompanied by a rising incidence in metabolic syndrome and related pathologies such as non-alcoholic fatty liver disease. Macrophages are hypothesized to play central roles in these diseases, through their role as inflammatory mediators and as such are thought to be potential targets for future therapies. Recently, single cell technologies have revealed significant heterogeneity within the macrophage pool in both liver and adipose tissue in obesity. Thus current efforts are focused on dissecting this heterogeneity and understanding the distinct functions of the individual subsets. In this review, we discuss the current knowledge regarding macrophage heterogeneity, ontogeny and functions in the context of obese adipose tissue and fatty liver disease and attempt to align the distinct populations described to date.

وصف الملف: text/plain

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::03d4176e5893622d3bdbf0e1629d38caTest
https://pubmed.ncbi.nlm.nih.gov/32411096Test

المؤلفون: F. Tuccillo, Joseph L. Evans, Antonella Borrelli, Franco M. Buonaguro, Ira D. Goldfine, P. Bonelli, Aldo Mancini

المصدر: Redox Biology, Vol 15, Iss C, Pp 467-479 (2018)
Redox Biology

مصطلحات موضوعية: Cirrhosis, HCC, Hepatocellular carcinoma, MnSOD, Manganese superoxide dismutase, Review Article, ecSOD, Extracellular Cu/ZnSOD, Biochemistry, Antioxidants, GIT, Gastrointestinal tract, 0302 clinical medicine, Fibrosis, MS, Metabolic syndrome, GLP-1, Glucagon-like peptide-1, LPS, Lipopolysaccharide, lcsh:QH301-705.5, Interventions, DASH, Drug-associated steatohepatitis, SSAO, Semicarbazide-sensitive amine oxidase, NKT, Natural killer T, Liver Neoplasms, NAFLD, Non-alcoholic fatty liver disease, PAMPs, Pathogen-associated molecular patterns (PAMPs), LPL, Lipoprotein lipase, PNPLA3, Patatin-like phospholipase 3, 030211 gastroenterology & hepatology, SCD1, Stearoyl-coenzyme A desaturase 1, AST, Aspartate aminotransferase, PGC-1α, Coactivator peroxisome proliferator-activated receptor-γ-1α, INT-747, Obeticholic acid (OCA), lcsh:Medicine (General), NADH, Nicotinamide adenine dinucleotide, LPB, Lipopolysaccharide-binding protein, Carcinoma, Hepatocellular, FIAF, Fasting-induced adipose factor, CS + WR, Cold storage and warm reperfusion, GF, Germ-free, FADH, Flavin adenine dinucleotide, NO, Nitric oxide, digestive system, CCR2/CCR5, C-C chemokine receptor types 2 and 5, 03 medical and health sciences, Manganese superoxide dismutase, Humans, CD14, Cluster of differentiation 14, NASH, Non-alcoholic steatohepatitis, Probiotics, nutritional and metabolic diseases, medicine.disease, VLX103, Venlafaxine-103, digestive system diseases, PIVENS, Pioglitazone versus Vitamin E versus Placebo, 030104 developmental biology, chemistry, PASH, PNPLA3-associated steatohepatitis, FXR, Farnesoid X receptor, CASH, Chemotherapy-associated steatohepatitis, LOXL, Lysyl oxidase and lysyl oxidase-like, Steatohepatitis, Reactive Oxygen Species, Mkt, Market, ROS, Reactive oxygen species, TZDs, Thiazolidinediones, 0301 basic medicine, ETC, Respiratory electron transport chain, Clinical Biochemistry, VAP-1, Vascular adhesion protein-1, PXS-4728A, SSAO/VAP-1 inhibitor BI 1467335, HVPG, Hepatic venous pressure gradient, •OH, Hydroxyl free radicals, HPC, Primary hepatic carcinoma, Chronic liver disease, SOD, Superoxide dismutase, FGF21, Fibroblast growth factor 21, aa, Amino acid, chemistry.chemical_compound, BASH, Both alcoholic and non-alcoholic liver disease, Non-alcoholic Fatty Liver Disease, H2, Molecular hydrogen, lcsh:R5-920, NAS, NAFLD activity score, medicine.diagnostic_test, NN2211, Liraglutide, O2, Molecular oxygen, Fatty liver, Elafibranor, Obeticholic acid, Drugs, ER, Estrogen receptor, IL-10, Interleukin-10, Liver, Liver biopsy, JNK, c-Jun N-terminal kinase, ASK1, Apoptosis signal- regulating kinase 1, Cu/ZnSOD, Copper/zinc superoxide dismutase, RG-125 AZD4076, N-acetylgalactosamine (GalNAc)-conjugated anti-miR-103/107 oligonucleotide, TLR, Toll-like receptor, H. pilory, Helicobacter pylori, HSCs, Hepatic stellate cells, PPAR, Peroxisome proliferator-activated receptor, medicine, ATP, Adenosine 5c-triphosphate, IL-6, Interleukin-6, MDA, Malondialdehyde, γgt, Gamma-glutamyl transferase, business.industry, Organic Chemistry, ALT, Alanine aminotransferase, TNF, Tumor necrosis factor, NF-κB, Nuclear factor kappa, O2·–, Superoxide anion, FGF19, Fibroblast growth factor 19, Gastrointestinal Microbiome, DPP-4 inhibitor, Dipeptidyl peptidase 4 inhibitor, FDA, Food and drug administration, Oxidative Stress, CVC, Cenicriviroc, lcsh:Biology (General), FFA, Free fatty acids, Cancer research, NAP, H. pylori-induced neutrophil-activating protein, Saroglitazar-ZYH1, [(S)-α-ethoxy-4-{2-[2-methyl-5-(4-methylthio) phenyl)]-1H-pyrrol-1-yl]-ethoxy})-benzenepropanoic acid magnesium salt], business

الوصف: Non-alcoholic fatty liver disease (NAFLD) represents the most common chronic liver disease in industrialized countries. NAFLD progresses through the inflammatory phase of non-alcoholic steatohepatitis (NASH) to fibrosis and cirrhosis, with some cases developing liver failure or hepatocellular carcinoma (HCC). Liver biopsy remains the gold standard approach to a definitive diagnosis of NAFLD and the distinction between simple steatosis and NASH. The pathogenesis of NASH is still not clear. Several theories have been proposed ranging from the "Two Hit Theory" to the "Multiple Hit Theory". However, the general consensus is that the gut microbiota, oxidative stress, and mitochondrial damage play key roles in the pathogenesis of NASH. The interaction between the gut epithelia and some commensal bacteria induces the rapid generation of reactive oxygen species (ROS). The main goal of any therapy addressing NASH is to reverse or prevent progression to liver fibrosis/cirrhosis. This problem represents the first "Achilles' heel" of the new molecules being evaluated in most ongoing clinical trials. The second is the inability of these molecules to reach the mitochondria, the primary sites of energy production and ROS generation. Recently, a variety of non-pharmacological and pharmacological treatment approaches for NASH have been evaluated including vitamin E, the thiazolidinediones, and novel molecules related to NASH pathogenesis (including obeticholic acid and elafibranor). Recently, a new isoform of human manganese superoxide dismutase (MnSOD) was isolated and obtained in a synthetic recombinant form designated rMnSOD. This protein has been shown to be a powerful antioxidant capable of mediating ROS dismutation, penetrating biological barriers via its uncleaved leader peptide, and reducing portal hypertension and fibrosis in rats affected by liver cirrhosis. Based on these distinctive characteristics, it can be hypothesized that this novel recombinant protein (rMnSOD) potentially represents a new and highly efficient adjuvant therapy to counteract the progression from NASH to HCC.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d2419fc2467afc0fef89a4f91dd16f4cTest
http://www.sciencedirect.com/science/article/pii/S2213231717309291Test

المؤلفون: Giuseppe Poli, Maria Blonda, Giorgia di Bello, Luigi Iuliano, Gaetano Serviddio, Gianluigi Vendemiale, Carlo Avolio, Giuseppina Iannelli, Antonio Facciorusso, Rosanna Tamborra, Francesco Bellanti, Rosanna Villani

المصدر: Redox Biology, Vol 15, Iss C, Pp 86-96 (2018)
Redox Biology

مصطلحات موضوعية: 0301 basic medicine, MMP, mitochondrial membrane potential, 5α, 6α-epoxy, 5α,6α-epoxycholesterol, Clinical Biochemistry, HF+HCh, high-fat+high-cholesterol, Respiratory chain, Apoptosis, Mitochondria, Liver, Mitochondrion, medicine.disease_cause, Biochemistry, SDM, standard deviation of the mean, cholesterol excess, fatty acids, mitochondria, non-alcoholic fatty liver disease, oxysterols, Nonalcoholic fatty liver disease, lcsh:QH301-705.5, ANOVA, analysis of variance, TNF, tumor necrosis factor, lcsh:R5-920, Chemistry, UCP2, uncoupling protein 2, Oxysterols, Cholesterol excess, Mitochondria, Mitochondrial respiratory chain, Lipotoxicity, Liver, CTRL, control, Disease Progression, lipids (amino acids, peptides, and proteins), FFAs, free fatty acids, lcsh:Medicine (General), Oxidation-Reduction, Research Paper, medicine.medical_specialty, NAFLD, non-alcoholic fatty liver disease, NASH, non-alcoholic steatohepatitis, Diet, High-Fat, 03 medical and health sciences, PA, palmitic acid, Δψ, mitochondrial membrane potential, HF, high-fat, Internal medicine, medicine, NAFL, non-alcoholic fatty liver, Humans, 5β, 6β-epoxy, 5β,6β-epoxycholesterol, Fatty acids, PGC1α, peroxisome proliferator-activated receptor-γ coactivator 1 α, TFAM, mitochondrial transcription factor A, NRF1, nuclear respiratory factor 1, Organic Chemistry, 6-oxo, 6-oxo-cholestan-3β,5α-diol, OA, oleic acid, CT, threshold cycle, medicine.disease, Lipid Metabolism, mtDNA, mitochondrial DNA, Oxidative Stress, 030104 developmental biology, Endocrinology, triol, 5α-cholestane-3β,5,6β-triol, Mitochondrial biogenesis, BN-PAGE, Blue Native bidimensional polyacrylamide gel electrophoresis, lcsh:Biology (General), Hepatocytes, 7β-OHC, 7β-hydroxycholesterol, Steatohepatitis, Reactive Oxygen Species, Oxidative stress, 7KC, 7-ketocholesterol, CYPs, cytochromes P450, Non-alcoholic fatty liver disease

الوصف: The complete mechanism accounting for the progression from simple steatosis to steatohepatitis in nonalcoholic fatty liver disease (NAFLD) has not been elucidated. Lipotoxicity refers to cellular injury caused by hepatic free fatty acids (FFAs) and cholesterol accumulation. Excess cholesterol autoxidizes to oxysterols during oxidative stress conditions. We hypothesize that interaction of FAs and cholesterol derivatives may primarily impair mitochondrial function and affect biogenesis adaptation during NAFLD progression. We demonstrated that the accumulation of specific non-enzymatic oxysterols in the liver of animals fed high-fat+high-cholesterol diet induces mitochondrial damage and depletion of proteins of the respiratory chain complexes. When tested in vitro, 5α-cholestane-3β,5,6β-triol (triol) combined to FFAs was able to reduce respiration in isolated liver mitochondria, induced apoptosis in primary hepatocytes, and down-regulated transcription factors involved in mitochondrial biogenesis. Finally, a lower protein content in the mitochondrial respiratory chain complexes was observed in human non-alcoholic steatohepatitis. In conclusion, hepatic accumulation of FFAs and non-enzymatic oxysterols synergistically facilitates development and progression of NAFLD by impairing mitochondrial function, energy balance and biogenesis adaptation to chronic injury.
Graphical abstract fx1
Highlights • Mitochondrial adaptation in NAFLD is lost in fatty acids + cholesterol-induced NASH. • Fatty acids + oxysterols alter mitochondria function/biogenesis inducing cell death. • Mitochondria respiratory proteins and biogenesis regulators are lower in human NASH. • Fatty acids and oxysterols interaction may explain mitochondria dysfunction in NASH.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b13897abda95ce40fb1e631f0e1a131eTest
http://www.sciencedirect.com/science/article/pii/S2213231717307425Test

المؤلفون: Miguel López, Rubén Nogueiras, Xabier Buqué, Maria J. Gonzalez-Rellan, Daniel Beiroa, Patricia Aspichueta, Uxia Fernandez, Begoña Porteiro, Rosalía Gallego, Carlos Dieguez, Guadalupe Sabio, Marcos F. Fondevila, Johan Fernø, Ana Senra, Alfonso Mora

المساهمون: Ministerio de Economía y Competitividad (España), Xunta de Galicia (España), Heise Vest RHF, Comunidad de Madrid (España), Basque Government (España), Fundación AstraZeneca, Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Unión Europea. Comisión Europea, Centro de Investigación Biomedica en Red - CIBER

المصدر: Molecular Metabolism, Vol 8, Iss, Pp 132-143 (2018)
Molecular Metabolism
Repisalud
Instituto de Salud Carlos III (ISCIII)

مصطلحات موضوعية: 0301 basic medicine, pIRE, Inositol-requiring enzyme 1 α, pJNK, phospho c-Jun N-terminal kinase, ACC, acetyl-CoA carboxylase, AST, aspartate aminotransferase, XBP1s, X-box binding protein 1, Abcd1, ATP binding cassette subfamily D member 1, Pharmacology, ER stress, endoplasmic reticulum stress, NFκβ, nuclear factor kappa b, FA, free fatty acid, Mice, Liver disease, UPR, unfolded protein response, 0302 clinical medicine, HFD, high fat diet, Non-alcoholic Fatty Liver Disease, Nonalcoholic fatty liver disease, DG, diacylglycerol, Topoisomerase II Inhibitors, IL6, initerleukin 6, Beta oxidation, Acadm, acyl-CoA deshydrogenase, medium chain, GFP, green fluorescent protein, IL10, interleukin 10, Acox, acyl-CoA oxidase 1, TG, triglyceride, Ad, adenovirus, Hep G2 Cells, Acadl, acyl-CoA deshydrogenase, long-chain, i.p., intraperitoneal, FAS, fatty acid synthase, 3. Good health, Liver, Pparα, peroxisome proliferator activated receptor alpha, JNK, c-Jun N-terminal kinase, Lipogenesis, DOX, Doxorubicin, DN, dominant negative, Original Article, ApoB, apolipoprotein b, Quer, quercetin, NAFLD, non-alcoholic fatty liver disease, lcsh:Internal medicine, ASM, acid-soluble metabolites, NASH, non-alcoholic steatohepatitis, TNFα, tumor necrosis factor alpha, GAPDH, glyceraldehyde-3-phosphate deshydrogenase, AUC, area under curve, Diet, High-Fat, Cell Line, SPF, specific pathogen free room, 03 medical and health sciences, GTT, glucose test tolerance, ALT, alanine aminotransferase, AAV8, adeno-associated virus serotype 8, medicine, Animals, Humans, Obesity, EC, sterified cholesterol, lcsh:RC31-1245, Molecular Biology, MCD, methionine-choline deficient diet, CHOP, C/EBP-homologous protein, Inflammation, business.industry, OA, oleic acid, Lipid metabolism, DIO, diet-induced obesity, Cell Biology, Lipid Metabolism, medicine.disease, CDHFD, choline-deficient high fat diet, Mice, Inbred C57BL, 030104 developmental biology, Doxorubicin, pACC, phospho acetyl-CoA carboxylase, Hepatic stellate cell, BSA, bovine serum albumin, Tumor Suppressor Protein p53, Steatohepatitis, Steatosis, business, Fatp2, solute carrier family 27 (fatty acid transporter) member 2, IL1β, interleukin 1beta, 030217 neurology & neurosurgery, ITT, insulin test tolerance

الوصف: Objective Recent reports have implicated the p53 tumor suppressor in the regulation of lipid metabolism. We hypothesized that the pharmacological activation of p53 with low-dose doxorubicin, which is widely used to treat several types of cancer, may have beneficial effects on nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Methods We used long-term pharmacological activation of p53 by i.p. or oral administration of low-dose doxorubicin in different animal models of NAFLD (high fat diet containing 45% and 60% kcal fat) and NASH (methionine- and choline-deficient diet and choline deficiency combined with high fat diet). We also administered doxorubicin in mice lacking p53 in the liver and in two human hepatic cells lines (HepG2 and THLE2). Results The attenuation of liver damage was accompanied by the stimulation of fatty acid oxidation and decrease of lipogenesis, inflammation, and ER stress. The effects of doxorubicin were abrogated in mice with liver-specific ablation of p53. Finally, the effects of doxorubicin on lipid metabolism found in animal models were also present in two human hepatic cells lines, in which the drug stimulated fatty acid oxidation and inhibited de novo lipogenesis at doses that did not cause changes in apoptosis or cell viability. Conclusion These data provide new evidence for targeting p53 as a strategy to treat liver disease.
Highlights • Intraperitoneal and oral low-dose doxorubicin ameliorates NAFLD and NASH in animal models. • Doxorubicin requires p53 for its hepatic actions. • Doxorubin decreases lipid content in human hepatocytes without affecting cell viability and apoptosis.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::df7642e1971aebb46c881386960e7affTest
http://www.sciencedirect.com/science/article/pii/S2212877817310116Test

المؤلفون: Adam J. Rauckhorst, Xiaorong Fu, Katherine N. Gibson-Corley, Alvin D. Pewa, Ryan D. Sheldon, Eric B. Taylor, James E. Cox, Charlotte R. Feddersen, Shawn C. Burgess, Adam J. Dupuy, Lawrence R. Gray

المصدر: Molecular Metabolism, Vol 6, Iss 11, Pp 1468-1479 (2017)
Molecular Metabolism

مصطلحات موضوعية: Blood Glucose, 0301 basic medicine, Mitochondria, Liver, Mitochondrion, Mitochondrial Membrane Transport Proteins, Mice, 0302 clinical medicine, HFD, high fat diet, Fibrosis, immune system diseases, Pyruvic Acid, digestive, oral, and skin physiology, Diabetes, Mitochondria, HOMA-IR, homeostatic model assessment of insulin resistance, medicine.anatomical_structure, Liver, Mitochondrial matrix, 030220 oncology & carcinogenesis, Hepatocyte, Original Article, MPC, mitochondrial pyruvate carrier, TCA, tricarboxylic acid cycle, Monocarboxylic Acid Transporters, NAFLD, non-alcoholic fatty liver disease, medicine.medical_specialty, lcsh:Internal medicine, NASH, non-alcoholic steatohepatitis, Anion Transport Proteins, Citric Acid Cycle, T2D, type 2 diabetes, Biology, Diet, High-Fat, Mitochondrial pyruvate carrier (MPC), 03 medical and health sciences, Internal medicine, medicine, Animals, Obesity, lcsh:RC31-1245, Molecular Biology, ITT, insulin tolerance test, Inflammation, NCD, normal chow diet, Gluconeogenesis, Membrane Transport Proteins, nutritional and metabolic diseases, Cell Biology, Metabolism, medicine.disease, Citric acid cycle, Disease Models, Animal, Cytosol, Glucose, 030104 developmental biology, Endocrinology, Diabetes Mellitus, Type 2, Hyperglycemia, Hepatocytes, Insulin Resistance

الوصف: Objective Excessive hepatic gluconeogenesis is a defining feature of type 2 diabetes (T2D). Most gluconeogenic flux is routed through mitochondria. The mitochondrial pyruvate carrier (MPC) transports pyruvate from the cytosol into the mitochondrial matrix, thereby gating pyruvate-driven gluconeogenesis. Disruption of the hepatocyte MPC attenuates hyperglycemia in mice during high fat diet (HFD)-induced obesity but exerts minimal effects on glycemia in normal chow diet (NCD)-fed conditions. The goal of this investigation was to test whether hepatocyte MPC disruption provides sustained protection from hyperglycemia during long-term HFD and the differential effects of hepatocyte MPC disruption on TCA cycle metabolism in NCD versus HFD conditions. Method We utilized long-term high fat feeding, serial measurements of postabsorptive blood glucose and metabolomic profiling and 13C-lactate/13C-pyruvate tracing to investigate the contribution of the MPC to hyperglycemia and altered hepatic TCA cycle metabolism during HFD-induced obesity. Results Hepatocyte MPC disruption resulted in long-term attenuation of hyperglycemia induced by HFD. HFD increased hepatic mitochondrial pyruvate utilization and TCA cycle capacity in an MPC-dependent manner. Furthermore, MPC disruption decreased progression of fibrosis and levels of transcript markers of inflammation. Conclusions By contributing to chronic hyperglycemia, fibrosis, and TCA cycle expansion, the hepatocyte MPC is a key mediator of the pathophysiology induced in the HFD model of T2D.
Graphical abstract Image 1
Highlights • Hepatic MPC disruption protects from hyperglycemia during long-term HFD. • HFD increases TCA cycle metabolite pool capacity and flux. • Hepatic MPC disruption abrogates HFD-induced TCA cycle expansion.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::80260421dd9726225c6f9a3cac3cf9faTest
http://www.sciencedirect.com/science/article/pii/S2212877817306828Test