المؤلفون: Justine Gillard, Laure-Alix Clerbaux, Bart Staels, Anne Tailleux, Isabelle Leclercq, Laure B. Bindels, Maxime Nachit, Christine Sempoux

المساهمون: UCL - SSS/LDRI - Louvain Drug Research Institute, UCL - SSS/IREC/GAEN - Pôle d'Hépato-gastro-entérologie, UCL - (SLuc) Service de gastro-entérologie

المصدر: JHEP reports, vol. 4, no. 1, pp. 100387
JHEP Reports, Vol 4, Iss 1, Pp 100387-(2022)
JHEP reports, Vol. 4, no.1, p. 100387 [1-13] (2022)
JHEP Reports

مصطلحات موضوعية: HFD, high-fat diet, CYP7A1, CYP8B1, sterol 12α-hydroxylase, WDF, western and high-fructose diet, FABP6, OGTT, oral glucose tolerance test, FGF15, RC799-869, ASBT, apical sodium-dependent BA transporter, chemistry.chemical_compound, OST, organic solute transporter, βMCA, β-muricholic acid, SHP, small heterodimer protein, WDF, CYP27A1, SHP, TNFα, Immunology and Allergy, LCA, lithocholic acid, DCA, FABP6, fatty acid binding protein 6, FGFR4, fibroblast growth factor receptor 4, CA, cholic acid, NAS, NAFLD activity score, CA, CYP7B1, CYP7B1, oxysterol 7α-hydroxylase, Bile acid, WT, αMCA, ND, normal diet, TGR5, Takeda G-protein coupled receptor 5, Chemistry, LCA, Deoxycholic acid, TLCA, TGR5, Gastroenterology, NASH, GLP-1, glucagon-like peptide-1, Diseases of the digestive system. Gastroenterology, G protein-coupled bile acid receptor, TNFα, tumor necrosis factor α, FXR, BA, bile acid, LPS, lipopolysaccharide, Research Article, CYP2A12, bile acid 7α-hydroxylase, ωMCA, NAFLD, non-alcoholic fatty liver disease, medicine.medical_specialty, ωMCA, ω-muricholic acid, LPS, normal diet, Normal diet, βMCA, medicine.drug_class, NASH, non-alcoholic steatohepatitis, education, tumor necrosis factor α, BA, digestive system, metabolic syndrome, CDCA, chenodeoxycholic acid, CYP2A12, CYP27A1, sterol 27-hydroxylase, Internal medicine, NAFLD, Internal Medicine, medicine, OGTT, CYP7A1, cholesterol 7α-hydroxylase, DCA, deoxycholic acid, FGF15, fibroblast growth factor 15, FXR, Farnesoid X receptor, TLCA, tauro-lithocholic acid, WT, wild-type, αMCA, α-muricholic acid, wild-type, CYP8B1, Hepatology, OST, medicine.disease, Endocrinology, NAS, FGFR4, CDCA, HFD, ND, Steatohepatitis, GLP-1, ASBT

الوصف: Background & Aims Through FXR and TGR5 signaling, bile acids (BAs) modulate lipid and glucose metabolism, inflammation and fibrosis. Hence, BAs returning to the liver after enteric secretion, modification and reabsorption may contribute to the pathogenesis of non-alcoholic steatohepatitis (NASH). Herein, we characterized the enterohepatic profile and signaling of BAs in preclinical models of NASH, and explored the consequences of experimental manipulation of BA composition. Methods We used high-fat diet (HFD)-fed foz/foz and high-fructose western diet-fed C57BL/6J mice, and compared them to their respective controls. Mice received a diet supplemented with deoxycholic acid (DCA) to modulate BA composition. Results Compared to controls, mice with NASH had lower concentrations of BAs in their portal blood and bile, while systemic BA concentrations were not significantly altered. Notably, the concentrations of secondary BAs, and especially of DCA, and the ratio of secondary to primary BAs were strikingly lower in bile and portal blood of mice with NASH. Hence, portal blood was poor in FXR and TGR5 ligands, and conferred poor anti-inflammatory protection in mice with NASH. Enhanced primary BAs synthesis and conversion of secondary to primary BAs in NASH livers contributed to the depletion in secondary BAs. Dietary DCA supplementation in HFD-fed foz/foz mice restored the BA concentrations in portal blood, increased TGR5 and FXR signaling, improved the dysmetabolic status, protected from steatosis and hepatocellular ballooning, and reduced macrophage infiltration. Conclusions BA composition in the enterohepatic cycle, but not in systemic circulation, is profoundly altered in preclinical models of NASH, with specific depletion in secondary BAs. Dietary correction of the BA profile protected from NASH, supporting a role for enterohepatic BAs in the pathogenesis of NASH. Lay summary This study clearly demonstrates that the alterations of enterohepatic bile acids significantly contribute to the development of non-alcoholic steatohepatitis in relevant preclinical models. Indeed, experimental modulation of bile acid composition restored perturbed FXR and TGR5 signaling and prevented non-alcoholic steatohepatitis and associated metabolic disorders.
Graphical abstract
Highlights • The enterohepatic bile acid profile is profoundly altered in mice with NASH. • Bile acid signaling through FXR and TGR5 is dampened in mice with NASH. • Modulation of bile acid composition prevents obesity, insulin resistance and NASH.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a4f803f3cd8976e73d533d8b1885ead5Test
https://serval.unil.ch/notice/serval:BIB_8BED7E41CA16Test

المؤلفون: Philippe Garteiser, Pauline Jouet, Marco Dioguardi Burgio, Bernard E. Van Beers, Pierre Bedossa, Daniela Calabrese, Séverine Ledoux, Laurent Castera, Muriel Coupaye, Marina Esposito-Farèse, Sabrina Doblas, Simon Msika

المصدر: JHEP Reports
JHEP Reports, Vol 3, Iss 6, Pp 100381-(2021)

مصطلحات موضوعية: medicine.medical_specialty, NAFLD, non-alcoholic fatty liver disease, bariatric surgery, NASH, non-alcoholic steatohepatitis, LSM, liver stiffness measurement, RC799-869, NAFLD, Nonalcoholic fatty liver disease, Non-invasive diagnosis, Internal Medicine, steatosis, AUROC, area under the receiver operating characteristic curve, Immunology and Allergy, Medicine, ST, SteatoTest, Grading (tumors), NAS, NAFLD activity score, Se, sensitivity, Hepatology, medicine.diagnostic_test, business.industry, Fatty liver, Gastroenterology, NASH, Diseases of the digestive system. Gastroenterology, medicine.disease, MRI-PDFF, MRI-proton density fat fraction, transient elastography, CAP, PPV, positive predictive value, Surgery, TE, transient elastography, FLIP, fatty liver inhibition of progression, HSI, hepatic steatosis index, NPV, negative predictive value, Liver biopsy, Sp, specificity, Steatosis, Steatohepatitis, CAP, controlled attenuation parameter, business, Transient elastography, Body mass index, MRI-PDFF, FLI, fatty liver index, Research Article

الوصف: Background & Aims Tools for the non-invasive diagnosis of non-alcoholic steatohepatitis (NASH) in morbidly obese patients with suspected non-alcoholic fatty liver disease (NAFLD) are an unmet clinical need. We prospectively compared the performance of transient elastography, MRI, and 3 serum scores for the diagnosis of NAFLD, grading of steatosis and detection of NASH in bariatric surgery candidates. Methods Of 186 patients screened, 152 underwent liver biopsy, which was used as a reference for NAFLD (steatosis [S]>5%), steatosis grading and NASH diagnosis. Biopsies were read by a single expert pathologist. MRI-based proton density fat fraction (MRI-PDFF) was measured in an open-bore, vertical field 1.0T scanner and controlled attenuation parameter (CAP) was measured by transient elastography, using the XL probe. Serum scores (SteatoTest, hepatic steatosis index and fatty liver index) were also calculated. Results The applicability of MRI was better than that of FibroScan (98% vs. 79%; p 5%, S>33%, S>66% and NASH, respectively. Transient elastography had an AUROC of 0.80 for significant fibrosis (F0-F1 vs. F2-F3). MRI-PDFF had AUROCs of 0.97, 0.95, 0.92 and 0.84 for S>5%, S>33%, S>66% and NASH, respectively. When compared head-to-head in the 97 patients with all valid tests available, MRI-PDFF outperformed CAP for grading steatosis (S>33%, AUROC 0.97 vs. 0.78; p 66%, AUROC 0.93 vs. 0.75; p = 0.0015) and diagnosing NASH (AUROC 0.82 vs. 0.68; p = 0.0056). When compared in “intention to diagnose” analysis, MRI-PDFF outperformed CAP, hepatic steatosis index and fatty liver index for grading steatosis (S>5%, S>33% and S>66%). Conclusion MRI-PDFF outperforms CAP for diagnosing NAFLD, grading steatosis and excluding NASH in morbidly obese patients undergoing bariatric surgery. Lay summary Non-invasive tests for detecting fatty liver and steatohepatitis, the active form of the disease, have not been well studied in obese patients who are candidates for bariatric surgery. The most popular tests for this purpose are Fibroscan, which can be used to measure the controlled attenuation parameter (CAP), and magnetic resonance imaging, which can be used to measure the proton density fat fraction (MRI-PDFF). We found that, when taking liver biopsy as a reference, MRI-PDFF performed better than CAP for detecting and grading fatty liver as well as excluding steatohepatitis in morbidly obese patients undergoing bariatric surgery.
Graphical abstract
Highlights • NAFLD/NASH is common in morbidly obese patients undergoing bariatric surgery. • Non-invasive diagnosis of NAFLD/NASH is an unmet need in this population. • We compared MRI-PDFF, CAP and serum scores for grading steatosis and diagnosing NASH, using liver biopsy as a reference. • Applicability of magnetic resonance imaging was better than that of Fibroscan. • MRI-PDFF outperformed CAP for diagnosing and grading steatosis, as well as excluding NASH.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::aa1cbf2a3776a631ccda6d1dc1a90b42Test
http://europepmc.org/articles/PMC8578045Test

المؤلفون: N. Thao N. Galvan, Mercedes Barzi, John A. Goss, William R. Lagor, David D. Moore, Adam Dean, Neil J. McKenna, Pavel Sumazin, Barry Zorman, Diane Yang, Beatrice Bissig-Choisat, Karl-Dimiter Bissig, Xavier Legras, David E. Cohen, Robert Brian York, Malgorzata Borowiak, Michele Alves-Bezerra, Scott A. Ochsner

المصدر: JHEP reports : innovation in hepatology, vol 3, iss 3
JHEP Reports
JHEP Reports, Vol 3, Iss 3, Pp 100281-(2021)

مصطلحات موضوعية: phosphatidylinositol, Cirrhosis, Steatosis, ALT, hexosylceramide, Humanised mice, SREBP, sterol regulatory element-binding protein, PI, RC799-869, CMHs, chimeric mouse hepatocytes, 0302 clinical medicine, GGT, gamma-glutamyl transpeptidase, aspartate aminotransferase, HCC, gamma-glutamyl transpeptidase, chemistry.chemical_classification, 0303 health sciences, education.field_of_study, Western-type diet, Gastroenterology, NASH, CHHs, Diseases of the digestive system. Gastroenterology, 3. Good health, confidence transcript, HCT, cholesteryl ester, human albumin, DCER, dihydroceramide, 030211 gastroenterology & hepatology, PC, non-alcoholic steatohepatitis, PE, transgene-free Il2rg-/-/Rag2-/-/Fah, free fatty acid, LPE, lysophosphatidylethanolamine, DCER, NASH, non-alcoholic steatohepatitis, HCER, hexosylceramide, NC, normal chow, TIRF, PE, phosphatidylethanolamine, nitisinone, lysophosphatidylethanolamine, 03 medical and health sciences, dihydroceramide, Human disease modelling, NAFLD, FFA, free fatty acid, LCER, DEG, MUFA, education, phosphatidylcholine, chimeric mouse hepatocytes, FAH, SM, sphingomyelin, ALP, alkaline phosphatase, FA, fatty acid, NTBC, Fatty acid, medicine.disease, differentially expressed gene, lactosylceramide, PNPLA3, patatin-like-phospholipase domain-containing protein 3, Lipid metabolism, chemistry, fatty acid, PUFA, hALB, human albumin, TIRF, transgene-free Il2rg-/-/Rag2-/-/Fah, AST, aspartate aminotransferase, CT, confidence transcript, PC, phosphatidylcholine, monounsaturated fatty acid, DEG, differentially expressed gene, MUFA, monounsaturated fatty acid, Immunology and Allergy, MAG, monoacylglycerol, PUFA, polyunsaturated free FA, CE, cholesteryl ester, CER, diacylglycerol, FAH, fumarylacetoacetate hydrolase, Fatty liver, SM, chimeric human hepatocytes, hepatocellular carcinoma, CBPEGs, cholesterol biosynthesis pathway enzyme genes, CE, MAG, LPC, patatin-like-phospholipase domain-containing protein 3, triacylglycerol, LPE, alkaline phosphatase, sterol regulatory element-binding protein, Polyunsaturated fatty acid, Research Article, CT, NAFLD, non-alcoholic fatty liver disease, FA, HCER, TAG, triacylglycerol, fumarylacetoacetate hydrolase, monoacylglycerol, alanine aminotransferase, Population, cholesterol biosynthesis pathway enzyme genes, Biology, SREBP, PI, phosphatidylinositol, sphingomyelin, lysophosphatidylcholine, WD, ALT, alanine aminotransferase, high confidence transcriptional target, Internal Medicine, medicine, CBPEGs, ceramide, hALB, LCER, lactosylceramide, normal chow, AST, polyunsaturated free FA, WD, Western-type diet, PNPLA3, 030304 developmental biology, Hepatitis, LPC, lysophosphatidylcholine, Hepatology, DAG, non-alcoholic fatty liver disease, NTBC, nitisinone, CMHs, GGT, HCT, high confidence transcriptional target, phosphatidylethanolamine, TAG, Cancer research, CHHs, chimeric human hepatocytes, ALP, Liver function, NC, CER, ceramide, HCC, hepatocellular carcinoma, FFA, DAG, diacylglycerol, Non-alcoholic fatty liver disease

الوصف: Background & Aims The accumulation of neutral lipids within hepatocytes underlies non-alcoholic fatty liver disease (NAFLD), which affects a quarter of the world’s population and is associated with hepatitis, cirrhosis, and hepatocellular carcinoma. Despite insights gained from both human and animal studies, our understanding of NAFLD pathogenesis remains limited. To better study the molecular changes driving the condition we aimed to generate a humanised NAFLD mouse model. Methods We generated TIRF (transgene-free Il2rg-/-/Rag2-/-/Fah-/-) mice, populated their livers with human hepatocytes, and fed them a Western-type diet for 12 weeks. Results Within the same chimeric liver, human hepatocytes developed pronounced steatosis whereas murine hepatocytes remained normal. Unbiased metabolomics and lipidomics revealed signatures of clinical NAFLD. Transcriptomic analyses showed that molecular responses diverged sharply between murine and human hepatocytes, demonstrating stark species differences in liver function. Regulatory network analysis indicated close agreement between our model and clinical NAFLD with respect to transcriptional control of cholesterol biosynthesis. Conclusions These NAFLD xenograft mice reveal an unexpected degree of evolutionary divergence in food metabolism and offer a physiologically relevant, experimentally tractable model for studying the pathogenic changes invoked by steatosis. Lay summary Fatty liver disease is an emerging health problem, and as there are no good experimental animal models, our understanding of the condition is poor. We here describe a novel humanised mouse system and compare it with clinical data. The results reveal that the human cells in the mouse liver develop fatty liver disease upon a Western-style fatty diet, whereas the mouse cells appear normal. The molecular signature (expression profiles) of the human cells are distinct from the mouse cells and metabolic analysis of the humanised livers mimic the ones observed in humans with fatty liver. This novel humanised mouse system can be used to study human fatty liver disease.
Graphical abstract
Highlights • Human liver chimeric mice fed a western diet develop NAFLD. • Within the same chimeric liver, human hepatocytes developed pronounced steatosis while murine hepatocytes remained normal. • Unbiased metabolomics and lipidomics of fatty humanised mouse livers revealed signatures of clinical NAFLD. • Transcriptomic analyses showed that molecular responses diverged sharply between murine and human hepatocytes. • This humanised NAFLD model is a physiologically relevant, experimentally tractable model for the study of steatosis.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::52b0393a5555874a5526c491b8421dfdTest
https://escholarship.org/uc/item/2hg8h2x9Test

المؤلفون: Shira Zelber-Sagi, Rebecca Dorner, Giulio Marchesini, Marko Korenjak, Christos Lionis, Jeffrey V. Lazarus, Sven Francque, Achim Kautz, Luca Busetto, José Willemse, G. Koek, Dror Dicker, Kate Hallsworth, Shlomo Vinker, Gema Frühbeck, Euan Woodward, Mehmet Ungan, Juan M. Mendive, Martine Walmsley

المساهمون: Francque, Sven M, Marchesini, Giulio, Kautz, Achim, Walmsley, Martine, Dorner, Rebecca, Lazarus, Jeffrey V, Zelber-Sagi, Shira, Hallsworth, Kate, Busetto, Luca, Frühbeck, Gema, Dicker, Dror, Woodward, Euan, Korenjak, Marko, Willemse, José, Koek, Gerardus H, Vinker, Shlomo, Ungan, Mehmet, Mendive, Juan M, Lionis, Christos, Interne Geneeskunde, MUMC+: MA Maag Darm Lever (9), RS: NUTRIM - R2 - Liver and digestive health

المصدر: JHEP Reports
JHEP Reports, Vol 3, Iss 5, Pp 100322-(2021)
JHEP Reports, 3(5):100322. Elsevier BV

مصطلحات موضوعية: NASH, non-alcoholic steatohepatiti, Y GASTRIC BYPASS, Disease, RC799-869, PLACEBO-CONTROLLED TRIAL, LIFE-STYLE MODIFICATION, cardiovascular disease, LDL, low-density lipoprotein, HEPATOCELLULAR-CARCINOMA, non-invasive test, T2D, GLP-1 RAs, glucagon-like receptor 1 agonists, European Association for the Study of Obesity, HCC, Gastroenterology, NASH, specific, Diseases of the digestive system. Gastroenterology, CAP, controlled attenuation parameter, CT, computed tomography, FXR, ASH, alcoholic steatohepatitis, GP, non-alcoholic steatohepatitis, GLP-1 RAs, glucagon-like receptor 1 agonist, LDL, low-density lipoproteins, medicine.medical_specialty, HDL, achievable, NASH, non-alcoholic steatohepatitis, T2D, type 2 diabetes, high-density lipoprotein, CVD, cardiovascular disease, LDL, Patient Guideline, Quality of life (healthcare), FXR, farnesoid X receptor, NAFLD, low-density lipoproteins, GP, general practitioner, NAFL, non-alcoholic fatty liver, FIB-4, fibrosis-4 index, Intensive care medicine, computed tomography, Guideline, medicine.disease, T1D, type 1 diabete, digestive system diseases, NIT, Human medicine, farnesoid X receptor, type 1 diabetes, BMI, body mass index, EASL, European Association for the Study of the Liver, Placebo-controlled study, Chronic liver disease, GLP-1 RAs, QUALITY-OF-LIFE, alcoholic steatohepatitis, European Association for the Study of Diabetes, EASD, European Association for the Study of Diabetes, Immunology and Allergy, magnetic resonance imaging, NASH Clinical Research Network, ALD, alcohol-related or alcoholic liver disease, Disease management (health), glucagon-like receptor 1 agonists, EASO, European Association for the Study of Obesity, NASH CRN, NASH Clinical Research Network, ASH, alcoholic steatohepatiti, Fatty liver, timely, hepatocellular carcinoma, CVD, magnetic resonance elastography, MRE, NAFL, FIB-4, non-alcoholic fatty liver, type 2 diabetes, T1D, type 1 diabetes, CAP, controlled attenuation parameter, CT, European Association for the Study of the Liver, MRI, fibrosis-4 index, NAFLD, non-alcoholic fatty liver disease, EASD, HDL, high-density lipoprotein, UNITED-STATES, ASH, body mass index, EASL, measurable, BMI, NIT, non-invasive test, Internal Medicine, medicine, NASH CRN, HEPATIC STEATOSIS, HCC, hepatocellular carcinoma, MRE, magnetic resonance elastography, MRI, magnetic resonance imaging, SMART, specific, measurable, achievable, relevant, timely, Disease burden, BARIATRIC SURGERY, Hepatology, SMART, business.industry, SERUM ALANINE AMINOTRANSFERASE, non-alcoholic fatty liver disease, PHYSICAL-ACTIVITY, alcohol-related or alcoholic liver disease, EASD, European Association for the Study of Diabete, EASO, ALD, general practitioner, relevant, T1D, business

الوصف: This patient guideline is intended for all patients at risk of or living with non-alcoholic fatty liver disease (NAFLD). NAFLD is the most frequent chronic liver disease worldwide and comes with a high disease burden. Yet, there is a lot of unawareness. Furthermore, many aspects of the disease are still to be unravelled, which has an important impact on the information that is given (or not) to patients. Its management requires a close interaction between patients and their many healthcare providers. It is important for patients to develop a full understanding of NAFLD in order to enable them to take an active role in their disease management. This guide summarises the current knowledge relevant to NAFLD and its management. It has been developed by patients, patient representatives, clinicians and scientists and is based on current scientific recommendations, intended to support patients in making informed decisions. (C) 2021 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL).

وصف الملف: ELETTRONICO

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::cc5e84bfe19b52d5e0324b299615b0e1Test
https://pubmed.ncbi.nlm.nih.gov/34693236Test