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Dietary sugars are linked to the development of non-alcoholic fatty liver disease (NAFLD) and dyslipidaemia, but it is unknown if NAFLD itself influences the effects of sugars on plasma lipoproteins. To study this further, men with NAFLD (n=11) and low liver fat 'controls' (n= 14) were fed two iso-energetic diets, high or low in sugars (26% or 6% total energy) for 12 weeks, in a randomised, cross-over design. Fasting plasma lipid and lipoprotein kinetics were measured after each diet by stable isotope trace-labelling. There were significant differences in the production and catabolic rates of VLDL subclasses between men with NAFLD and controls, in response to the high and low sugar diets. Men with NAFLD had higher plasma concentrations of VLDL1-triacylglycerol (TAG) after the high ( P <0.02) and low sugar ( P <0.0002) diets, a lower VLDL1-TAG fractional catabolic rate after the high sugar diet ( P <0.01), and a higher VLDL1-TAG production rate after the low sugar diet ( P <0.01), relative to controls. An effect of the high sugar diet, was to channel hepatic TAG into a higher production of VLDL1-TAG ( P <0.02) in the controls, but in contrast, a higher production of VLDL2-TAG ( P <0.05) in NAFLD. These dietary effects on VLDL subclass kinetics could be explained, in part, by differences in the contribution of fatty acids from intra-hepatic stores, and de novo lipogenesis. This study provides new evidence that liver fat accumulation leads to a differential partitioning of hepatic TAG into large and small VLDL subclasses, in response to high and low intakes of sugars. ; The work was supported by a UK government grant from the Biological Biotechnology Scientific Research Council (Grant no. BB/G009899/1); University of Surrey PhD scholarship for AM; Medical Research Council (body composition measurements) and infrastructure support from the National Institute of Health Research at the Cambridge Biomedical Research Centre.

Non-Alcoholic Fatty Liver Disease (NAFLD), a progressive liver disease that is closely associated with obesity, type 2 diabetes, hypertension and dyslipidaemia, represents an increasing global public health challenge. There is significant variability in the disease course: the majority exhibit only fat accumulation in the liver but a significant minority develop a necroinflammatory form of the disease (non-alcoholic steatohepatitis, NASH) that may progress to cirrhosis and hepatocellular carcinoma. At present our understanding of pathogenesis, disease natural history and long-term outcomes remain incomplete. There is a need for large, well characterised patient cohorts that may be used to address these knowledge gaps and to support the development of better biomarkers and novel therapies. The European NAFLD Registry is an international, prospectively recruited observational cohort study that aims to establish a large, highly-phenotyped patient cohort and linked bioresource. Here we describe the infrastructure, data management and monitoring plans, and the standard operating procedures implemented to ensure the timely and systematic collection of high-quality data and samples. Already recruiting subjects at secondary/tertiary care centres across Europe, the Registry is supporting the European Union IMI2-funded LITMUS 'Liver Investigation: Testing Marker Utility in Steatohepatitis' consortium, which is a major international effort to robustly validate biomarkers that diagnose, risk stratify and/or monitor NAFLD progression and liver fibrosis stage. The European NAFLD Registry has the demonstrable capacity to support research and biomarker development at scale and pace.

María D. Navarro-Hortal is a FPU fellow from the Spanish Ministry of Educación y Formación Profesional. The research group was partially supported by the Visiting Scholar Program from the University of Granada. The authors acknowledge Nutraceutical Translations for English language editing of this manuscript. ; Increasing evidence connects periodontitis with a variety of systemic diseases, including metabolic syndrome, atherosclerosis, and non-alcoholic fatty liver disease (NAFLD). The proposal of this study was to evaluate the role of diets rich in saturated fat and cholesterol in some aspects of periodontal diseases in a lipopolysaccharide (LPS)-induced model of periodontal disease in rabbits and to assess the influence of a periodontal intervention on hyperlipidemia, atherosclerosis, and NAFLD progression to non-alcoholic steatohepatitis. Male rabbits were maintained on a commercial standard diet or a diet rich in saturated fat (3% lard w/w) and cholesterol (1.3% w/w) (HFD) for 40 days. Half of the rabbits on each diet were treated 2 days per week with intragingival injections of LPS from Porphyromonas gingivalis. Morphometric analyses revealed that LPS induced higher alveolar bone loss (ABL) around the first premolar in animals receiving standard diets, which was exacerbated by the HFD diet. A higher score of acinar inflammation in the liver and higher blood levels of triglycerides and phospholipids were found in HFD-fed rabbits receiving LPS. These results suggest that certain dietary habits can exacerbate some aspects of periodontitis and that bad periodontal health can contribute to dyslipidemia and promote NAFLD progression, but only under certain conditions. ; Ministry of Education, Culture and Sport (Spain) ; Spanish Government ; Traslados Temporales FPU (University of Kings College of London)

[Background & Aims] Non-alcoholic fatty liver disease (NAFLD), which is closely associated with obesity, metabolic syndrome, and diabetes, is a highly prevalent emerging condition that can be optimally managed through a multidisciplinary patient-centred approach. National preparedness to address NAFLD is essential to ensure that health systems can deliver effective care. We present a NAFLD Preparedness Index for Europe. ; [Methods] In June 2019, data were extracted by expert groups from 29 countries to complete a 41-item questionnaire about NAFLD. Questions were classified into 4 categories: policies/civil society (9 questions), guidelines (16 questions), epidemiology (4 questions), and care management (12 questions). Based on the responses, national preparedness for each indicator was classified into low, middle, or high-levels. We then applied a multiple correspondence analysis to obtain a standardised preparedness score for each country ranging from 0 to 100. ; [Results] The analysis estimated a summary factor that explained 71.3% of the variation in the dataset. No countries were found to have yet attained a high-level of preparedness. Currently, the UK (75.5) scored best, although falling within the mid-level preparedness band, followed by Spain (56.2), and Denmark (43.4), whereas Luxembourg and Ireland were the lowest scoring countries with a score of 4.9. Only Spain scored highly in the epidemiology indicator category, whereas the UK was the only country that scored highly for care management. ; [Conclusions] The NAFLD Preparedness Index indicates substantial variation between countries' readiness to address NAFLD. Notably, even those countries that score relatively highly exhibit deficiencies in key domains, suggesting that structural changes are needed to optimise NAFLD management and ensure effective public health approaches are in place. ; [Lay summary] Non-alcoholic fatty liver disease (NAFLD), which is closely associated with obesity, metabolic syndrome, and diabetes, is a highly prevalent condition that can be optimally managed through a multidisciplinary patient-centred approach. National preparedness to address NAFLD is essential to allow for effective public health measures aimed at preventing disease while also ensuring that health systems can deliver effective care to affected populations. This study defined preparedness as having adequate policies and civil society engagement, guidelines, epidemiology, and care management. NAFLD preparedness was found to be deficient in all 29 countries studied, with great variation among the countries and the 4 categories studied. ; The original data collection was funded by the EASL International Liver Foundation with support from Gilead Sciences Europe Ltd., Allergan Pharmaceutical International Ltd., Bristol-Myers-Squibb Company, Pfizer Inc., and Resoundant Inc. The statistical analysis was funded by the EASL International Liver Foundation with support from Bristol-Myers-Squibb Company, Intercept, and Genfit. JVL is supported by a Spanish Ministry of Science, Innovation and Universities Miguel Servet grant (Instituto de Salud Carlos III/ESF, European Union [CP18/00074]) and further acknowledges institutional support from the Spanish Ministry of Science, Innovation and Universities through the 'Centro de Excelencia Severo Ochoa 2019–2023' Programme (CEX2018-000806-S), and support from the Government of Catalonia through the CERCA Programme. QMA and VR are members of the EPoS (Elucidating Pathways of Steatohepatitis) consortium funded by the Horizon 2020 Framework Program of the European Union under Grant Agreement 634413. QMA, VR, HCP, ME, and MRG are members of the LITMUS (Liver Investigation: Testing Marker Utility in Steatohepatitis) consortium funded by the IMI2 Program of the European Union under Grant Agreement 777377. QMA is a Newcastle NIHR Biomedical Research Centre investigator. AP, PC, GM, KN, FT, and SZS have no financial support statements to disclose. ; With funding from the Spanish government through the "Severo Ochoa Centre of Excellence" accreditation (CEX2018-000806-S). ; Peer reviewed

Metabolic syndrome (MetS) components are strongly associated with increased risk of non-alcoholic fatty liver disease (NAFLD) development. Several studies have supported that resveratrol is associated with anti-inflammatory and antioxidant effects on health status. The main objective of this study was to assess the putative associations between some urinary resveratrol phase II metabolites, cardiometabolic, and liver markers in individuals diagnosed with MetS. In this cross-sectional study, 266 participants from PREDIMED Plus study (PREvención con DIeta MEDiterránea) were divided into tertiles of total urinary resveratrol phase II metabolites (sum of five resveratrol conjugation metabolites). Urinary resveratrol metabolites were analyzed by ultra- performance liquid chromatography coupled to triple quadrupole mass spectrometry (UPLC-Q-q-Q MS), followed by micro-solid phase extraction (µ-SPE) method. Liver function markers were assessed using serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl transferase (GGT). Moreover, lipid profile was measured by triglycerides, very-low-density lipoprotein cholesterol (VLDL-c), and total cholesterol/high-density lipoprotein ratio (total cholesterol/HDL). Linear regression adjusted models showed that participants with higher total urine resveratrol concentrations exhibited improved lipid and liver markers compared to the lowest tertile. For lipid determinations: log triglycerides (βT3= -0.15, 95% CI; -0.28, -0.02, p-trend = 0.030), VLDL-c, (βT3= -4.21, 95% CI; -7.97, -0.46, p-trend = 0.039), total cholesterol/HDL ratio Moreover, (βT3= -0.35, 95% CI; -0.66, -0.03, p-trend = 0.241). For liver enzymes: log AST (βT3= -0.12, 95% CI; -0.22, -0.02, p-trend = 0.011, and log GGT (βT3= -0.24, 95% CI; -0.42, -0.06, p-trend = 0.002). However, there is no difference found on glucose variables between groups. To investigate the risk of elevated serum liver markers, flexible regression models indicated that total urine resveratrol metabolites were associated with a lower risk of higher ALT (169.2 to 1314.3 nmol/g creatinine), AST (599.9 to 893.8 nmol/g creatinine), and GGT levels (169.2 to 893.8 nmol/g creatinine). These results suggested that higher urinary concentrations of some resveratrol metabolites might be associated with better lipid profile and hepatic serum enzymes. Moreover, urinary resveratrol excreted showed a reduced odds ratio for higher liver enzymes, which are linked to NAFLD. ; The PREDIMED-Plus trial was supported by the European Research Council (Advanced Research grant 2014–2019; agreement #340918; granted to Martínez-González); the official Spanish institutions for funding scientific biomedical research, CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn) and Instituto de Salud Carlos III (ISCIII) through the Fondo de Investigación para la Salud (FIS) that is co-funded by the European Regional Development Fund (coordinated FIS projects led by Salas-Salvadó and Vidal, including the following projects: PI13/00673, PI13/00492, PI13/00272, PI13/01123, PI13/00462, PI13/00233, PI13/02184, PI13/00728, PI13/01090, PI13/01056, PI14/01722, PI14/00636, PI14/00618, PI14/00696, PI14/01206, PI14/01919, PI14/00853, PI14/01374, PI14/00972, PI14/00728, PI14/01471, PI16/00473, PI16/00662, PI16/01873, PI16/01094, PI16/00501, PI16/00533, PI16/00381, PI16/00366, PI16/01522, PI16/01120, PI17/00764, PI17/01183, PI17/00855, PI17/01347, PI17/00525, PI17/01827, PI17/00532, PI17/00215, PI17/01441, PI17/00508, PI17/01732, PI17/00926, PI19/00957, PI19/00386, PI19/00309, PI19/01032, PI19/00576, PI19/00017, PI19/01226, PI19/00781, PI19/01560, PI19/01332), and the Especial Action Project "Implementación y evaluación de una intervención intensiva sobre la actividad física Cohorte PREDIMED-Plus" (Salas-Salvadó); the Recercaixa (grant number 2013ACUP00194) (Salas-Salvadó). Moreover, J. Salas-Salvadó, gratefully acknowledges the financial support by ICREA under the ICREA Academia program; the SEMERGEN grant; International Nut and Dried Fruit Council–FESNAD (Long-term effects of an energy-restricted Mediterranean diet on mortality and cardiovascular disease 2014–2015; No. 201302) (Martinez-Gonzalez); Department of Health of the Government of Navarra (61/2015), the Fundació La Marató de TV (Ref. 201630.10); the AstraZeneca Young Investigators Award in Category of Obesity and T2D 2017 (Romaguera); grants from the Consejería de Salud de la Junta de Andalucía (PI0458/2013; PS0358/2016; PI0137/2018), the PROMETEO/2017/017 grant from the Generalitat Valenciana, the SEMERGEN grant; grant of support to research groups 35/2011 (Balearic Islands Gov; FEDER funds) (Tur and Bouz). J.K. is contracted for the "FOLIUM" program within the FUTURMed project. Talent for the medicine within the future from the Fundación Instituto de Investigación Sanitaria Illes Balears (financed by 2017 annual plan of the sustainable tourism tax and at 50% with charge to the ESF Operational Program 2014–2020 of the Balearic Islands). V.B.-V. received a grant from the Center for Nutrition Research of the University of Navarra.

Nonalcoholic fatty liver disease (NAFLD) can progress from simple steatosis (i.e., nonalcoholic fatty liver [NAFL]) to nonalcoholic steatohepatitis (NASH), cirrhosis, and cancer. Currently, the driver for this progression is not fully understood; in particular, it is not known how NAFLD and its early progression affects the distribution of lipids in the liver, producing lipotoxicity and inflammation. In this study, we used dietary and genetic mouse models of NAFL and NASH and translated the results to humans by correlating the spatial distribution of lipids in liver tissue with disease progression using advanced mass spectrometry imaging technology. We identified several lipids with distinct zonal distributions in control and NAFL samples and observed partial to complete loss of lipid zonation in NASH. In addition, we found increased hepatic expression of genes associated with remodeling the phospholipid membrane, release of arachidonic acid (AA) from the membrane, and production of eicosanoid species that promote inflammation and cell injury. The results of our immunohistochemistry analyses suggest that the zonal location of remodeling enzyme LPCAT2 plays a role in the change in spatial distribution for AA-containing lipids. This results in a cycle of AA-enrichment in pericentral hepatocytes, membrane release of AA, and generation of proinflammatory eicosanoids and may account for increased oxidative damage in pericentral regions in NASH. CONCLUSION: NAFLD is associated not only with lipid enrichment, but also with zonal changes of specific lipids and their associated metabolic pathways. This may play a role in the heterogeneous development of NAFLD. (Hepatology 2017;65:1165-1180). ; Medical Research Council (MRC). Horizon 2020 Framework Program of the European Union.

Background & Aims: Non-alcoholic fatty liver disease (NAFLD), which is closely associated with obesity, metabolic syndrome, and diabetes, is a highly prevalent emerging condition that can be optimally managed through a multidisciplinary patientcentred approach. National preparedness to address NAFLD is essential to ensure that health systems can deliver effective care. We present a NAFLD Preparedness Index for Europe. Methods: In June 2019, data were extracted by expert groups from 29 countries to complete a 41-item questionnaire about NAFLD. Questions were classified into 4 categories: policies/civil society (9 questions), guidelines (16 questions), epidemiology (4 questions), and care management (12 questions). Based on the responses, national preparedness for each indicator was classified into low, middle, or high-levels. We then applied a multiple correspondence analysis to obtain a standardised preparedness score for each country ranging from 0 to 100. Results: The analysis estimated a summary factor that explained 71.3% of the variation in the dataset. No countries were found to have yet attained a high-level of preparedness. Currently, the UK (75.5) scored best, although falling within the midlevel preparedness band, followed by Spain (56.2), and Denmark (43.4), whereas Luxembourg and Ireland were the lowest scoring countries with a score of 4.9. Only Spain scored highly in the epidemiology indicator category, whereas the UK was the only country that scored highly for care management. Conclusions: The NAFLD Preparedness Index indicates substantial variation between countries readiness to address NAFLD. Notably, even those countries that score relatively highly exhibit deficiencies in key domains, suggesting that structural changes are needed to optimise NAFLD management and ensure effective public health approaches are in place. Lay summary: Non-alcoholic fatty liver disease (NAFLD), which is closely associated with obesity, metabolic syndrome, and diabetes, is a highly prevalent condition that can be optimally managed through a multidisciplinary patient-centred approach. National preparedness to address NAFLD is essential to allow for effective public health measures aimed at preventing disease while also ensuring that health systems can deliver effective care to affected populations. This study defined preparedness as having adequate policies and civil society engagement, guidelines, epidemiology, and care management. NAFLD preparedness was found to be deficient in all 29 countries studied, with great variation among the countries and the 4 categories studied. (C) 2021 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). ; Funding Agencies|EASL International Liver Foundation; Gilead Sciences Europe Ltd.Gilead Sciences; Allergan Pharmaceutical International Ltd.AbbVieAllergan; Bristol-Myers-Squibb CompanyBristol-Myers Squibb; Pfizer Inc.Pfizer; Resoundant Inc.; Intercept; Genfit; Spanish Ministry of Science, Innovation and Universities Miguel Servet grant (Instituto de Salud Carlos III/ESF, European Union) [CP18/00074]; Spanish Ministry of Science, Innovation and Universities through the Centro de Excelencia Severo Ochoa 2019-2023 Programme [CEX2018-000806-S]; Government of Catalonia through the CERCA Programme; Horizon 2020 Framework Program of the European Union [634413]; IMI2 Program of the European Union [777377]

Since its discovery twenty-five years ago, the fat-derived hormone leptin has provided a revolutionary framework for studying the physiological role of adipose tissue as an endocrine organ. Leptin exerts pleiotropic effects on many metabolic pathways and is tightly connected with the liver, the major player in systemic metabolism. As a consequence, understanding the metabolic and hormonal interplay between the liver and adipose tissue could provide us with new therapeutic targets for some chronic liver diseases, an increasing problem worldwide. In this review, we assess relevant literature regarding the main metabolic effects of leptin on the liver, by direct regulation or through the central nervous system (CNS). We draw special attention to the contribution of leptin to the non-alcoholic fatty liver disease (NAFLD) pathogenesis and its progression to more advanced stages of the disease as non-alcoholic steatohepatitis (NASH). Likewise, we describe the contribution of leptin to the liver regeneration process after partial hepatectomy, the mainstay of treatment for certain hepatic malignant tumors ; M.G.N. is recipient of "Juan de la Cierva-Incorporación" fellowship (IJCI-2017-32606) from Ministerio de Ciencia, Innovación y Universidades, Spain. This work was supported by grants from FEDER/Ministerio de Ciencia, Innovación y Universidades-Agencia Estatal de Investigación (CD: BFU2017-87721) and the TALENTO Program from the Madrid Government (MAFR 2016/T1- BIO-1854). Financial support from the Xunta de Galicia (Centro singular de investigación de Galicia accreditation 2019-2022- ED431G 2019/02) and the European Union (European Regional Development Fund—ERDF), is gratefully acknowledged. Centro de Investigación Biomédica en Red (CIBER) de Fisiopatología de la Obesidad y Nutrición (CIBERobn) is an initiative of the Instituto de Salud Carlos III (ISCIII) of Spain, which is supported by FEDER funds (EU) ; SI

Background & Aims: Genetic factors associated with nonalcoholic fatty liver disease (NAFLD) remain incompletely understood. To date, most genome-wide association studies (GWASs) have adopted radiologically assessed hepatic triglyceride content as the reference phenotype and so cannot address steatohepatitis or fibrosis. We describe a GWAS encompassing the full spectrum of histologically characterised NAFLD. Methods: The GWAS involved 1,483 European NAFLD cases and 17,781 genetically matched controls. A replication cohort of 559 NAFLD cases and 945 controls was genotyped to confirm signals showing genome-wide or close to genome-wide significance. Results: Case-control analysis identified signals showing p values = F3), the signals on chr2, chr19 and chr22 maintained their genome-wide significance. Except for GCKR/C2ORF16, the genome-wide significance signals were replicated. Conclusions: This study confirms PNPLA3 as a risk factor for the full histological spectrum of NAFLD at genome-wide significance levels, with important contributions from TM6SF2 and HSD17B13. PYGO1 is a novel steatosis modifier, suggesting that Wnt signalling pathways may be relevant in NAFLD pathogenesis. Lay summary: Non-alcoholic fatty liver disease is a common disease where excessive fat accumulates in the liver and may result in cirrhosis. To understand who is at risk of developing this disease and suffering liver damage, we undertook a genetic study to compare the genetic profiles of people suffering from fatty liver disease with genetic profiles seen in the general population. We found that particular sequences in 4 different areas of the human genome were seen at different frequencies in the fatty liver disease cases. These sequences may help predict an individuals risk of developing advanced disease. Some genes where these sequences are located may also be good targets for future drug treatments. (C) 2020 European Association for the Study of the Liver. Published by Elsevier B.V. ; Funding Agencies|EPoS (Elucidating Pathways of Steatohepatitis) consortium - Horizon 2020 Framework Program of the European Union [634413]; FLIP consortium(EuropeanUnion FP7 grant) [241762]; Newcastle NIHR Biomedical Research Centre

International audience ; Background & aims: Non-alcoholic fatty liver disease (NAFLD), which is closely associated with obesity, metabolic syndrome, and diabetes, is a highly prevalent emerging condition that can be optimally managed through a multidisciplinary patient-centred approach. National preparedness to address NAFLD is essential to ensure that health systems can deliver effective care. We present a NAFLD Preparedness Index for Europe.Methods: In June 2019, data were extracted by expert groups from 29 countries to complete a 41-item questionnaire about NAFLD. Questions were classified into 4 categories: policies/civil society (9 questions), guidelines (16 questions), epidemiology (4 questions), and care management (12 questions). Based on the responses, national preparedness for each indicator was classified into low, middle, or high-levels. We then applied a multiple correspondence analysis to obtain a standardised preparedness score for each country ranging from 0 to 100.Results: The analysis estimated a summary factor that explained 71.3% of the variation in the dataset. No countries were found to have yet attained a high-level of preparedness. Currently, the UK (75.5) scored best, although falling within the mid-level preparedness band, followed by Spain (56.2), and Denmark (43.4), whereas Luxembourg and Ireland were the lowest scoring countries with a score of 4.9. Only Spain scored highly in the epidemiology indicator category, whereas the UK was the only country that scored highly for care management.Conclusions: The NAFLD Preparedness Index indicates substantial variation between countries' readiness to address NAFLD. Notably, even those countries that score relatively highly exhibit deficiencies in key domains, suggesting that structural changes are needed to optimise NAFLD management and ensure effective public health approaches are in place.Lay summary: Non-alcoholic fatty liver disease (NAFLD), which is closely associated with obesity, metabolic syndrome, and diabetes, is a highly ...

International audience ; Background & aims: Non-alcoholic fatty liver disease (NAFLD), which is closely associated with obesity, metabolic syndrome, and diabetes, is a highly prevalent emerging condition that can be optimally managed through a multidisciplinary patient-centred approach. National preparedness to address NAFLD is essential to ensure that health systems can deliver effective care. We present a NAFLD Preparedness Index for Europe.Methods: In June 2019, data were extracted by expert groups from 29 countries to complete a 41-item questionnaire about NAFLD. Questions were classified into 4 categories: policies/civil society (9 questions), guidelines (16 questions), epidemiology (4 questions), and care management (12 questions). Based on the responses, national preparedness for each indicator was classified into low, middle, or high-levels. We then applied a multiple correspondence analysis to obtain a standardised preparedness score for each country ranging from 0 to 100.Results: The analysis estimated a summary factor that explained 71.3% of the variation in the dataset. No countries were found to have yet attained a high-level of preparedness. Currently, the UK (75.5) scored best, although falling within the mid-level preparedness band, followed by Spain (56.2), and Denmark (43.4), whereas Luxembourg and Ireland were the lowest scoring countries with a score of 4.9. Only Spain scored highly in the epidemiology indicator category, whereas the UK was the only country that scored highly for care management.Conclusions: The NAFLD Preparedness Index indicates substantial variation between countries' readiness to address NAFLD. Notably, even those countries that score relatively highly exhibit deficiencies in key domains, suggesting that structural changes are needed to optimise NAFLD management and ensure effective public health approaches are in place.Lay summary: Non-alcoholic fatty liver disease (NAFLD), which is closely associated with obesity, metabolic syndrome, and diabetes, is a highly ...