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1. Nutritional Intake after Liver Transplant: Systematic Review and Meta-Analysis

Author

Lynsey N. Spillman, Angela M. Madden, Holly Richardson, Fumiaki Imamura, Danielle Jones, Marilyn Nash, Hong Kai Lim, Holly N. Hellawell, Kirsten L. Rennie, Linda M. Oude Griep, Michael Allison, Simon J. Griffin, Spillman, Lynsey N [0000-0003-1409-0273], Madden, Angela M [0000-0001-6353-6492], Jones, Danielle [0000-0003-0372-5579], Lim, Hong Kai [0000-0002-7266-7790], Oude Griep, Linda M [0000-0001-7697-7473], Allison, Michael [0000-0003-3677-3294], and Apollo - University of Cambridge Repository

Subjects
Transplantation, Nutrition and Dietetics, Liver Disease, Prevention, 42 Health Sciences, 32 Biomedical and Clinical Sciences, Organ Transplantation, Cardiovascular, Oral and gastrointestinal, Diet, Liver Transplantation, Eating, Cardiovascular Diseases, Fruit, 3210 Nutrition and Dietetics, Vegetables, 4206 Public Health, Humans, Digestive Diseases, Liver transplant, Metabolic and endocrine, Food Science, Cancer, Nutrition
Abstract

Cardiovascular disease and its concurrent risk factors are prevalent after liver transplant (LT). Most of these risk factors are modifiable by diet. We aimed to synthesise the literature reporting the nutritional intake of liver transplant recipients (LTR) and the potential determinants of intake. We performed a systematic review and meta-analyses of studies published up until July 2021 reporting the nutritional intake of LTR. The pooled daily mean intakes were recorded as 1998 (95% CI 1889, 2108) kcal, 17 (17, 18)% energy from protein, 49 (48, 51)% energy from carbohydrates, 34 (33, 35)% energy from total fat, 10 (7, 13)% energy from saturated fat, and 20 (18, 21) g of fibre. The average fruit and vegetable intake ranged from 105 to 418 g/day. The length of time post-LT and the age and sex of the cohorts, as well as the continent and year of publication of each study, were sources of heterogeneity. Nine studies investigated the potential determinants of intake, time post-LT, gender and immunosuppression medication, with inconclusive results. Energy and protein requirements were not met in the first month post-transplant. After this point, energy intake was significantly higher and remained stable over time, with a high fat intake and low intake of fibre, fruits and vegetables. This suggests that LTR consume a high-energy, low-quality diet in the long term and do not adhere to the dietary guidelines for cardiovascular disease prevention.

Published
2023

2. Metabolic signatures across the full spectrum of non-alcoholic fatty liver disease

Author

Aidan J. McGlinchey, Olivier Govaere, Dawei Geng, Vlad Ratziu, Michael Allison, Jerome Bousier, Salvatore Petta, Claudia de Oliviera, Elisabetta Bugianesi, Jörn M. Schattenberg, Ann K. Daly, Tuulia Hyötyläinen, Quentin M. Anstee, Matej Orešič, McGlinchey, Aidan J, Govaere, Olivier, Geng, Dawei, Ratziu, Vlad, Allison, Michael, Bousier, Jerome, Petta, Salvatore, de Oliviera, Claudia, Bugianesi, Elisabetta, Schattenberg, Jörn M, Daly, Ann K, Hyötyläinen, Tuulia, Anstee, Quentin M, Orešič, Matej, Govaere, Olivier [0000-0002-4426-6930], Allison, Michael [0000-0003-3677-3294], Bugianesi, Elisabetta [0000-0002-0502-4381], Schattenberg, Jörn M [0000-0002-4224-4703], and Apollo - University of Cambridge Repository

Subjects
ALT, type 2 diabetes mellitus, ROC, receiving operator characteristic, aspartate aminotransferase, HSD, LDL, low-density lipoprotein, UHPLC, ultrahigh-performance liquid chromatography, ROC, HCC, Non-alcoholic steatohepatitis, GC, PCA, NASH, Gastroenterology, 2-HB, 2-hydroxybutanoic acid, 3-HB, 3-hydroxybutanoic acid, ALT, alanine aminotransferase, AST, aspartate aminotransferase, CE, cholesterol ester, Cer, ceramide, FFA, free fatty acid, FLIP, Fatty Liver Inhibition of Progression, Fibrosis, GC, gas chromatography, HCC, hepatocellular carcinoma, HSD, honest significant difference, LC, lipid cluster, LM, lipid and metabolite, LMC, lipid, metabolite, and clinical variable, LPC, lysophosphatidylcholine, Lipidomics, Mass spectrometry, Metabolomics, NAFL, non-alcoholic fatty liver, NAFLD, non-alcoholic fatty liver disease, NAS, NASH activity score, NASH, non-alcoholic steatohepatitis, NIDDK NASH-CRN, National Institute of Digestive Diseases and Kidney NASH Clinical Research Network, NRR, non-rejection rate, PC(O), ether PC, PC, phosphatidylcholine, PCA, principal component analysis, PE, phosphatidylethanolamine, QTOFMS, quadrupole-time-of-flight mass spectrometry, SAF, steatosis, activity, and fibrosis, SM, sphingomyelin, T2DM, type 2 diabetes mellitus, TG, triacylglycerol, SAF, honest significant difference, non-rejection rate, cholesterol ester, PC, PE, free fatty acid, FLIP, BIOMARKERS, T2DM, LDL, lipid, NAFLD, 2-HB, LMC, phosphatidylcholine, Science & Technology, Gastroenterology & Hepatology, activity, nutritional and metabolic diseases, ACIDS, receiving operator characteristic, digestive system diseases, quadrupole-time-of-flight mass spectrometry, low-density lipoprotein, NAS, QTOFMS, ether PC, NRR, SCORING SYSTEM, principal component analysis, gas chromatography, LC, 2-hydroxybutanoic acid, PROGRESSION, LM, PC(O), MARKERS, UHPLC, steatosis, TOOL, Immunology and Allergy, INSULIN-RESISTANCE, Cer, SM, Fatty Liver Inhibition of Progression, hepatocellular carcinoma, 2-HB, 2-hydroxybutanoic acid, NIDDK NASH-CRN, National Institute of Digestive Diseases and Kidney NASH Clinical Research Network, NRR, non-rejection rate, Non-alcoholic steatohepatitis, PC(O), ether PC, PC, phosphatidylcholine, PCA, principal component analysis, PE, phosphatidylethanolamine, QTOFMS, quadrupole-time-of-flight mass spectrometry, ROC, receiving operator characteristic, SAF, steatosis, activity, and fibrosis, SM, T2DM, type 2 diabetes mellitus, TG, triacylglycerol, UHPLC, ultrahigh-performance liquid chromatography, ultrahigh-performance liquid chromatography, CE, LPC, 3-HB, NAFL, non-alcoholic fatty liver, TG, triacylglycerol, Life Sciences & Biomedicine, alanine aminotransferase, metabolite, sphingomyelin, lysophosphatidylcholine, and fibrosis, Internal Medicine, ceramide, National Institute of Digestive Diseases and Kidney NASH Clinical Research Network, AST, Hepatology, non-alcoholic fatty liver disease, and clinical variable, 3-hydroxybutanoic acid, NASH activity score, NIDDK NASH-CRN, lipid cluster, lipid and metabolite, phosphatidylethanolamine, FFA
Abstract

Funder: European Commission, BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is a progressive liver disease with potentially severe complications including cirrhosis and hepatocellular carcinoma. Previously, we have identified circulating lipid signatures associating with liver fat content and non-alcoholic steatohepatitis (NASH). Here, we develop a metabolomic map across the NAFLD spectrum, defining interconnected metabolic signatures of steatosis (non-alcoholic fatty liver, NASH, and fibrosis). METHODS: We performed mass spectrometry analysis of molecular lipids and polar metabolites in serum samples from the European NAFLD Registry patients (n = 627), representing the full spectrum of NAFLD. Using various univariate, multivariate, and machine learning statistical approaches, we interrogated metabolites across 3 clinical perspectives: steatosis, NASH, and fibrosis. RESULTS: Following generation of the NAFLD metabolic network, we identify 15 metabolites unique to steatosis, 18 to NASH, and 15 to fibrosis, with 27 common to all. We identified that progression from F2 to F3 fibrosis coincides with a key pathophysiological transition point in disease natural history, with n = 73 metabolites altered. CONCLUSIONS: Analysis of circulating metabolites provides important insights into the metabolic changes during NAFLD progression, revealing metabolic signatures across the NAFLD spectrum and features that are specific to NAFL, NASH, and fibrosis. The F2-F3 transition marks a critical metabolic transition point in NAFLD pathogenesis, with the data pointing to the pathophysiological importance of metabolic stress and specifically oxidative stress. CLINICAL TRIALS REGISTRATION: The study is registered at Clinicaltrials.gov (NCT04442334). LAY SUMMARY: Non-alcoholic fatty liver disease is characterised by the build-up of fat in the liver, which progresses to liver dysfunction, scarring, and irreversible liver failure, and is markedly increasing in its prevalence worldwide. Here, we measured lipids and other small molecules (metabolites) in the blood with the aim of providing a comprehensive molecular overview of fat build-up, liver fibrosis, and diagnosed severity. We identify a key metabolic 'watershed' in the progression of liver damage, separating severe disease from mild, and show that specific lipid and metabolite profiles can help distinguish and/or define these cases.

Published
2021

3. NASH limits anti-tumour surveillance in immunotherapy-treated HCC

Author

Stephan Spahn, Florian Müller, Revant Gupta, Dominik Pfister, Kornelius Schulze, Pierre Bedossa, Eleni Kotsiliti, Lars Zender, Mathias Heikenwalder, Nicolás Gonzalo Núñez, Peter Schirmacher, Axel Schulz, Jan Kosla, Adrian T. Billeter, Thomas Engleitner, Aleksandra Deczkowska, Danijela Heide, Donato Inverso, Susanne Roth, Olivier Govaere, Carla Montironi, Martha M. Kirstein, Dan G. Duda, Antonio D'Alessio, Jörn M. Schattenberg, Ekaterina Friebel, Tiziana Pressiani, F. Hucke, Jörg Trojan, Michael Bitzer, Suhail Yousuf, Bernhard Scheiner, Marina Ruiz de Galarreta, Markus Peck-Radosavljevic, Michael Allison, Nuh N. Rahbari, Simon Cockell, Brinda Emu, Ahmed Kaseb, David J. Pinato, Matthias P. Ebert, Joachim C. Mertens, Jean-François Dufour, Fabian Rössler, Achim Weber, Katharina Wolter, Thomas Decaens, Amaia Lujambio, Anja Moncsek, Daniela Lenggenhager, Katharina Pomej, Nisar P. Malek, Fabian Finkelmeier, Elisabetta Bugianesi, Valentina Leone, Ann K. Daly, Michael Dudek, Manfred Claassen, Zuzana Macek Jilkova, Henning Wege, Florian Castet, Marta Szydlowska, Beat P. Müller-Stich, Ramy Younes, Nicola Personeni, Philipp K. Haber, Marco Bueter, Manfred Jugold, Andrea Schietinger, Hiroto Kikuchi, Ido Amit, Sandra Koch, Dina Tiniakos, Ana Teijeiro, Jan-Philipp Mallm, Josep M. Llovet, Indrabahadur Singh, Percy A. Knolle, Sara De Dosso, Roland Rad, Arndt Vogel, Henrik E. Mei, Burkhard Becher, Nabil Djouder, Tom Luedde, Felix Meissner, Oliver Waidmann, Parice N. Marche, Viktor Umansky, Hellmut G. Augustin, Thomas U. Marron, Matthias Pinter, Mengjie Qiu, Arndt Weinmann, Ankit Sinha, Kristian Unger, Assaf Weiner, Vlad Ratziu, Quentin M. Anstee, Kristin Stirm, Yi Hsiang Huang, Alexander Siebenhüner, Fabian Kütting, Lorenza Rimassa, Dirk Waldschmidt, Masatoshi Kudo, Marc Ringelhan, Michele Vacca, Roser Pinyol, Fabio Marra, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Novo Nordisk A/S [Maløv, Denmark], Universität Zürich [Zürich] = University of Zurich (UZH), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Newcastle University [Newcastle], Medizinische Universität Wien = Medical University of Vienna, University of Tübingen, UniversitätsKlinikum Heidelberg, Weizmann Institute of Science [Rehovot, Israël], Max Planck Institute of Biochemistry (MPIB), Max-Planck-Gesellschaft, Technical University of Munich (TUM), University hospital of Zurich [Zurich], Helmholtz-Zentrum München (HZM), Heidelberg University, Spanish National Cancer Research Center (CNIO), Icahn School of Medicine at Mount Sinai [New York] (MSSM), National and Kapodistrian University of Athens (NKUA), University of Turin, Addenbrooke's Hospital, Cambridge University NHS Trust, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), University Medical Center [Mainz], Cambridge University Hospitals - NHS (CUH), University of Cambridge [UK] (CAM), Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7), Istituto Clinico Humanitas [Milan] (IRCCS Milan), Humanitas University [Milan] (Hunimed), Hannover Medical School [Hannover] (MHH), University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein (UKSH), Kiel University, Klinikum Klagenfurt am Wörthersee, Universitätsklinikum Frankfurt, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Oncology Institute of Southern Switzerland (IOSI), Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Memorial Sloane Kettering Cancer Center [New York], Weill Medical College of Cornell University [New York], Heidelberg University Hospital [Heidelberg], Medical Faculty [Mannheim], Massachusetts General Hospital [Boston], University of Cologne, Deutsches Rheuma-ForschungsZentrum (DRFZ), Deutsches Rheuma-ForschungsZentrum, German Center for Infection Research, Partnersite Munich (DZIF), University Medical Center [Tubingen, Germany], Inselspital Bern, University of Bern, The University of Texas M.D. Anderson Cancer Center [Houston], Kindai University, National Yang Ming University (NYMU), Taipei Veterans General Hospital [Taiwan], Universitätsklinikum Tübingen - University Hospital of Tübingen, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Eberhard Karls University [Tübingen, Germany], Université Grenoble Alpes (UGA), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), CHU Grenoble, Hammersmith Hospital NHS Imperial College Healthcare, Università degli Studi del Piemonte Orientale - Amedeo Avogadro (UPO), Institució Catalana de Recerca i Estudis Avançats (ICREA), Pfister, Dominik [0000-0002-0542-2638], Núñez, Nicolás Gonzalo [0000-0003-3837-270X], Govaere, Olivier [0000-0002-4426-6930], Szydlowska, Marta [0000-0002-4660-899X], Gupta, Revant [0000-0002-0881-5074], Deczkowska, Aleksandra [0000-0003-0844-4346], Friebel, Ekaterina [0000-0003-1419-2376], Lenggenhager, Daniela [0000-0002-5382-9854], Moncsek, Anja [0000-0002-1191-5842], Inverso, Donato [0000-0003-0987-3345], Vacca, Michele [0000-0002-1973-224X], Marra, Fabio [0000-0001-8629-0878], Allison, Michael [0000-0003-3677-3294], D'Alessio, Antonio [0000-0002-9164-3671], Personeni, Nicola [0000-0002-7995-272X], Rimassa, Lorenza [0000-0001-9957-3615], Pomej, Katharina [0000-0002-2807-3565], Peck-Radosavljevic, Markus [0000-0002-0597-2728], Mallm, Jan-Philipp [0000-0002-7059-4030], Schietinger, Andrea [0000-0003-3644-1687], Augustin, Hellmut G [0000-0002-7173-4242], Kikuchi, Hiroto [0000-0002-3601-8435], Duda, Dan G [0000-0001-7065-8797], Mei, Henrik E [0000-0003-0697-7755], Schulz, Axel Ronald [0000-0002-5106-0148], Ringelhan, Marc [0000-0003-3131-5657], Lujambio, Amaia [0000-0002-2798-1481], Dufour, Jean-Francois [0000-0002-8062-1346], Kudo, Masatoshi [0000-0002-4102-3474], Djouder, Nabil [0000-0001-8423-1030], Zender, Lars [0000-0001-7626-2849], Pinato, David J [0000-0002-3529-0103], Rad, Roland [0000-0002-6849-9659], Mertens, Joachim C [0000-0003-2007-0308], Weber, Achim [0000-0003-0073-3637], Meissner, Felix [0000-0003-1000-7989], Amit, Ido [0000-0003-2968-877X], Knolle, Percy [0000-0003-2983-0414], Becher, Burkhard [0000-0002-1541-7867], Llovet, Josep M [0000-0003-0547-2667], Heikenwalder, Mathias [0000-0002-3135-2274], Apollo - University of Cambridge Repository, Max-Planck-Institut für Biochemie = Max Planck Institute of Biochemistry (MPIB), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Helmholtz Zentrum München = German Research Center for Environmental Health, Università degli studi di Torino = University of Turin (UNITO), Università degli Studi di Firenze = University of Florence (UniFI), MARCHE, Patrice, D’Alessio, Antonio [0000-0002-9164-3671], Augustin, Hellmut G. [0000-0002-7173-4242], Duda, Dan G. [0000-0001-7065-8797], Mei, Henrik E. [0000-0003-0697-7755], Pinato, David J. [0000-0002-3529-0103], Mertens, Joachim C. [0000-0003-2007-0308], and Llovet, Josep M. [0000-0003-0547-2667]

Subjects
Male, Carcinogenesis, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Programmed Cell Death 1 Receptor, CD8-Positive T-Lymphocytes, B7-H1 Antigen, 13/2, 13/1, Mice, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, LIVER-CANCER, R PACKAGE, RNA-SEQ, 14/19, Cancer, 0303 health sciences, Multidisciplinary, NONALCOHOLIC STEATOHEPATITIS, Liver Neoplasms, article, ddc, 3. Good health, 13/31, Multidisciplinary Sciences, medicine.anatomical_structure, Liver, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Disease Progression, Science & Technology - Other Topics, [SDV.IMM]Life Sciences [q-bio]/Immunology, 64/60, Tumor necrosis factor alpha, Immunotherapy, Adjuvant, 631/67, Carcinoma, Hepatocellular, [SDV.IMM] Life Sciences [q-bio]/Immunology, T cell, 610 Medicine & health, [SDV.CAN]Life Sciences [q-bio]/Cancer, 14/32, 03 medical and health sciences, 14/34, 13/21, [SDV.CAN] Life Sciences [q-bio]/Cancer, ADVANCED HEPATOCELLULAR-CARCINOMA, NAFLD, medicine, Animals, Humans, 14/35, 030304 developmental biology, Science & Technology, Tumor Necrosis Factor-alpha, business.industry, 631/250/251, medicine.disease, PHASE-III, digestive system diseases, 13/51, 14/63, 59/57, T-CELLS, Cancer research, Steatohepatitis, business, CD8
Abstract

Hepatocellular carcinoma (HCC) can have viral or non-viral causes1–5. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need6,7. Here we report the progressive accumulation of exhausted, unconventionally activated CD8+PD1+ T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8+PD1+ T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH–HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8+PD1+CXCR6+, TOX+, and TNF+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8+ T cells or TNF neutralization, suggesting that CD8+ T cells help to induce NASH–HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8+PD1+ T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH–HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment., In hepatocellular carcinoma driven by non-alcoholic steatohepatitis, aberrant T cell activation and impaired immune surveillance seem to make hepatocellular carcinoma less responsive to anti-PD1 or anti-PDL1 immunotherapy.

Published
2021
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4. Hepatic steatosis risk is partly driven by increased de novo lipogenesis following carbohydrate consumption

Author

Sanders, Francis WB, Acharjee, Animesh, Walker, Celia, Marney, Luke, Roberts, Lee D, Imamura, Fumiaki, Jenkins, Benjamin, Case, Jack, Ray, Sumantra, Virtue, Samuel, Vidal-Puig, Antonio, Kuh, Diana, Hardy, Rebecca, Allison, Michael, Forouhi, Nita, Murray, Andrew, Wareham, Nicholas, Vacca, Michele, Koulman, Albert, Griffin, Julian, Acharjee, Animesh [0000-0003-2735-7010], Roberts, Lee D [0000-0002-1455-5248], Imamura, Fumiaki [0000-0002-6841-8396], Vidal-Puig, Antonio [0000-0003-4220-9577], Hardy, Rebecca [0000-0001-9949-0799], Allison, Michael [0000-0003-3677-3294], Forouhi, Nita [0000-0002-5041-248X], Murray, Andrew [0000-0002-0929-9315], Wareham, Nicholas [0000-0003-1422-2993], Vacca, Michele [0000-0002-1973-224X], Koulman, Albert [0000-0001-9998-051X], Griffin, Julian [0000-0003-1336-7744], and Apollo - University of Cambridge Repository

Subjects
Risk, Male, lcsh:QH426-470, Bioinformatics, 05 Environmental Sciences, Carbohydrates, Mice, Obese, Mice, Direct infusion mass spectrometry, Animals, Humans, lcsh:QH301-705.5, De novo lipogenesis, Triglycerides, Research, Lipogenesis, 06 Biological Sciences, Middle Aged, Lipids, Diet, Mice, Inbred C57BL, Fatty Liver, lcsh:Genetics, lcsh:Biology (General), Liver, Triacylglycerols, Female, 08 Information and Computing Sciences, Non-alcoholic fatty liver disease
Abstract

Background Diet is a major contributor to metabolic disease risk, but there is controversy as to whether increased incidences of diseases such as non-alcoholic fatty liver disease arise from consumption of saturated fats or free sugars. Here, we investigate whether a sub-set of triacylglycerols (TAGs) were associated with hepatic steatosis and whether they arise from de novo lipogenesis (DNL) from the consumption of carbohydrates. Results We conduct direct infusion mass spectrometry of lipids in plasma to study the association between specific TAGs and hepatic steatosis assessed by ultrasound and fatty liver index in volunteers from the UK-based Fenland Study and evaluate clustering of TAGs in the National Survey of Health and Development UK cohort. We find that TAGs containing saturated and monounsaturated fatty acids with 16–18 carbons are specifically associated with hepatic steatosis. These TAGs are additionally associated with higher consumption of carbohydrate and saturated fat, hepatic steatosis, and variations in the gene for protein phosphatase 1, regulatory subunit 3b (PPP1R3B), which in part regulates glycogen synthesis. DNL is measured in hyperphagic ob/ob mice, mice on a western diet (high in fat and free sugar) and in healthy humans using stable isotope techniques following high carbohydrate meals, demonstrating the rate of DNL correlates with increased synthesis of this cluster of TAGs. Furthermore, these TAGs are increased in plasma from patients with biopsy-confirmed steatosis. Conclusion A subset of TAGs is associated with hepatic steatosis, even when correcting for common confounding factors. We suggest that hepatic steatosis risk in western populations is in part driven by increased DNL following carbohydrate rich meals in addition to the consumption of saturated fat. Electronic supplementary material The online version of this article (10.1186/s13059-018-1439-8) contains supplementary material, which is available to authorized users.

Published
2018
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