@article{2371d54285fd43c49b9460a5528edd8a,
title = "Causal relationship of hepatic fat with liver damage and insulin resistance in nonalcoholic fatty liver",
abstract = "Background and Aims: Nonalcoholic fatty liver disease is epidemiologically associated with hepatic and metabolic disorders. The aim of this study was to examine whether hepatic fat accumulation has a causal role in determining liver damage and insulin resistance. Methods: We performed a Mendelian randomization analysis using risk alleles in PNPLA3, TM6SF2, GCKR and MBOAT7, and a polygenic risk score for hepatic fat, as instruments. We evaluated complementary cohorts of at-risk individuals and individuals from the general population: 1515 from the liver biopsy cohort (LBC), 3329 from the Swedish Obese Subjects Study (SOS) and 4570 from the population-based Dallas Heart Study (DHS). Results: Hepatic fat was epidemiologically associated with liver damage, insulin resistance, dyslipidemia and hypertension. The impact of genetic variants on liver damage was proportional to their effect on hepatic fat accumulation. Genetically determined hepatic fat was associated with aminotransferases, and with inflammation, ballooning and fibrosis in the LBC. Furthermore, in the LBC, the causal association between hepatic fat and fibrosis was independent of disease activity, suggesting that a causal effect of long-term liver fat accumulation on liver disease is independent of inflammation. Genetically determined hepatic steatosis was associated with insulin resistance in the LBC and SOS. However, this association was dependent on liver damage severity. Genetically determined hepatic steatosis was associated with liver fibrosis/cirrhosis and with a small increase in risk of type 2 diabetes in publicly available databases. Conclusion: These data suggest that long-term hepatic fat accumulation plays a causal role in the development of chronic liver disease.",
keywords = "fibrosis, genetics, insulin resistance, mendelian randomization, nonalcoholic fatty liver disease, type 2 diabetes",
author = "P. Dongiovanni and S. Stender and A. Pietrelli and Mancina, {R. M.} and A. Cespiati and S. Petta and S. Pelusi and P. Pingitore and S. Badiali and M. Maggioni and V. Mannisto and S. Grimaudo and Pipitone, {R. M.} and J. Pihlajamaki and A. Craxi and M. Taube and Carlsson, {L. M.S.} and S. Fargion and S. Romeo and J. Kozlitina and L. Valenti",
note = "Funding Information: This work was supported by Associazione Italiana Ricerca sul Cancro, myFIRST Grant AIRC (16888), Molecular Medicine Grant Fondazione IRCCS Ca' Granda and INGM 2014, Ricerca Corrente Fondazione Ca' Granda IRCCS Policlinico of Milan, Associazione Malattie Metaboliche del Fegato ONLUS (L.V.); the National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK090066); NIH, National Heart, Lung, and Blood Institute (P01 HL20948); NIH, National Center for Advancing Translational Sciences (UL1TR001105) (J.K.); the Swedish Research Council (Vetenskapsr{\aa}det), grants 254439006 and K2013-54X-11285-19; the Swedish Heart Lung Foundation (244439007), the Swedish federal government funding under the Agreement on Medical Training and Medical Research (76290), Sahlgrenska University Hospital ALF research grant ALFGBG-428911, the Novonordisk Foundation Grant for Excellence in Endocrinology (244439012), the Swedish Diabetes Foundation (DIA 2014-052) (S.R.), the Wilhelm and Martina Lundgren Science Fund (R.M.M, P.P, and S.R.), the Nilsson-Ehle funds from the Fysiografiska S{\"a}llsk-apet in Lund (R.M.M.), and the Danish Council for Independent Research, Medical Sciences (Sapere Aude 4004-00398) (S.S.). Funding Information: This work was supported by Associazione Italiana Ricerca sul Cancro, myFIRST Grant AIRC (16888), Molecular Medicine Grant Fondazione IRCCS Ca{\textquoteright} Granda and INGM 2014, Ricerca Corrente Fon-dazione Ca{\textquoteright} Granda IRCCS Policlinico of Milan, Associazione Malattie Metaboliche del Fegato ONLUS (L.V.); the National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK090066); NIH, National Heart, Lung, and Blood Institute (P01 HL20948); NIH, National Center for Advancing Translational Sciences (UL1TR001105) (J.K.); the Swedish Research Council (Vetenskapsr{\textcopyright}adet), grants 254439006 and K2013-54X-11285-19; the Swedish Heart Lung Foundation (244439007), the Swedish federal government funding under the Agreement on Medical Training and Medical Research (76290), Sahlgrenska University Hospital ALF research grant ALFGBG-428911, the Novo-nordisk Foundation Grant for Excellence in Endocrinology (244439012), the Swedish Diabetes Foundation (DIA 2014-052) (S.R.), the Wilhelm and Martina Lundgren Science Fund (R.M.M, P.P, and S.R.), the Nilsson-Ehle funds from the Fys-iografiska Sa€llsk-apet in Lund (R.M.M.), and the Danish Council for Independent Research, Medical Sciences (Sapere Aude 4004-00398) (S.S.). Publisher Copyright: {\textcopyright} 2017 The Authors Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine",
year = "2018",
month = apr,
doi = "10.1111/joim.12719",
language = "English (US)",
volume = "283",
pages = "356--370",
journal = "Journal of Internal Medicine",
issn = "0954-6820",
publisher = "Wiley-Blackwell",
number = "4",
}