Panu K. Luukkonen, Sami Qadri, Noora Ahlholm, Kimmo Porthan, Ville Männistö, Henna Sammalkorpi, Anne K. Penttilä, Antti Hakkarainen, Tiina E. Lehtimäki, Melania Gaggini, Amalia Gastaldelli, Mika Ala-Korpela, Marju Orho-Melander, Johanna Arola, Anne Juuti, Jussi Pihlajamäki, Leanne Hodson, Hannele Yki-Järvinen, Distinct contributions of metabolic dysfunction and genetic risk factors in the pathogenesis of non-alcoholic fatty liver disease, Journal of Hepatology, Volume 76, Issue 3, 2022, Pages 526-535, ISSN 0168-8278, https://doi.org/10.1016/j.jhep.2021.10.013
Distinct contributions of metabolic dysfunction and genetic risk factors in the pathogenesis of non-alcoholic fatty liver disease
|Author:||Luukkonen, Panu K.1,2,3; Qadri, Sami2,3; Ahlholm, Noora2,3;|
1Department of Internal Medicine, Yale University, New Haven, CT, USA
2Department of Medicine, University of Helsinki and Helsinki University Hospital, Finland
3Minerva Foundation Institute for Medical Research, Helsinki, Finland
4Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
5Department of Abdominal Surgery, Abdominal Center, University of Helsinki and Helsinki University Hospital, Finland
6Department of Radiology, HUS Medical Imaging Center, University of Helsinki and Helsinki University Hospital, Finland
7Department of Neuroscience and Biomedical Engineering, Aalto University School of Science, Espoo, Finland
8Institute of Clinical Physiology, CNR, Pisa, Italy
9Computational Medicine, Faculty of Medicine, University of Oulu and Biocenter Oulu, Finland
10Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland
11University of Eastern Finland, Kuopio, Finland
12NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
13Department of Clinical Sciences, Diabetes and Endocrinology, University Hospital Malmö, Lund University, Malmö, Sweden
14Department of Pathology, University of Helsinki and Helsinki University Hospital, Finland
15Institute of Public Health and Clinical Nutrition, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
16Department of Medicine, Endocrinology and Clinical Nutrition, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
17Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford & NIHR Oxford Biomedical Research Centre, Oxford University Hospitals Foundation Trust, UK
|Online Access:||PDF Full Text (PDF, 1 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe2022052037401
|Publish Date:|| 2022-05-20
Background & Aims: There is substantial inter-individual variability in the risk of non-alcoholic fatty liver disease (NAFLD). Part of which is explained by insulin resistance (IR) (‘MetComp’) and part by common modifiers of genetic risk (‘GenComp’). We examined how IR on the one hand and genetic risk on the other contribute to the pathogenesis of NAFLD.
Methods: We studied 846 individuals: 492 were obese patients with liver histology and 354 were individuals who underwent intrahepatic triglyceride measurement by proton magnetic resonance spectroscopy. A genetic risk score was calculated using the number of risk alleles in PNPLA3, TM6SF2, MBOAT7, HSD17B13 and MARC1. Substrate concentrations were assessed by serum NMR metabolomics. In subsets of participants, non-esterified fatty acids (NEFAs) and their flux were assessed by D₅-glycerol and hyperinsulinemic-euglycemic clamp (n = 41), and hepatic de novo lipogenesis (DNL) was measured by D₂O (n = 61).
Results: We found that substrate surplus (increased concentrations of 28 serum metabolites including glucose, glycolytic intermediates, and amino acids; increased NEFAs and their flux; increased DNL) characterized the ‘MetComp’. In contrast, the ‘GenComp’ was not accompanied by any substrate excess but was characterized by an increased hepatic mitochondrial redox state, as determined by serum β-hydroxybutyrate/acetoacetate ratio, and inhibition of hepatic pathways dependent on tricarboxylic acid cycle activity, such as DNL. Serum β-hydroxybutyrate/acetoacetate ratio correlated strongly with all histological features of NAFLD. IR and hepatic mitochondrial redox state conferred additive increases in histological features of NAFLD.
Conclusions: These data show that the mechanisms underlying ‘Metabolic’ and ‘Genetic’ components of NAFLD are fundamentally different. These findings may have implications with respect to the diagnosis and treatment of NAFLD.
Lay summary: The pathogenesis of non-alcoholic fatty liver disease can be explained in part by a metabolic component, including obesity, and in part by a genetic component. Herein, we demonstrate that the mechanisms underlying these components are fundamentally different: the metabolic component is characterized by hepatic oversupply of substrates, such as sugars, lipids and amino acids. In contrast, the genetic component is characterized by impaired hepatic mitochondrial function, making the liver less able to metabolize these substrates.
Journal of hepatology
|Pages:||526 - 535|
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
3121 General medicine, internal medicine and other clinical medicine
This study was supported by Academy of Finland Grant 309263 (H.Y.-J.) and Grant 138006 (J.P.), EU H2020 project ‘Elucidating Pathways of Steatohepatitis’ EPoS Grant 634413 (H.Y.-J.), H2020-JTI-IMI2 EU project 777377-2 Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS) (H.Y.-J.), Government Funding (H.Y.-J.), Novo Nordisk Foundation (H.Y.-J., P.K.L., M.A.-K.), Ralph Gräsbeck Scholarship of the Minerva Foundation (P.K.L.), Novo Nordisk Foundation (P.K.L.), Juho Vainio Foundation (J.P.), Finnish Medical Foundation (V.M.), British Heart Foundation Senior Research Fellowship in Basic Science (FS/15/56/31645) (L.H.) and Kuopio University Hospital Project grant (J.P., EVO/VTR grants 2005-2019).
© 2021 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). J. Hepatol. 2022, 76, 526–535.