Sökning: onr:"swepub:oai:lup.lub.lu.se:6eafb112-5323-4cc8-9779-09d8d0b0b232" >
Distinct contributi...
Distinct contributions of metabolic dysfunction and genetic risk factors in the pathogenesis of non-alcoholic fatty liver disease
-
- Luukkonen, Panu K. (författare)
- University of Helsinki,Yale University,Minerva Foundation Institute for Medical Research
-
- Qadri, Sami (författare)
- University of Helsinki,Minerva Foundation Institute for Medical Research
-
- Ahlholm, Noora (författare)
- University of Helsinki,Minerva Foundation Institute for Medical Research
-
visa fler...
-
- Porthan, Kimmo (författare)
- Minerva Foundation Institute for Medical Research,University of Helsinki
-
- Männistö, Ville (författare)
- University of Eastern Finland
-
- Sammalkorpi, Henna (författare)
- University of Helsinki
-
- Penttilä, Anne K. (författare)
- University of Helsinki
-
- Hakkarainen, Antti (författare)
- Aalto University,University of Helsinki
-
- Lehtimäki, Tiina E. (författare)
- University of Helsinki
-
- Gaggini, Melania (författare)
- CNR Institute of Clinical Physiology (IFC-CNR)
-
- Gastaldelli, Amalia (författare)
- CNR Institute of Clinical Physiology (IFC-CNR)
-
- Ala-Korpela, Mika (författare)
- University of Oulu,University of Eastern Finland
-
- Orho-Melander, Marju (författare)
- Lund University,Lunds universitet,Diabetes - kardiovaskulär sjukdom,Forskargrupper vid Lunds universitet,Diabetes - Cardiovascular Disease,Lund University Research Groups
-
- Arola, Johanna (författare)
- University of Helsinki
-
- Juuti, Anne (författare)
- University of Helsinki
-
- Pihlajamäki, Jussi (författare)
- University of Eastern Finland
-
- Hodson, Leanne (författare)
- University of Oxford
-
- Yki-Järvinen, Hannele (författare)
- University of Helsinki,Minerva Foundation Institute for Medical Research
-
visa färre...
-
(creator_code:org_t)
- Elsevier BV, 2022
- 2022
- Engelska 10 s.
-
Ingår i: Journal of Hepatology. - : Elsevier BV. - 0168-8278. ; 76:3, s. 526-535
- Relaterad länk:
-
http://dx.doi.org/10... (free)
-
visa fler...
-
http://www.journal-o...
-
https://lup.lub.lu.s...
-
https://doi.org/10.1...
-
visa färre...
Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
Nyckelord
- adipose tissue lipolysis
- de novo lipogenesis
- hepatic mitochondrial redox state
- HSD17B13
- insulin resistance
- MARC1
- MBOAT7
- metabolomics
- PNPLA3
- TM6SF2
Publikations- och innehållstyp
- art (ämneskategori)
- ref (ämneskategori)
Hitta via bibliotek
Till lärosätets databas
- Av författaren/redakt...
-
Luukkonen, Panu ...
-
Qadri, Sami
-
Ahlholm, Noora
-
Porthan, Kimmo
-
Männistö, Ville
-
Sammalkorpi, Hen ...
-
visa fler...
-
Penttilä, Anne K ...
-
Hakkarainen, Ant ...
-
Lehtimäki, Tiina ...
-
Gaggini, Melania
-
Gastaldelli, Ama ...
-
Ala-Korpela, Mik ...
-
Orho-Melander, M ...
-
Arola, Johanna
-
Juuti, Anne
-
Pihlajamäki, Jus ...
-
Hodson, Leanne
-
Yki-Järvinen, Ha ...
-
visa färre...
- Om ämnet
-
- MEDICIN OCH HÄLSOVETENSKAP
-
MEDICIN OCH HÄLS ...
-
och Klinisk medicin
-
och Endokrinologi oc ...
- Artiklar i publikationen
-
Journal of Hepat ...
- Av lärosätet
-
Lunds universitet