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J Clin Endocrinol Metab. 2015 May;100(5):E821-5. doi: 10.1210/jc.2014-4464. Epub 2015 Mar 12.

Paradoxical dissociation between hepatic fat content and de novo lipogenesis due to PNPLA3 sequence variant.

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Department of Molecular and Clinical Medicine (R.M.M, C.M, S.R., J.B.), University of Gothenburg, S-413 45 Gothenburg, Sweden; Department of Medicine, Cardiovascular Research Unit, Diabetes and Obesity Research Program (N.M., S.S., M.-R.T.), Heart and Lung Centre and Division of Endocrinology and Helsinki University Central Hospital, University of Helsinki, 00100 Helsinki, Finland; Department of Radiology, HUS Medical Imaging Center (N.L., A.H.), Helsinki University Central Hospital, University of Helsinki, 00100 Helsinki, Finland; Departments of Internal Medicine (R.R, S.F., L.V.), and General Surgery (E.M.), Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Policlinico, and Department of Pathophysiology and Transplantation Università degli Studi di Milano, 20122 Milano, Italy; and Department of Medical and Surgical Sciences (S.R.), Clinical Nutrition Unit, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy.



Nonalcoholic fatty liver disease (NAFLD) is an emerging epidemic disease characterized by increased hepatic fat, due to an imbalance between synthesis and removal of hepatic lipids. In particular, increased hepatic de novo lipogenesis (DNL) is a key feature associated with NAFLD. The genetic variations I148M in PNPLA3 and E167K in TM6SF2 confer susceptibility to NAFLD.


Here we aimed to investigate the contribution of DNL to liver fat accumulation in the PNPLA3 I148M or TM6SF2 E167K genetic determinants of NAFLD.


The PNPLA3 I148M and TM6SF2 E167K were genotyped in two well-characterized cohorts of Europeans. In the first cohort (Helsinki cohort; n = 88), we directly quantified hepatic DNL using deuterated water. In the second cohort (Milan cohort; n = 63), we quantified the hepatic expression of SREBP1c that we have found previously associated with increased fat content. Liver fat was measured by magnetic resonance proton spectroscopy in the Helsinki cohort, and by histological assessment of liver biopsies in the Milan cohort.


PNPLA3 148M was associated with lower DNL and expression of the lipogenic transcription factor SREBP1c despite substantial increased hepatic fat content.


Our data show a paradoxical dissociation between hepatic DNL and hepatic fat content due to the PNPLA3 148M allele indicating that increased DNL is not a key feature in all individuals with hepatic steatosis, and reinforces the contribution of decreased mobilization of hepatic triglycerides for hepatic lipid accumulation in subject with the PNPLA3 148M allele.

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