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

The Journal of Clinical Endocrinology and Metabolism
Rosellina M MancinaJan Borén

Abstract

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 he...Continue Reading

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Citations

Jun 24, 2015·Nutrients·Elisa Fabbrini, Faidon Magkos
Jan 30, 2016·Metabolism: Clinical and Experimental·Elena BuzzettiEmmanuel A Tsochatzis
Nov 26, 2015·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Benedetta DonatiLuca Valenti
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