The I148 M variant in PNPLA3 is associated with altered hepatic lipid composition in humans

A Peter; M Kovarova; A Königsrainer; F Machicao; N Stefan; HU Häring; E Schleicher

doi:10.1055/s-0034-1372076

Experimental and Clinical Endocrinology & Diabetes, Inhaltsverzeichnis

The I148 M variant in PNPLA3 is associated with altered hepatic lipid composition in humans

A Peter ¹^,²^,³, M Kovarova ¹^,⁴, A Königsrainer ⁵, F Machicao ¹^,²^,³, N Stefan ²^,³^,⁶, HU Häring ²^,³^,⁶, E Schleicher ¹^,²^,³

¹Universität Tübingen, Med. Klinik IV – Zentrallabor, Tübingen, Germany
²Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
³German Center for Diabetes Research (DZD), Neuherberg, Germany
⁴University of Pardubice, Faculty of Chemical Technology, Department of Biological and Biochemical Sciences, Pardubice, Czech Republic
⁵Department of General, Visceral and Transplant Surgery, University of Tübingen, Tübingen, Germany
⁶Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology, Clinical Chemistry and Pathobiochemistry, University of Tübingen, Tübingen, Germany

Abstract

The common sequence variant I148 M in patatin-like phospholipase domain 3 (PNPLA3) is associated with increased hepatic triacylglyceride (TAG) content but not with insulin resistance or diabetes in humans. In vitro data and a transgenic mouse model demonstrated that PNPLA3 I148 M not only increases hepatic lipid content, but also confers qualitative changes in hepatic lipid composition which may contribute to the metabolic consequences. Therefore we hypothesised that PNPLA3 I148 M impacts the hepatic lipid composition also in humans and analyzed the fatty acid composition of 5 lipid fractions in liver biopsies from 47 human subjects including 18 carriers of the PNPLA3 I148 M variant. PNPLA3 I148 M was associated with a strong increase (1.7-fold) in liver TAG but not other lipid fractions. The relative fatty acid composition of the TAGs showed a distinct pattern with significantly increased content of the n-3 polyunsaturated fatty acid (PUFA) alpha-linolenic acid (18:3 n-3) by 44% and decreased fatty acids of the n-6 series: eicosatrienoic acid (20:3) by 34%, arachidonic acid (20:4) by 44%, docosatetraenoic acid (22:4) by 50% and the end product docosapentaenoic acid (22:5) by 39%. These results are in part concordant with the changes detected in mouse livers overexpressing human PNPLA3 I148 M. Noteworthy, most PUFAs also showed an inverse correlation with TAG content independent of the PNPLA3 genotype. In a multivariate model including liver fat content, PNPLA3 genotype and fatty acid composition, two significant changes remained: reduced stearate and increased alpha-linoleate content in hepatic TAG. These two changes in fatty acid composition can be exclusively attributed to the PNPLA3 I148 M mutation and not general steatosis. Since stearate can induce insulin resistance and alpha-linoleate can protect from it, these changes may be part of the mechanism how PNPLA3 I148 M increases liver fat content without causing insulin resistance.