Abstract
Aims/hypothesis
The common sequence variant I148M of the patatin-like phospholipase domain-containing protein 3 gene (PNPLA3) is associated with increased hepatic triacylglycerol (TAG) content, but not with insulin resistance, in humans. The PNPLA3 I148M variant was previously reported to alter the specificity of the encoded enzyme and subsequently affect lipid composition.
Methods
We analysed the fatty acid composition of five lipid fractions from liver tissue samples from 52 individuals, including 19 carriers of the minor PNPLA3 I148M variant.
Results
PNPLA3 I148M was associated with a strong increase (1.75-fold) in liver TAGs, but with no change in other lipid fractions. PNPLA3 I148M minor allele carriers had an increased n-3 polyunsaturated fatty acid (PUFA) α-linolenic acid content and reductions in several n-6 PUFAs in the liver TAG fraction. Furthermore, there was a strong inverse correlation between n-6 PUFA and TAG content independent of PNPLA3 genotype. In a multivariate model including liver fat content, PNPLA3 genotype and fatty acid composition, two significant differences could be exclusively attributed to the PNPLA3 I148M minor allele: reduced stearic acid and increased α-linolenic acid content in the hepatic TAG fraction.
Conclusions
These changes therefore suggest a mechanism to explain the PNPLA3 I148M-dependent increase in liver fat content without causing insulin resistance. Stearic acid can induce insulin resistance, whereas α-linolenic acid may protect against it.
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Abbreviations
- MUFA:
-
Monounsaturated fatty acids
- NAFL:
-
Nonalcoholic fatty liver
- PUFA:
-
Polyunsaturated fatty acid
- SFA:
-
Saturated fatty acid
- TAG:
-
Triacylglycerol
- WT:
-
Wild-type
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Acknowledgements
We thank M. Walenta (Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Germany) for expert technical assistance.
Funding
This work was supported by grants from the German Research Foundation (GRK 1302/2) and the Ministry of Education, Youth, and Sport of the Czech Republic (MSM0021627502). Part of this work was supported by a grant from the German Federal Ministry of Education and Research to the German Center for Diabetes Research and the Kompetenznetz Diabetes Mellitus (Competence Network for Diabetes Mellitus; FKZ 01GI0803–04). NS is currently supported by a Heisenberg Professorship from the Deutsche Forschungsgemeinschaft (STE 1096/3–1). Funding did not include industrial sponsorship.
Duality of interest
All authors declare that there is no duality of interest associated with this manuscript.
Contribution statement
All authors substantially contributed to the conception and design of the study; data acquisition, analysis and interpretation; and drafting the manuscript or critically revising it for important intellectual content. All authors approved the final version for publication. The most important contributions of each author are: AP and ES designed the study, performed experiments and wrote the manuscript; MK SN, TC, FM and AK analysed data and edited the manuscript; NS and HUH contributed to discussions and reviewed the manuscript; and AP is the guarantor of this work.
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Peter, A., Kovarova, M., Nadalin, S. et al. PNPLA3 variant I148M is associated with altered hepatic lipid composition in humans. Diabetologia 57, 2103–2107 (2014). https://doi.org/10.1007/s00125-014-3310-0
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DOI: https://doi.org/10.1007/s00125-014-3310-0