TM6SF2 is a regulator of liver fat metabolism influencing triglyceride secretion and hepatic lipid droplet content
Open accessAbstract
Significance: Genome-wide association studies have uncovered a genetic locus in chromosome 19 associated with the plasma triglyceride (TG) concentration, a risk factor for coronary heart disease. The identity and functional role of the gene responsible for this association is unknown. Gene expression analysis of 206 human liver samples led to the identification of transmembrane 6 superfamily member 2 ( TM6SF2 ), a gene with hitherto unknown function, as the putative causal gene. Functional studies in human liver cells demonstrated that inhibition of TM6SF2 was associated with reduced secretion of TG-rich lipoproteins (TRLs) and increased cellular TG concentration, while TM6SF2 overexpression reduced cellular TG concentration. We conclude that TM6SF2 is a novel regulator of liver fat metabolism with opposing effects on the secretion of TRLs and hepatic TG content.
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The liver/lipid cluster includes loci GCKR, PNPLA3, and TM6SF2, which functional experiments have shown to relate to liver lipid metabolism.
“The liver/lipid cluster includes loci GCKR, PNPLA3, and TM6SF2, which have been shown through functional experiments to relate to liver lipid metabolism (24–31).”
From Increased genetic risk for β-cell failure is associated with β-cell function decline in people with prediabetes (2024) · cites this paper as [29]
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- Authors
- Mahdessian, H., Taxiarchis, A., Popov, S., Silveira, A., Franco-Cereceda, A., Hamsten, A., Eriksson, P., & van't Hooft, F.
- Affiliations
- Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine, Solna, and
- Cardiothoracic Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, SE-171 76 Stockholm, Sweden
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2014-06-04
- Volume
- 111
- Issue
- 24
- Pages
- 8913-8918
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4066487
- OpenAlex
- W2054311777
- Cited by
- 369
- References
- 20
- Citations by year
- 2026: 22 · 2025: 26 · 2024: 46 · 2023: 26 · 2022: 24 · 2021: 36 · 2020: 45 · 2019: 30 · 2018: 30 · 2017: 25 · 2016: 27 · 2015: 25 · 2014: 5
- FWCI
- 18.78
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Stiftelsen för Gamla Tjänarinnor
- European Commission (LSHM-CT-2007–037273)
- Fondation Leducq
- Hjärt-Lungfonden (12660)
- Karolinska Institutet
- Knut och Alice Wallenbergs Stiftelse
- Stockholms Läns Landsting (560283)
- Vetenskapsrådet (12660)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- TM6SF2, triglyceride secretion, TG-rich lipoproteins, hepatic lipid droplets, non-alcoholic fatty liver disease, plasma triglycerides, endoplasmic reticulum, ER-Golgi intermediate compartment, hepatic steatosis, causal gene identification
- MeSH terms
- Animals, Cattle, Dogs, Endoplasmic Reticulum, Gene Expression Regulation, Genotype, Golgi Apparatus, Guinea Pigs, Humans, Lipids, Liver, Membrane Proteins, Tissue Distribution, Triglycerides, Gene Expression Profiling, RNA, Small Interfering, Quantitative Trait Loci, Cell Line, Tumor, Lipid Metabolism, Mice, Rats, Genome-Wide Association Study, Hep G2 Cells
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