TM6SF2 Determines Both the Degree of Lipidation and the Number of VLDL Particles Secreted by the Liver
Open accessAbstract
In 2014, exome-wide studies identified a glutamine176lysine (p.E167K) substitution in a protein of unknown function named transmembrane 6 superfamily member 2 (TM6SF2). The p.E167K variant was associated with increased hepatic fat content and reduced levels of plasma TG and LDL cholesterol. Over the next several years, additional studies defined the role of TM6SF2, which resides in the ER and the ER-Golgi interface, in the lipidation of nascent VLDL to generate mature, more TG-rich VLDL. Consistent results from cells and rodents indicated that the secretion of TG was reduced in the p.E167K variant or when hepatic TM6SF2 was deleted. However, data for secretion of APOB was inconsistent, either reduced or increased secretion was observed. A recent study of people homozygous for the variant demonstrated reduced in vivo secretion of large, TG-rich VLDL1 into plasma; both TG and APOB secretion were reduced. Here we present new results demonstrating increased secretion of VLDL APOB with no change in TG secretion in p.E167K homozygous individuals from the Lancaster Amish community compared to their wild-type siblings. Our in vivo kinetic tracer results are supported by in vitro experiments in HepG2 and McA cells with knock-down or Crispr-deletions of TM6SF2, respectively. We offer a model to potentially explain all of the prior data and our new results.
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The disease-promoting variant of TM6SF2 (E167K) suppresses hepatic triglyceride secretion without affecting ApoB secretion, meaning that affected patients still secrete VLDL particles but with low lipid content.
“although the disease-promoting variant of TM6SF2 (E167K) suppresses hepatic triglyceride secretion, it does so without affecting ApoB secretion, meaning that affected patients still secrete VLDL particles but with low lipid content (11–13).”
From Loss of function of T-box 3 in the liver protects against MASLD (2025) · cites this paper as [12]
The Results (Lipoprotein APOB100 and lipid levels; page unavailable) report no difference in VLDL triglyceride production between variant carriers and their siblings, but significantly greater VLDL-APOB100 production in carriers. The Discussion likewise describes increased secretion of smaller, less-lipidated particles. Thus the smaller-particle conclusion is supported, but the claimed combination of suppressed triglyceride secretion and unaffected ApoB secretion is contrary to this paper’s human findings. (LLM, conf=0.90)
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Loss of function of T-box 3 in the liver protects against MASLD
Maher, J. J. (2025) · Journal of Clinical Investigation · doi:10.1172/jci197143
Hong, S., Wang, J., Mitsche, M. A., Cohen, J. C., Li, X., & Hobbs, H. H. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.08.17.745233
- Authors
- Reyes-Soffer, G., Liu, J., Thomas, T., Matveyenko, A., Seid, H., Ramakrishnan, R., Holleran, S., Zaghloul, N., Sztalryd-Woodle, C., Pollin, T., & Ginsberg, H. N.
- Affiliations
- Columbia University (US)
- University of Maryland, Baltimore (US)
- Venue
- medRxiv
- Publisher
- openRxiv
- Published
- 2023-06-29
- PMC
- PMC10327233
- OpenAlex
- W4382516479
- Cited by
- 6
- References
- 39
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 4
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Locations
- medRxiv (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R35HL135833)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- TM6SF2, VLDL secretion, apolipoprotein B secretion, ER-Golgi interface, hepatic fat content, LDL cholesterol, lipid metabolism
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