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Cited by 19Lipid metabolism and disordersCholesterol and Lipid MetabolismLiver Disease Diagnosis and Treatment

Basic and translational evidence supporting the role of TM6SF2 in VLDL metabolism

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Liu, Jing, Ginsberg, Henry N., Reyes-Soffer, Gissette·2024·Current Opinion in Lipidology
DOI 10.1097/mol.0000000000000930PMC PMC11168781
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Abstract

Purpose of review: Transmembrane 6 superfamily member 2 (TM6SF2) gene was identified through exome-wide studies in 2014. A genetic variant from glutamic acid to lysine substitution at amino acid position 167 (NM_001001524.3:c.499G> A) (p.Gln167Lys/p.E167K, rs58542926) was discovered (p.E167K) to be highly associated with increased hepatic fat content and reduced levels of plasma triglycerides and LDL cholesterol. In this review, we focus on the discovery of TM6SF2 and its role in VLDL secretion pathways. Human data suggest TM6SF2 is linked to hepatic steatosis and cardiovascular disease (CVD), hence understanding its metabolic pathways is of high scientific interest. Recent findings: Since its discovery, completed research studies in cell, rodent and human models have defined the role of TM6SF2 and its links to human disease. TM6SF2 resides in the endoplasmic reticulum (ER) and the ER-Golgi interface and helps with the lipidation of nascent VLDL, the main carrier of triglycerides from the liver to the periphery. Consistent results from cells and rodents indicated that the secretion of triglycerides is reduced in carriers of the p.E167K variant or when hepatic TM6SF2 is deleted. However, data for secretion of APOB, the main protein of VLDL particles responsible for triglycerides transport, are inconsistent. Summary: The identification of genetic variants that are highly associated with human disease presentation should be followed by the validation and investigation into the pathways that regulate disease mechanisms. In this review, we highlight the role of TM6SF2 and its role in processing of liver triglycerides.

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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 [13]

    The section on TM6SF2 regulation reports reduced VLDL triglyceride secretion, and the Conclusion describes TM6SF2’s role in adding triglycerides to nascent, lipid-poor VLDL. But the Conclusion says APOB100 secretion has been reported as unchanged, reduced, or increased; the Human Studies section likewise reports reduced APOB production in one study and increased secretion in another. The claim that affected patients secrete VLDL without any change in ApoB secretion is therefore too categorical. Page numbers were not supplied for these passages. (LLM, conf=0.88)

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References 37 · Cited by 19

Research works printed but not linked: 30

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Authors
Liu, J., Ginsberg, H. N., & Reyes-Soffer, G.
Affiliations
Columbia University (US)
ORCID
Venue
Current Opinion in Lipidology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2024-03-08
Volume
35
Issue
3
Pages
157-161
ISSN
  • 0957-9672 (ISSN-L)
  • 1473-6535
DOI
10.1097/mol.0000000000000930
PMC
PMC11168781
OpenAlex
W4392658541
Cited by
19
References
37
Citations by year
2026: 6 · 2025: 9 · 2024: 4
FWCI
1.50
Type
journal article
Language
en
Open access
Licence
Locations
  • Current Opinion in Lipidology (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
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
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
Keywords
TM6SF2, VLDL secretion, hepatic steatosis, triglyceride secretion, rs58542926, apolipoprotein B, endoplasmic reticulum, ER-Golgi interface, lipid modification, cardiovascular disease, LDL cholesterol, plasma triglycerides, genetic variants
MeSH terms
Animals, Humans, Lipoproteins, VLDL, Membrane Proteins, Translational Research, Biomedical

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