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Cited by 81Lipid metabolism and disordersLiver Disease Diagnosis and TreatmentCholesterol and Lipid Metabolism

Effects of TM6SF2 E167K on hepatic lipid and very low-density lipoprotein metabolism in humans

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Borén, Jan, Adiels, Martin, Björnson, Elias, Matikainen, Niina, Söderlund, Sanni, Rämö, Joel, Ståhlman, Marcus, Ripatti, Pietari +7 more·2020·JCI Insight
DOI 10.1172/jci.insight.144079PMC PMC7819740
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Abstract

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation. The transmembrane 6 superfamily member 2 ( TM6SF2 ) E167K genetic variant associates with NAFLD and with reduced plasma triglyceride levels in humans. However, the molecular mechanisms underlying these associations remain unclear. We hypothesized that TM6SF2 E167K affects hepatic very low-density lipoprotein (VLDL) secretion and studied the kinetics of apolipoprotein B100 (apoB100) and triglyceride metabolism in VLDL in homozygous subjects. In 10 homozygote TM6SF2 E167K carriers and 10 matched controls, we employed stable-isotope tracer and compartmental modeling techniques to determine apoB100 and triglyceride kinetics in the 2 major VLDL subfractions: large triglyceride-rich VLDL 1 and smaller, less triglyceride-rich VLDL 2 . VLDL 1 -apoB100 production was markedly reduced in homozygote TM6SF2 E167K carriers compared with controls. Likewise, VLDL 1 -triglyceride production was 35% lower in the TM6SF2 E167K carriers. In contrast, the direct production rates for VLDL 2 -apoB100 and triglyceride were not different between carriers and controls. In conclusion, the TM6SF2 E167K genetic variant was linked to a specific reduction in hepatic secretion of large triglyceride-rich VLDL 1 . The impaired secretion of VLDL 1 explains the reduced plasma triglyceride concentration and provides a basis for understanding the lower risk of cardiovascular disease associated with the TM6SF2 E167K genetic variant.

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  • The two variants with the highest significance in nearly all GWAS - PNPLA3 and TM6SF2 - both affect hepatic lipid disposal.

    “the two variants with the highest significance in nearly all GWAS — PNPLA3 (patatin-like phospholipase domain-containing protein 3) and TM6SF2 — both affect hepatic lipid disposal (16, 17).”

    From Loss of function of T-box 3 in the liver protects against MASLD (2025) · cites this paper as [17]

    The Discussion (page unavailable) reports that TM6SF2 E167K increases liver fat while reducing VLDL1 secretion, supporting an effect on hepatic lipid disposal. The paper does not establish that PNPLA3 also affects disposal or that these are the two most significant variants in nearly all GWAS; the Introduction calls TM6SF2 one of the most important genetic determinants of hepatic fat content. (LLM, conf=0.85)

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Authors
Borén, J., Adiels, M., Björnson, E., Matikainen, N., Söderlund, S., Rämö, J., Ståhlman, M., Ripatti, P., Ripatti, S., Palotie, A., Mancina, R. M., Hakkarainen, A., Romeo, S., Packard, C. J., & Taskinen, M.-R.
Affiliations
  • Sahlgrenska University Hospital (SE)
  • University of Gothenburg (SE)
  • University of Helsinki (FI)
  • Broad Institute (US)
  • University of Glasgow (GB)
Corresponding author
Borén, Jan
ORCID
Venue
JCI Insight
Publisher
American Society for Clinical Investigation
Published
2020-12-17
Volume
5
Issue
24
ISSN
2379-3708 (ISSN-L)
DOI
10.1172/jci.insight.144079
PMC
PMC7819740
OpenAlex
W3100423115
Cited by
81
References
52
Citations by year
2026: 21 · 2025: 8 · 2024: 18 · 2023: 12 · 2022: 11 · 2021: 11
FWCI
5.26
Type
journal article
Language
en
Open access
Licence
Locations
  • JCI Insight (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Työväentutkimus Vuosikirja (submittedVersion, other-oa)
Funders
  • Swedish Heart-Lung Foundation (jb)
  • Swedish Research Council (jb)
  • ALF grant from the Sahlgrenska University Hospital (jb)
  • Novo Nordisk Foundation (jb)
  • Sigrid Juselius Foundation (mrt)
  • Helsinki University Hospital Government Research funds (mrt)
  • Finnish Heart Foundation (mrt)
  • Finnish Diabetes Research Foundation (mrt)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Keywords
non-alcoholic fatty liver disease, very low density lipoprotein secretion, apolipoprotein B-100, triglyceride metabolism, hepatic lipid metabolism, VLDL1, plasma triglycerides, cardiovascular risk, genetic variants
MeSH terms
Female, Humans, Lipase, Lipids, Lipoproteins, LDL, Lipoproteins, VLDL, Liver, Male, Membrane Proteins, Middle Aged, Triglycerides, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Lipid Metabolism, Apolipoprotein B-100, Non-alcoholic Fatty Liver Disease

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