Depletion of TM6SF2 disturbs membrane lipid composition and dynamics in HuH7 hepatoma cells
Open accessAbstract
A polymorphism of TM6SF2 associates with hepatic lipid accumulation and reduction of triacylglycerol (TAG) secretion, but the function of the encoded protein has remained enigmatic. We studied the effect of stable TM6SF2 knock-down on the lipid content and composition, mitochondrial fatty acid oxidation and organelle structure of HuH7 hepatoma cells. Knock-down of TM6SF2 resulted in intracellular accumulation of TAGs, cholesterol esters, phosphatidylcholine (PC) and phosphatidylethanolamine. In all of these lipid classes, polyunsaturated lipid species were significantly reduced while saturated and monounsaturated species increased their proportions. The PCs encountered relative and absolute arachidonic acid (AA, 20:4n-6) depletion, and AA was also reduced in the total cellular fatty acid pool. Synthesis and turnover of the hepatocellular glycerolipids was enhanced. The TM6SF2 knock-down cells secreted lipoprotein-like particles with a smaller diameter than in the controls, and more lysosome/endosome structures appeared in the knock-down cells. The mitochondrial capacity for palmitate oxidation was significantly reduced. These observations provide novel clues to TM6SF2 function and raise altered mebrane lipid composition and dynamics among the mechanism(s) by which the protein deficiency disturbs hepatic TAG secretion.
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High phospholipid unsaturation may modify membrane physical properties and augment release of cholesteryl ester and triacylglycerol-containing vesicles from the endoplasmic reticulum.
“High PL unsaturation may modify membrane physical properties and augment release of CE and TAG-containing vesicles from ER45,46.”
From An iPSC-derived astrocyte model of fragile X syndrome exhibits dysregulated cholesterol homeostasis (2023) · cites this paper as [46]
The Discussion (page unavailable in our copy) links phospholipid fatty-acid composition to lipoprotein secretion and proposes that altered ER membrane structure could reduce the size of secreted lipid particles. It does not specifically say that high phospholipid unsaturation augments release of CE- and TAG-containing vesicles from the ER; the study instead examines TM6SF2 depletion and reduced arachidonate-containing phospholipids. (LLM, conf=0.82)
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An iPSC-derived astrocyte model of fragile X syndrome exhibits dysregulated cholesterol homeostasis
Talvio, K., Wagner, V. A., Minkeviciene, R., Kirkwood, J. S., Kulinich, A. O., Umemori, J., Bhatia, A., Hur, M., Käkelä, R., Ethell, I. M., et al. (2023) · Communications Biology · doi:10.1038/s42003-023-05147-9 · Cited by 8 · see citing works
Self-citation
- Authors
- Ruhanen, H., Nidhina Haridas, P. A., Eskelinen, E.-L., Eriksson, O., Olkkonen, V. M., & Käkelä, R.
- Affiliations
- University of Helsinki (FI)
- Corresponding author
- Käkelä, Reijo
- Venue
- Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
- Publisher
- Elsevier BV
- Published
- 2017-07
- Volume
- 1862
- Issue
- 7
- Pages
- 676-685
- ISSN
- 1388-1981 (ISSN-L)
- OpenAlex
- W2606596305
- Cited by
- 37
- References
- 7
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 3 · 2023: 3 · 2022: 2 · 2021: 11 · 2020: 6 · 2019: 2 · 2018: 4 · 2017: 1
- FWCI
- 1.80
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- Locations
- Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids (publishedVersion)
- PubMed (publishedVersion)
- Työväentutkimus Vuosikirja (submittedVersion, other-oa)
- Funders
- Foundation for Cardiovascular Research
- Helsingin Yliopisto
- Magnus Ehrnroothin Säätiö
- Sydäntutkimussäätiö
- Instrumentariumin Tiedesäätiö
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- TM6SF2, hepatic lipid accumulation, triacylglycerol secretion, membrane lipid composition, lipid dynamics, polyunsaturated fatty acids, phosphatidylcholine, phosphatidylethanolamine, cholesterol esters, mitochondrial fatty acid oxidation, palmitate oxidation, Huh7 cells
- MeSH terms
- Cholesterol Esters, Fatty Acids, Carcinoma, Hepatocellular, Humans, Lipoproteins, Liver Neoplasms, Lysosomes, Membrane Lipids, Membrane Proteins, Oxidation-Reduction, Phosphatidylcholines, Phosphatidylethanolamines, Endosomes, Triglycerides, Arachidonic Acid, Hepatocytes, Cell Line, Tumor, Lipid Metabolism, Gene Knockdown Techniques
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