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Hepatic Tm6sf2 overexpression affects cellular ApoB-trafficking, plasma lipid levels, hepatic steatosis and atherosclerosis.
- Source :
-
Human molecular genetics [Hum Mol Genet] 2017 Jul 15; Vol. 26 (14), pp. 2719-2731. - Publication Year :
- 2017
-
Abstract
- The human transmembrane 6 superfamily member 2 (TM6SF2) gene has been implicated in plasma lipoprotein metabolism, alcoholic and non-alcoholic fatty liver disease and myocardial infarction in multiple genome-wide association studies. To investigate the role of Tm6sf2 in metabolic homeostasis, we generated mice with elevated expression using adeno-associated virus (AAV)-mediated gene delivery. Hepatic overexpression of mouse Tm6sf2 resulted in phenotypes previously observed in Tm6sf2-deficient mice including reduced plasma lipid levels, diminished hepatic triglycerides secretion and increased hepatosteatosis. Furthermore, increased hepatic Tm6sf2 expression protected against the development of atherosclerosis in LDL-receptor/ApoB48-deficient mice. In cultured human hepatocytes, Tm6sf2 overexpression reduced apolipoprotein B secretion and resulted in its accumulation within the endoplasmic reticulum (ER) suggesting impaired ER-to-Golgi trafficking of pre-very low-density lipoprotein (VLDL) particles. Analysis of two metabolic trait-associated coding polymorphisms in the human TM6SF2 gene (rs58542926 and rs187429064) revealed that both variants impact TM6SF2 expression by affecting the rate of protein turnover. These data demonstrate that rs58542926 (E167K) and rs187429064 (L156P) are functional variants and suggest that they influence metabolic traits through altered TM6SF2 protein stability. Taken together, our results indicate that cellular Tm6sf2 level is an important determinant of VLDL metabolism and further implicate TM6SF2 as a causative gene underlying metabolic disease and trait associations at the 19p13.11 locus.<br /> (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Subjects :
- Animals
Apolipoproteins B genetics
Atherosclerosis blood
Atherosclerosis genetics
Cells, Cultured
Endoplasmic Reticulum metabolism
Female
Genome-Wide Association Study
Golgi Apparatus metabolism
Hep G2 Cells
Hepatocytes metabolism
Humans
Lipoproteins blood
Male
Membrane Proteins genetics
Membrane Proteins metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Non-alcoholic Fatty Liver Disease blood
Non-alcoholic Fatty Liver Disease genetics
Polymorphism, Single Nucleotide
Protein Transport
Triglycerides blood
Apolipoproteins B metabolism
Atherosclerosis metabolism
Liver metabolism
Membrane Proteins biosynthesis
Non-alcoholic Fatty Liver Disease metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2083
- Volume :
- 26
- Issue :
- 14
- Database :
- MEDLINE
- Journal :
- Human molecular genetics
- Publication Type :
- Academic Journal
- Accession number :
- 28449094
- Full Text :
- https://doi.org/10.1093/hmg/ddx159