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Publication
Hepatic Tm6sf2 overexpression affects cellular ApoB-trafficking, plasma lipid
levels, hepatic steatosis and atherosclerosis.
Authors Ehrhardt N, Doche ME, Chen S, Mao HZ, Walsh MT, Bedoya C, Guindi M, Xiong W,
Ignatius Irudayam J, Iqbal J, Fuchs S, French SW, Mahmood Hussain M, Arditi M,
Arumugaswami V, Péterfy M
Submitted By Submitted Externally on 4/12/2018
Status Published
Journal Human molecular genetics
Year 2017
Date Published 7/1/2017
Volume : Pages 26 : 2719 - 2731
PubMed Reference 28449094
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.




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