The U2-spliceosome and its interactors regulate the levels and activity of the LDL receptor in humans
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2020-12
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Other Journal Item
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yes
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Abstract
Background and Aims: The low-density lipoprotein receptor (LDLR) in the liver is the major determinant of LDL-cholesterol levels in humans. The discovery of novel genes that regulate the activity of LDLR could lead to the identification of pathomechanisms of hypercholesterolemia and novel therapeutic targets against atherosclerotic cardiovascular disease.
Methods: We performed a genome-wide RNAi screen for fluorescent LDL uptake in Huh-7 hepatocarcinoma cells and validated our top hit genes in vitro, ex vivo as well as in population genetics datasets.
Results: In our genome-wide RNAi screen, the knock-down of 54 genes led to a significant inhibition of LDL uptake. Fifteen of these genes encode for proteins involved in splicing, especially components or interactors of the U2-spliceosome. Knocking down 11 out of 15 genes resulted in the selective retention of intron 3 of LDLR. The transcript is translated into an LDLR fragment, which lacks 88% of the full length LDLR and is detectable in cells and their medium upon overexpression, but neither in non-transfected cells nor in human plasma. The intron 3 retention transcript is expressed in considerable amounts in human liver and in blood cells. Its expression correlates with plasma LDL-cholesterol and age and increases after bariatric surgery. Single nucleotide polymorphisms and rare variants of one spliceosome gene, RBM25, are associated with LDL-cholesterol in the population and familial hypercholesterolemia, respectively.
Conclusions: We identified a novel mechanism of post-transcriptional regulation of LDLR activity in humans.
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published
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315
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Elsevier
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02891 - ScopeM / ScopeM
08839 - Zamboni, Nicola (Tit.-Prof.)