학술논문
Posttranscriptional Regulation of the Human LDL Receptor by the U2-Spliceosome
Document Type
Electronic Resource
Author
Zanoni, Paolo; Panteloglou, Grigorios; Othman, Alaa; Haas, Joel T.; Meier, Roger; Rimbert, Antoine; Futema, Marta; Khalil, Yara Abou; Norrelykke, Simon F.; Rzepiela, Andrzej J.; Stoma, Szymon; Stebler, Michael; Van Dijk, Freerk; Wijers, Melinde; Wolters, Justina C.; Dalila, Nawar; Huijkman, Nicolette C.A.; Smit, Marieke; Gallo, Antonio; Carreau, Valérie; Philippi, Anne; Rabès, Jean Pierre; Boileau, Catherine; Visentin, Michele; Vonghia, Luisa; Weyler, Jonas; Francque, Sven; Verrijken, An; Verhaegen, Ann; Van Gaal, Luc; Van Der Graaf, Adriaan; Van Rosmalen, Belle V.; Robert, Jerome; Velagapudi, Srividya; Yalcinkaya, Mustafa; Keel, Michaela; Radosavljevic, Silvija; Geier, Andreas; Tybjaerg-Hansen, Anne; Varret, Mathilde; Rohrer, Lucia; Humphries, Steve E.; Staels, Bart; Van De Sluis, Bart; Kuivenhoven, Jan Albert; Von Eckardstein, Arnold
Source
Zanoni , P , Panteloglou , G , Othman , A , Haas , J T , Meier , R , Rimbert , A , Futema , M , Khalil , Y A , Norrelykke , S F , Rzepiela , A J , Stoma , S , Stebler , M , Van Dijk , F , Wijers , M , Wolters , J C , Dalila , N , Huijkman , N C A , Smit , M , Gallo , A , Carreau , V , Philippi , A , Rabès , J P , Boileau , C , Visentin , M , Vonghia , L , Weyler , J , Francque , S , Verrijken , A , Verhaegen , A , Van Gaal , L , Van Der Graaf , A , Van Rosmalen , B V , Robert , J , Velagapudi , S , Yalcinkaya , M , Keel , M , Radosavljevic , S , Geier , A , Tybjaerg-Hansen , A , Varret , M , Rohrer , L , Humphries , S E , Staels , B , Van De Sluis , B , Kuivenhoven , J A & Von Eckardstein , A 2022 , ' Posttranscriptional Regulation of the Human LDL Receptor by the U2-Spliceosome ' , Circulation Research , vol. 130 , no. 1 , pp. 80-95 .
Subject
Language
Abstract
BACKGROUND: The LDLR (low-density lipoprotein receptor) in the liver is the major determinant of LDL-cholesterol levels in human plasma. The discovery of genes that regulate the activity of LDLR helps to identify pathomechanisms of hypercholesterolemia and novel therapeutic targets against atherosclerotic cardiovascular disease. METHODS: We performed a genome-wide RNA interference screen for genes limiting the uptake of fluorescent LDL into Huh-7 hepatocarcinoma cells. Top hit genes were validated by in vitro experiments as well as analyses of data sets on gene expression and variants in human populations. RESULTS: The knockdown of 54 genes significantly inhibited LDL uptake. Fifteen of them encode for components or interactors of the U2-spliceosome. Knocking down any one of 11 out of 15 genes resulted in the selective retention of intron 3 of LDLR. The translated LDLR fragment lacks 88% of the full length LDLR and is detectable neither in nontransfected cells nor in human plasma. The hepatic expression of the intron 3 retention transcript is increased in nonalcoholic fatty liver disease as well as after bariatric surgery. Its expression in blood cells correlates with LDL-cholesterol and age. Single nucleotide polymorphisms and 3 rare variants of one spliceosome gene, RBM25, are associated with LDL-cholesterol in the population and familial hypercholesterolemia, respectively. Compared with overexpression of wild-type RBM25, overexpression of the 3 rare RBM25 mutants in Huh-7 cells led to lower LDL uptake. CONCLUSIONS: We identified a novel mechanism of posttranscriptional regulation of LDLR activity in humans and associations of genetic variants of RBM25 with LDL-cholesterol levels.