title: SUGP1 is a novel regulator of cholesterol metabolism.
abstract: A large haplotype on chromosome 19p13.11 tagged by rs10401969 in intron 8 of SURP and G patch domain containing 1 (SUGP1) is associated with coronary artery disease (CAD), plasma LDL cholesterol levels, and other energy metabolism phenotypes. Recent studies have suggested that TM6SF2 is the causal gene within the locus, but we postulated that this locus could harbor additional CAD risk genes, including the putative splicing factor SUGP1 Indeed, we found that rs10401969 regulates SUGP1 exon 8 skipping, causing non-sense-mediated mRNA decay. Hepatic Sugp1 overexpression in CD1 male mice increased plasma cholesterol levels 20-50%. In human hepatoma cell lines, SUGP1 knockdown stimulated 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) alternative splicing and decreased HMGCR transcript stability, thus reducing cholesterol synthesis and increasing LDL uptake. Our results strongly support a role for SUGP1 as a novel regulator of cholesterol metabolism and suggest that it contributes to the relationship between rs10401969 and plasma cholesterol.
authors.affiliation: Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA.
authors.forename: Mee J
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA.
authors.forename: Chi-Yi
authors.initials: CY
authors.lastname: Yu
authors.affiliation: Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Theusch
authors.affiliation: Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA.
authors.forename: Devesh
authors.initials: D
authors.lastname: Naidoo
authors.affiliation: Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Stevens
authors.affiliation: Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA.
authors.forename: Yu-Lin
authors.initials: YL
authors.lastname: Kuang
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Schuetz
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Amarjit S
authors.initials: AS
authors.lastname: Chaudhry
authors.affiliation: Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA mwmedina@chori.org.
authors.forename: Marisa W
authors.initials: MW
authors.lastname: Medina
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D002784:Cholesterol / Q000097:blood / Q000235:genetics*; D008078:Cholesterol, LDL / Q000097:blood / Q000235:genetics*; D003324:Coronary Artery Disease / Q000097:blood / Q000235:genetics* / Q000473:pathology; D005091:Exons / Q000235:genetics; D005786:Gene Expression Regulation; D006239:Haplotypes; D056945:Hep G2 Cells; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics*; D008297:Male; D051379:Mice; D020641:Polymorphism, Single Nucleotide; D000072260:RNA Splicing Factors / Q000096:biosynthesis / Q000235:genetics*; D020871:RNA Stability
chemical_list: D008078:Cholesterol, LDL; D000072260:RNA Splicing Factors; C473326:SUGP1 protein, human; D002784:Cholesterol