title: The impact of severe LDL receptor mutations on SREBP-pathway regulation in homozygous familial hypercholesterolemia (FH).
abstract: Familial hypercholesterolemia (FH), Niemann-Pick disease type C (NPC) and Tangier disease (TD) are genetic inherited disorders with impaired processing of cholesterol, caused by mutations in genes that regulate cellular uptake, intracellular movement and transport of cholesterol. Various studies have shown a crucial regulatory role of the SREBP-pathway for cellular cholesterol homeostasis in these diseases. Since cholesterol is an essential structural component of cells, we assessed the impact of a severe FH causing LDLR mutation (FH p.W556R) on the SREBP pathway in primary FH fibroblasts. Primary FH fibroblasts derived from patients with the LDL receptor mutation p.W556R were used for gene expression experiments. Gene expression studies revealed increased expressions of SREBP regulated genes HMGCR, LDLR, SREBP-2, SREBP-1, SR-BI, INSIG-1, but interestingly not SCAP. In contrast expression of ABCA1, was strongly decreased in homozygous, but not in heterozygous p.W556R fibroblasts. Gene expression experiments with LDL receptor lacking primary FH fibroblasts, revealed that SR-BI and ABCA1 are important regulators for cholesterol acquisition in FH cells, consistent with findings in cells from NPC and TD patients.
authors.affiliation: Department of Internal Medicine, Cardiology, Philipps-University Marburg, Germany. soufi@staff.uni-marburg.de
authors.forename: Muhidien
authors.initials: M
authors.lastname: Soufi
authors.forename: Volker
authors.initials: V
authors.lastname: Ruppert
authors.forename: Bilgen
authors.initials: B
authors.lastname: Kurt
authors.forename: Juergen R
authors.initials: JR
authors.lastname: Schaefer
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D000328:Adult; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D057809:HEK293 Cells; D006720:Homozygote; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008954:Models, Biological; D009154:Mutation / Q000502:physiology; D061251:Primary Cell Culture; D011973:Receptors, LDL / Q000235:genetics*; D051122:Scavenger Receptors, Class B / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D051779:Sterol Regulatory Element Binding Proteins / Q000235:genetics / Q000378:metabolism*; D014430:Twins, Monozygotic
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D011973:Receptors, LDL; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; D051779:Sterol Regulatory Element Binding Proteins