title: Amyloid precursor protein α- and β-cleaved ectodomains exert opposing control of cholesterol homeostasis via SREBP2.
abstract: Amyloid precursor protein (APP) is ubiquitously expressed. Studies in neuronal cells have implicated APP or its fragments as negative regulators of cholesterol metabolism. In the current study, APP acted, via its α-cleavage, as a positive regulator of sterol regulatory element-binding protein-2 (SREBP2) signaling in human astrocytic cells (U251MG), hepatic cells (HepG2), and primary fibroblasts, leading to an approximate 30% increase in SRE-dependent gene expression and, consequently, enhanced cholesterol biosynthesis and LDL receptor levels. This effect was mediated via the secretory ectodomain APPsα. The β-cleaved ectodomain, in turn, repressed SRE-dependent gene expression by up to ∼ 30%. This resulted in decreased cholesterol synthesis and LDL receptor content, establishing a physiological feedback loop in cholesterol-loaded cells, where APP undergoes preferential β-cleavage. Patients with familial Alzheimer's disease had decreased circulating lathosterol, reflecting hepatic cholesterol synthesis, and their fibroblasts had reduced LDL receptor content, which was alleviated by decreasing β-cleavage. These results show that APP regulates cholesterol metabolism in cells relevant for whole-body cholesterol balance and reveal that APP α- and β-cleavages produce opposing paracrine regulators of SREBP2 signaling.
authors.affiliation: 2Institute of Biomedicine, Haartmaninkatu 8, FI-00014 University of Helsinki, Finland. elina.ikonen@helsinki.fi.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Aino-Liisa
authors.initials: AL
authors.lastname: Mutka
authors.forename: Ursula Prosenc
authors.initials: UP
authors.lastname: Zmrzljak
authors.forename: Damjana
authors.initials: D
authors.lastname: Rozman
authors.forename: Heikki
authors.initials: H
authors.lastname: Tanila
authors.forename: Helena
authors.initials: H
authors.lastname: Gylling
authors.forename: Anne M
authors.initials: AM
authors.lastname: Remes
authors.forename: Henri J
authors.initials: HJ
authors.lastname: Huttunen
authors.forename: Elina
authors.initials: E
authors.lastname: Ikonen
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D056945:Hep G2 Cells; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics / Q000502:physiology; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; D034741:RNA, Small Interfering; D011973:Receptors, LDL; C497390:SREBF2 protein, human; D051782:Sterol Regulatory Element Binding Protein 2; D002784:Cholesterol
keywords: APP processing; LDL uptake