title: Fibroblast growth factor-21 (FGF21) regulates low-density lipoprotein receptor (LDLR) levels in cells via the E3-ubiquitin ligase Mylip/Idol and the Canopy2 (Cnpy2)/Mylip-interacting saposin-like protein (Msap).
abstract: The LDLR is a critical factor in the regulation of blood cholesterol levels that are altered in different human diseases. The level of LDLR in the cell is regulated by both transcriptional and post-transcriptional events. The E3 ubiquitin ligase, myosin regulatory light chain-interacting protein (Mylip)/inducible degrader of the LDL-R (Idol) was shown to induce degradation of LDLR via protein ubiquitination. We have here studied novel factors and mechanisms that may regulate Mylip/Idol in human hepatocyte cells and in mouse macrophages. We observed that FGF21 that is present in serum in different conditions reduced Mylip/Idol at the RNA and protein level, and increased LDLR levels and stability in the cells. FGF21 also enhanced expression of Canopy2 (Cnpy2)/MIR-interacting Saposin-like protein (Msap) that is known to interact with Mylip/Idol. Overexpression of Cnpy2/Msap increased LDLRs, and knockdown experiments showed that Cnpy2/Msap is crucial for the FGF21 effect on LDLRs. Experiments using DiI-labeled LDL particles showed that FGF21 increased lipoprotein uptake and the effect of FGF21 was additive to that of statins. Our results are consistent with an important role of FGF21 and Cnpy2/Msap in the regulation of LDLRs in cultured cells, which warrants further studies using human samples.
authors.affiliation: Institute of Biomedicine/Biochemistry and Developmental Biology, University of Helsinki, Haartmaninkatu 8, FIN-00290 Helsinki, Finland.
authors.forename: Hai Thi
authors.initials: HT
authors.lastname: Do
authors.forename: Timofey V
authors.initials: TV
authors.lastname: Tselykh
authors.forename: Johanna
authors.initials: J
authors.lastname: Mäkelä
authors.forename: Tho Huu
authors.initials: TH
authors.lastname: Ho
authors.forename: Vesa M
authors.initials: VM
authors.lastname: Olkkonen
authors.forename: Beat C
authors.initials: BC
authors.lastname: Bornhauser
authors.forename: Laura
authors.initials: L
authors.lastname: Korhonen
authors.forename: Noam
authors.initials: N
authors.lastname: Zelcer
authors.forename: Dan
authors.initials: D
authors.lastname: Lindholm
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002784:Cholesterol / Q000493:pharmacokinetics*; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D050356:Lipid Metabolism / Q000187:drug effects / Q000502:physiology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D011973:Receptors, LDL / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C502333:CNPY2 protein, human; C000603106:Canopy 2 protein, mouse; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011973:Receptors, LDL; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D002784:Cholesterol; C403126:MYLIP protein, human; D044767:Ubiquitin-Protein Ligases