title: The impact of LDLR function on fibroblast growth factor 21 levels.
abstract: BACKGROUND
  Fibroblast growth factor 21 (FGF21) has been described to have beneficial effects on glucose and lipid metabolism, and FGF21 analogs are currently evaluated in phase 1 trials. However, the complete spectrum of effects and regulators of FGF21 is yet partly elucidated. Recent studies have shown that FGF21 plays a role in transmembrane cholesterol transport.
  
  
  OBJECTIVE
  We set out to examine the association between FGF21 and LDLR mediated transmembrane cholesterol transport, by comparing FGF21 levels in patients with genetically impaired LDLR function and unaffected relatives. Secondly, we explored whether the severity of the LDLR mutation was associated with FGF21 levels.
  
  
  METHODS
  We performed a cross-sectional study in carriers of an LDLR mutation and their unaffected relatives. Subjects were eligible if they participated in the Dutch national screening program for familial hypercholesterolemia (FH), were 18-55 years old, and were carrier of a pathogenic LDLR mutation with an untreated LDL-C level below the 75(th) or above the 90(th) percentile of the general population, or did not carry an FH mutation. The outcome measure was the level of FGF21, which was assessed using ELISA.
  
  
  RESULTS
  We included 224 carriers of an LDLR mutation and 148 unaffected relatives. FGF21 levels were lower in LDLR mutation carriers compared to unaffected relatives (median [interquartile range]: 96.92 [60.80-174.05] versus 136.98 [77.34-219.47] pg/mL, respectively; p = 0.08), but after adjusting for potential confounders, there was no association between LDLR mutations and FGF21 levels (p = 0.70). Neither, did we find a relationship between the severity of LDLR mutations and FGF21 levels (p = 0.51, after adjustment for potential confounders).
  
  
  CONCLUSIONS
  We showed that levels of FGF21 are not different in patients with and without LDLR mutations, which suggests that decreased LDLR expression does not have a negative effect on FGF21 levels. Given the potential beneficial effects of FGF21 analogs on lipids and lipoproteins in a phase 1 study, we deem this of great interest for future treatment options for FH patients.
authors.affiliation: Departments of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands. Electronic address: j.besseling@amc.nl.
authors.forename: Joost
authors.initials: J
authors.lastname: Besseling
authors.affiliation: Centre for Vascular Research, University of New South Wales, Sydney, Australia.
authors.forename: Kwok Leung
authors.initials: KL
authors.lastname: Ong
authors.affiliation: Departments of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Roeland
authors.initials: R
authors.lastname: Huijgen
authors.affiliation: Centre for Vascular Research, University of New South Wales, Sydney, Australia.
authors.forename: Kerry-Anne
authors.initials: KA
authors.lastname: Rye
authors.affiliation: Departments of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: G Kees
authors.initials: GK
authors.lastname: Hovingh
authors.affiliation: Clinical Epidemiology Bioinformatics and Biostatistics, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Hutten
authors.affiliation: Centre for Vascular Research, University of New South Wales, Sydney, Australia; Labaratoire UMR PhAN 1280, Université de Nantes, Faculté de Médecine, Nantes, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Lambert
mesh_terms: D000293:Adolescent; D000328:Adult; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D008078:Cholesterol, LDL / Q000097:blood; D003430:Cross-Sectional Studies; D004252:DNA Mutational Analysis; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005346:Fibroblast Growth Factors / Q000097:blood*; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D008072:Hyperlipoproteinemia Type I / Q000097:blood* / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009426:Netherlands; D010641:Phenotype; D011973:Receptors, LDL / Q000235:genetics*; D012307:Risk Factors; D055815:Young Adult
chemical_list: D015415:Biomarkers; D008078:Cholesterol, LDL; D005819:Genetic Markers; C573412:LDLR protein, human; D011973:Receptors, LDL; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors
keywords: Familial hypercholesterolemia; Fibroblast growth factor 21; Low-density lipoprotein receptor