The impact of LDLR function on fibroblast growth factor 21 levels

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. 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. 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. 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). 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