MON-163 Lowering of Circulating FGF21 by Modulation of Bile Acid Metabolism in Healthy Males

Abstract

FGF21 is a circulating protein of hepatic origin proposed to be involved in the regulation of lipid and glucose metabolism. Increased levels have been reported in conditions of metabolic overload. Recent animal studies have also suggested that FGF21 levels may be influenced by modulation of bile acid metabolism, but knowledge about the human situation is sparse. In this study we aimed to evaluate the response of circulating FGF21 to perturbations of bile acid metabolism in healthy humans. We studied samples obtained from two clinical studies characterizing bile acid metabolism: (i) Eight healthy males underwent repeated blood sampling during 32 hr in three experiments: under basal conditions, following initiation of treatment with cholestyramine (CME), and following initiation of CME when under treatment with atorvastatin (CME+STAT). (ii) 54 healthy males were randomized into 8 groups that were treated orally with a single dose of placebo or the nonsteroidal FXR agonist, Px-102 (0.15mg/kg, 0.3mg/kg, 0.6mg/kg, 1.12mg/kg, 2.25mg/kg, 3.38mg/kg, or 4.5mg/kg) and monitored for 24 hr. Serum levels of FGF21 were related to previously reported levels of markers of cholesterol and bile acid metabolism. (iii) In a third previously conducted study based on a survival training program for healthy volunteers, FGF21 serum levels were investigated during 50 hrs of sleep and 66 hrs of food deprivations. In the untreated normal subjects, serum FGF21 levels displayed a distinct diurnal rhythm, characterized by an early morning peak. Following CME and CME+STAT treatment, circulating FGF21 was lowered and the early morning peak was abolished. Intake of Px-102 strongly and rapidly reduced FGF21 levels which remained lowered for the 24 hr-period. There was no obvious correlation of FGF21 levels to the diurnal variation patterns of the enterohepatic circulation of BAs, nor to those of cholesterol and bile acid syntheses or serum FGF19. Our data also failed to show any clear effects of sleep deprivation or 66 hrs of starvation on circulating FGF21. Both during marked stimulation and pronounced reduction of bile acid synthesis, serum FGF21 levels were reduced. The results do not support the proposal that FXR activation is an important regulator of hepatic FGF21 secretion in humans, which has been suggested from animal experiments. Instead, we would propose that our findings reflect the response to depletion of intracellular bile acid levels, both when caused by interruption of their normal enterohepatic circulation and by suppression of their de novo synthesis from cholesterol.