An FXR Agonist Reduces Bile Acid Synthesis Independently of Increases in FGF19 in Healthy Volunteers

Abstract

Bile acid (BA) synthesis is regulated through suppression of hepatic cholesterol 7α-hydroxylase via farnesoid X receptor (FXR) activation in hepatocytes and/or enterocytes; in enterocytes, this process requires FGF19 signaling. To study these pathways, we quantified markers of BA synthesis (7α-hydroxy-4-cholesten-3-one [C4]) and cholesterol production (lathosterol), fibroblast growth factor (FGF)19, and BAs in serum from healthy male volunteers given 1 oral dose of the nonsteroidal FXR agonist Px-102 (0.15 mg/kg, 0.3 mg/kg, 0.6 mg/kg, 1.12 mg/kg, 2.25 mg/kg, 3.38 mg/kg, or 4.5 mg/kg). After 8 hours, serum levels of C4 decreased by 80% in volunteers given 0.15 mg/kg, whereas serum levels of FGF19 were unchanged. Serum levels of FGF19 increased significantly, in a dose-dependent manner, in volunteers given >0.3 mg/kg Px-102, up to as much as 1600%, whereas C4 levels remained significantly reduced (by >80%). For all doses, FGF19 levels returned to normal 24 hours after administration of Px-102. Serum levels of C4 decreased before levels of FGF19 levels increased, and were still reduced by 95% 24 hours after the highest dose (4.5 mg/kg) of Px-102, even though levels of FGF19 had returned to baseline. Our findings indicate that activation of hepatic FXR is able to suppress BA synthesis, independent of FGF19.

The Nonsteroidal Farnesoid X Receptor Agonist Cilofexor (GS‐9674) Improves Markers of Cholestasis and Liver Injury in Patients With Primary Sclerosing Cholangitis

“…(18) Interestingly, a recent study that included healthy volunteers administered a different nonsteroidal FXR agonist (Px-102), suggesting that these compounds may reduce bile acid synthesis independent of FGF19 production. (19) Finally, although changes in liver stiffness by FibroScan and ELF scores were not observed, patients treated with cilofexor 100 mg had a trend toward reduced serum levels of the profibrogenic cytokine TIMP-1, suggesting a potential antifibrotic effect of this treatment. Future trials of longer duration with liver histology will be necessary to confirm this finding.…”

“…Indeed, data from healthy volunteers has confirmed a rapid, dose‐dependent increase in FGF19 levels when measured serially following cilofexor administration . Interestingly, a recent study that included healthy volunteers administered a different nonsteroidal FXR agonist (Px‐102), suggesting that these compounds may reduce bile acid synthesis independent of FGF19 production . Finally, although changes in liver stiffness by FibroScan and ELF scores were not observed, patients treated with cilofexor 100 mg had a trend toward reduced serum levels of the pro‐fibrogenic cytokine TIMP‐1, suggesting a potential antifibrotic effect of this treatment.…”

Lean NAFLD: A Distinct Entity Shaped by Differential Metabolic Adaptation

“…It is of interest that it has been suggested that cholesterol intake is higher in lean compared with obese NAFLD . BAs also regulate glucose and lipid metabolism and energy expenditure, and in turn their production, transport, and metabolism are regulated by specific nuclear BA receptors, the farnesoid X receptor (FXR) and circulating fibroblast growth factor (FGF19), likely by means of dependent and independent mechanisms . The gut microbiome is also intimately involved in the pathogenesis of several metabolic diseases, including body weight regulation, NAFLD, and liver cancer, in part through direct interactions with BAs …”

“…(12)(13)(14) BAs also regulate glucose and lipid metabolism and energy expenditure, (15) and in turn their production, transport, and metabolism are regulated by specific nuclear BA receptors, the farnesoid X receptor (FXR) and circulating fibroblast growth factor (FGF19), likely by means of dependent and independent mechanisms. (15,16) The gut microbiome is also intimately involved in the pathogenesis of several metabolic diseases, including body weight regulation, NAFLD, and liver cancer, in part through direct interactions with BAs. (17)(18)(19) We hypothesized that the pathogenesis of lean and obese NAFLD and their distinct metabolic and histological profiles is caused by more than just differences in body weight and BMI.…”

Role of the Gut–Liver Axis in Liver Inflammation, Fibrosis, and Cancer: A Special Focus on the Gut Microbiota Relationship

“…FXR agonists reduce the expression of CYP7A1 and Na+/taurocholate cotransporting polypeptide (NTCP), one of the key transporters in hepatocytes that uptake BAs from the sinusoids, but up‐regulate the expression of bile salt export pump, the major transporter for the excretion of BAs from hepatocytes into bile canaliculi (Fig. ).…”