Endocrine Abstracts

Bile acids (BAs) are potent signaling molecules that regulate glucose, lipid and energy homeostasis predominantly via farnesoid X receptor (FXR) and transmembrane G protein-coupled receptor 5 (TGR5). Modulation of bile acid profiles might affect the treatment of metabolic diseases, indicating new possible therapeutic avenues. The sodium taurocholate co-transporting polypeptide (NTCP) plays a pivotal role in the enterohepatic circulation of bile salts as the main uptake transporter of conjugated BAs from the (portal) blood into the liver. The inhibition on NTCP will lead to a temporary increase in systemic bile acid levels in humans. However, either the direct quantitative relation between NTCP and BAs in systemic circulation or the metabolic effect by inhibiting NTCP has not been studied previously in human. Hepalatide is a NTCP inhibitor with 47aa synthetic peptide. In our current randomized placebo-controlled double-blind phase I clinical trials, 80 healthy subjects were administrated with s.c. single dose or multiple dose (once/day for 7 days). The BA profiles were analyzed. The conjugated BAs (GCDCA, GCA, TCDCA, GDCA, TCA, TDCA, GUDCA, TUDCA, TLCA, and GLCA) and unconjugated BAs (CA, UDCA, CDCA, DCA, and LCA) in peripheral plasma sampled before injection (bi) and at 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h post injection (pi) were measured by HPLC-mass method. Among 17 healthy subjects with placebo, just as physiological state, circulating conjugated BAs peak at day, while unconjugated BAs peak late at night. Hepalatide dramatically amplified conjugated BAs diurnal rhythm in a dose dependent manner but not affected unconjugated BAs. The mean AUC0–24 h of total conjugated BAs in cohort with single hepalatide adminstration at 10.5 mg was 20.64 times of that in placebo-controlled subjects. BAs are synthesized in hepatocytes from cholesterol and feedback represses BAs synthesis. Hepalatide is expected to uncouple BA synthesis from negative feedback leading more cholesterol to break down. At the end of the 7-day treatment, serum total cholesterol (TC) was reduced in a dose-dependent manner, and it was significantly lower in 8.4 mg cohort than in placebo cohort (P = 0.0029). The LDL-c also decreased with an average of 20% in the 6.3 mg and 8.4 mg cohorts vs the placebo cohort, with a maximum decrease of 39% in one healthy subject. In conclusion, NTCP is a surprising molecule to redistribute BAs between liver and peripheral tissues, which make it a promising target to modulate BAs signal with therapeutic effects on metabolic diseases.