Treatment with the natural FXR agonist chenodeoxycholic acid reduces clearance of plasma LDL whilst decreasing circulating PCSK 9, lipoprotein(a) and apolipoprotein C‐ III

• Published in: Journal of internal medicine Vol. 281; no. 6; pp. 575 - 585
• Main Authors: Ghosh Laskar, M., Eriksson, M., Rudling, M., Angelin, B.
• Format: Journal Article
• Language: English
• Published: 01-06-2017
• ISSN: 0954-6820; 1365-2796
• DOI: 10.1111/joim.12594

Abstract
Background
The natural farnesoid X receptor (
FXR
) agonist chenodeoxycholic acid (
CDCA
) suppresses hepatic cholesterol and bile acid synthesis and reduces biliary cholesterol secretion and triglyceride production. Animal studies have shown that bile acids downregulate hepatic
LDL
receptors (
LDLR
s); however, information on
LDL
metabolism in humans is limited.
Methods
Kinetics of autologous
125
I‐
LDL
were determined in 12 male subjects at baseline and during treatment with
CDCA
(15 mg kg
−1
day
−1
). In seven patients with gallstones treated with
CDCA
for 3 weeks before cholecystectomy, liver biopsies were collected and analysed for enzyme activities and for specific
LDLR
binding. Serum samples obtained before treatment and at surgery were analysed for markers of lipid metabolism, lipoproteins and the
LDLR
modulator proprotein convertase subtilisin/kexin type 9 (
PCSK
9).
Results
Chenodeoxycholic acid treatment increased plasma
LDL
cholesterol by ~10% as a result of reduced clearance of plasma
LDL
‐apolipoprotein (apo)B;
LDL
production was somewhat reduced. The reduction in
LDL
clearance occurred within 1 day after initiation of treatment. In
CDCA
‐treated patients with gallstones, hepatic microsomal cholesterol 7α‐hydroxylase and
HMG
‐CoA reductase activities were reduced by 83% and 54%, respectively, and specific
LDLR
binding was reduced by 20%. During treatment, serum levels of fibroblast growth factor 19 and total and
LDL
cholesterol increased, whereas levels of 7α‐hydroxy‐4‐cholesten‐3‐one, lathosterol,
PCSK
9, apoA‐I, apoC‐
III
, lipoprotein(a), triglycerides and insulin were reduced.
Conclusions
Chenodeoxycholic acid has a broad influence on lipid metabolism, including reducing plasma clearance of
LDL
. The reduction in circulating
PCSK
9 may dampen its effect on hepatic
LDLR
s and plasma
LDL
cholesterol. Further studies of the effects of other
FXR
agonists on cholesterol metabolism in humans seem warranted, considering the renewed interest for such therapy in liver disease and diabetes.