Pegbelfermin selectively reduces secondary bile acid concentrations in patients with non-alcoholic steatohepatitis

Autor: Petia Shipkova, Giridhar S. Tirucherai, Arun J. Sanyal, Diane E. Shevell, Benjamin E. Decato, Colleen A. McNaney, Yi Luo, Edgar D. Charles, Abraham Apfel
Rok vydání: 2021
Předmět:
GCDCA
glyco-chenodeoxycholic acid
C4
7α-hydroxy-4-cholesten-3-one
Deoxycholic acid
FGF21
fibroblast growth factor 21
AST
aspartate aminotransferase
PGBF
pegbelfermin
Gastroenterology
chemistry.chemical_compound
FGF21
QD
once daily
Chenodeoxycholic acid
Nonalcoholic fatty liver disease
Immunology and Allergy
LCA
lithocholic acid
CA
cholic acid
Bile acid
LC
liquid chromatography
Fatty liver
baiH
7β-hydroxy-3-oxo-delta4-cholenoic acid oxidoreductase
BA
bile acid
Research Article
TCDCA
tauro-chenodeoxycholic acid
medicine.medical_specialty
NAFLD
non-alcoholic fatty liver disease
medicine.drug_class
NASH
non-alcoholic steatohepatitis
TDCA
tauro-deoxycholic acid
hdhA
7-alpha-hydroxysteroid dehydrogenase
GUDCA
glyco-ursodeoxycholic acid
Bile salt hydrolase
CYP7A1
cytochrome P450 7A1
PEGylated
polyethylene glycol-conjugated
UDCA
ursodeoxycholic acid
CDCA
chenodeoxycholic acid
FXR
farnesoid X receptor
TCA
tauro-cholic acid
Internal medicine
7α-Hydroxy-4-cholesten-3-one
ALT
alanine aminotransferase
Internal Medicine
medicine
GCA
glyco-cholic acid
C4
Hepatology
business.industry
T2DM
type 2 diabetes mellitus
medicine.disease
GDCA
glyco-deoxycholic acid
QW
once weekly
chemistry
DCA
deoxycholic acid
MS
mass spectrometry
BSH
bile salt hydrolase
baiCD
7α-hydroxy-3-oxo-delta4-cholenoic acid oxidoreductase
PRO-C3
N-terminal type III collagen propeptide
HbA1c
glycated haemoglobin
Microbiome
HFF
hepatic fat fraction
Steatosis
Steatohepatitis
business
ApoA1
apolipoprotein A1
Biomarkers
Zdroj: JHEP Reports
ISSN: 2589-5559
Popis: Background & Aims Increased serum bile acids (BAs) have been observed in patients with non-alcoholic steatohepatitis (NASH). Pegbelfermin (PGBF), a polyethylene glycol-modified (PEGylated) analogue of human fibroblast growth factor 21 (FGF21), significantly decreased hepatic steatosis and improved fibrosis biomarkers and metabolic parameters in patients with NASH in a phase IIa trial. This exploratory analysis evaluated the effect of PGBF on serum BAs and explored potential underlying mechanisms. Methods Serum BAs and 7α-hydroxy-4-cholesten-3-one (C4) were measured by HPLC-mass spectrometry (MS) using serum collected in studies of patients with NASH (NCT02413372) and in overweight/obese adults (NCT03198182) who received PGBF. Stool samples were collected in NCT03198182 to evaluate faecal BAs by liquid chromatography (LC)-MS and the faecal microbiome by metagenetic and metatranscriptomic analyses. Results Significant reductions from baseline in serum concentrations of the secondary BA, deoxycholic acid (DCA), and conjugates, were observed with PGBF, but not placebo, in patients with NASH; primary BA concentrations did not significantly change in any arm. Similar effects of PGBF on BAs were observed in overweight/obese adults, allowing for an evaluation of the effects of PGBF on the faecal microbiome and BAs. Faecal transcriptomic analysis showed that the relative abundance of the gene encoding choloylglycine hydrolase, a critical enzyme for secondary BA synthesis, was reduced after PGBF, but not placebo, administration. Furthermore, a trend of reduction in faecal secondary BAs was observed. Conclusions PGBF selectively reduced serum concentrations of DCA and conjugates in patients with NASH and in healthy overweight/obese adults. Reduced choloylglycine hydrolase gene expression and decreased faecal secondary BA levels suggest a potential role for PGBF in modulating secondary BA synthesis by gut microbiome. The clinical significance of DCA reduction post-PGBF treatment warrants further investigation. Lay summary Pegbelfermin (PGBF) is a hormone that is currently being studied in clinical trials for the treatment of non-alcoholic fatty liver disease. In this study, we show that PGBF treatment can reduce bile acids that have previously been shown to have toxic effects on the liver. Additional studies to understand how PGBF regulates bile acids may provide additional information about its potential use as a treatment for fatty liver.
Graphical abstract
Highlights • Bile acids are elevated in patients with non-alcoholic steatohepatitis. • Pegbelfermin, a PEGylated human FGF21 analogue, is in phase II trials for non-alcoholic steatohepatitis. • Pegbelfermin treatment was associated with secondary, but not primary, bile acid reductions. • Pegbelfermin reduced expression of a gene responsible for secondary bile acid synthesis. • Further study is needed to assess the clinical significance of these observations.
Databáze: OpenAIRE
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