Potent suppression of hydrophobic bile acids by aldafermin, an FGF19 analogue, across metabolic and cholestatic liver diseases
| Autor: | Hsiao D. Lieu, Gideon M. Hirschfield, Arun J. Sanyal, Stephen A. Harrison, Lei Ling, Ulrich Beuers, Alex M. DePaoli |
|---|---|
| Přispěvatelé: | Gastroenterology and Hepatology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism |
| Rok vydání: | 2021 |
| Předmět: |
Fibroblast growth factor
RC799-869 AST aspartate aminotransferase chemistry.chemical_compound Chenodeoxycholic acid GCA glycocholic acid Immunology and Allergy Bile acid synthesis LCA lithocholic acid NASH CRN NASH Clinical Research Network Non-alcoholic steatohepatitis TCDCA taurochenodeoxycholic acid CA cholic acid GCDCA glycochenodeoxycholic acid Bile acid Primary sclerosing cholangitis Deoxycholic acid Gastroenterology ELF test Enhanced Liver Fibrosis test Diseases of the digestive system. Gastroenterology Ursodeoxycholic acid FGF19 fibroblast growth factor 19 Glycodeoxycholic acid G/T ratio ratio of glycine to taurine conjugates of bile acids NAS non-alcoholic fatty liver disease activity score BAAT bile acid-CoA:amino acid N-acyltransferase TDCA taurodeoxycholic acid medicine.drug Research Article medicine.medical_specialty NAFLD non-alcoholic fatty liver disease medicine.drug_class NASH non-alcoholic steatohepatitis TCA taurocholic acid Glycocholic acid digestive system Pro-C3 UDCA ursodeoxycholic acid CDCA chenodeoxycholic acid FXR farnesoid X receptor Internal medicine ALT alanine aminotransferase Internal Medicine medicine MRI-PDFF magnetic resonance imaging-proton density fat fraction GDCA glycodeoxycholic acid GLCA glycolithocholic acid Hepatology ALP alkaline phosphatase Cholic acid FGF19 Fibrogenesis Endocrinology PSC primary sclerosing cholangitis chemistry DCA deoxycholic acid Pro-C3 neoepitope-specific N-terminal pro-peptide of type III collagen TLCA taurolithocholic acid |
| Zdroj: | JHEP Reports JHEP Reports, Vol 3, Iss 3, Pp 100255-(2021) JHEP Reports, 3(3):100255. Elsevier |
| ISSN: | 2589-5559 |
| Popis: | Summary Background & Aims Higher serum bile acid levels are associated with an increased risk of cirrhosis and liver-related morbidity and mortality. Herein, we report secondary analyses of aldafermin, an engineered analogue of the gut hormone fibroblast growth factor 19, on the circulating bile acid profile in prospective, phase II studies in patients with metabolic or cholestatic liver disease. Methods One hundred and seventy-six patients with biopsy-confirmed non-alcoholic steatohepatitis (NASH) and fibrosis and elevated liver fat content (≥8% by magnetic resonance imaging-proton density fat fraction) received 0.3 mg (n = 23), 1 mg (n = 49), 3 mg (n = 49), 6 mg (n = 28) aldafermin or placebo (n = 27) for 12 weeks. Sixty-two patients with primary sclerosing cholangitis (PSC) and elevated alkaline phosphatase (>1.5× upper limit of normal) received 1 mg (n = 21), 3 mg (n = 21) aldafermin or placebo (n = 20) for 12 weeks. Serum samples were collected on day 1 and week 12 for determination of bile acid profile and neoepitope-specific N-terminal pro-peptide of type III collagen (Pro-C3), a direct measure of fibrogenesis. Results Treatment with aldafermin resulted in significant dose-dependent reductions in serum bile acids. In particular, bile acids with higher hydrophobicity indices, such as deoxycholic acid, lithocholic acid, glycodeoxycholic acid, glycochenodeoxycholic acid, and glycocholic acid, were markedly lowered by aldafermin in both NASH and PSC populations. Moreover, aldafermin predominantly suppressed the glycine-conjugated bile acids, rather than the taurine-conjugated bile acids. Changes in levels of bile acids correlated with changes in the novel fibrogenesis marker Pro-C3, which detects a neo-epitope of the type III collagen during its formation, in the pooled NASH and PSC populations. Conclusions Aldafermin markedly reduced major hydrophobic bile acids that have greater detergent activity and cytotoxicity. Our data provide evidence that bile acids may contribute to sustaining a pro-fibrogenic microenvironment in the liver across metabolic and cholestatic liver diseases. Lay summary Aldafermin is an analogue of a gut hormone, which is in development as a treatment for patients with chronic liver disease. Herein, we show that aldafermin can potently and robustly suppress the toxic, hydrophobic bile acids irrespective of disease aetiology. The therapeutic strategy utilising aldafermin may be broadly applicable to other chronic gastrointestinal and liver disorders. Clinical Trials Registration The study is registered at Clinicaltrials.govNCT02443116 and NCT02704364. Graphical abstract Highlights • Higher serum bile acid levels are associated with an increased risk of liver-related morbidity and mortality. • Aldafermin produces significant dose-dependent reductions in toxic hydrophobic bile acids in NASH and PSC. • Changes in bile acids correlate with changes in the novel fibrogenesis marker Pro-C3. • Bile acids may contribute to a pro-fibrogenic microenvironment in the liver. |
| Databáze: | OpenAIRE |
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