Discovery biomarker to optimize Obeticholic acid treatment for non-alcoholic fatty liver disease

Abstract

Background: Though obeticholic acid (OCA) is a promising drug for non-alcoholic fatty liver disease (NAFLD), the response rate of OCA is limited. This study aimed to develop a biomarker to optimize OCA treatment for NAFLD. Methods: C57BL/6 mice males were fed on a western diet for 24 weeks. Pre-study liver biopsy performed at 12 weeks and stratified according to disease severity. Next, the mice were administered with OCA (5 mg/kg/day) or vehicle for additional eight weeks. Hepatic transcriptome, metabolome and intestinal microbiome analyses compared according to OCA treatment responder and non-responder using pre-study and end of study samples. LX-2 cells transfected with short-interfering RNA against CYP7B1 (siCYP7B1) and/or treated with OCA to evaluate the role of CYP7B1 in NAFLD. Result: Resolution rate of steatohepatitis in the OCA and vehicle groups were 36.8% and 0%, respectively. The hepatic transcriptome and bile acid metabolite profile analyses revealed that the alternative bile acid synthesis pathway (Cyp7b1 and muricholic acid) in the OCA-responder group were upregulated compared with those in the OCA-non-responder group. Intestinal microbiome analysis also revealed that the abundances of Bacteroidaceae, Parabacteroides, and Bacteroides, which were positively correlated with the alternative bile acid synthesis pathway, were higher in the OCA-responder group than in the non-responder group. Pre-study hepatic mRNA levels of Cyp8b1 (classic pathway) were downregulated in the OCA-responder group. The OCA response rate increased up to 80% in cases with a hepatic Cyp7b1/Cyp8b1 ratio ≥ 5.0. CYP7B1 expression was regulated by glucose concentration, and anti-fibrotic effect of OCA showed CYP7B1 dependent manner. Conclusion: The upregulated alternative bile acid synthesis pathway or high hepatic CYP7B1 can be a potential biomarker for predicting OCA response.