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FASEB J. 2018 Jul;32(7):3792-3802. doi: 10.1096/fj.201701084RR. Epub 2018 Feb 26.

Therapeutic modulation of the bile acid pool by Cyp8b1 knockdown protects against nonalcoholic fatty liver disease in mice.

Author information

1
Translational Laboratory in Genetic Medicine, Agency for Science, Technology, and Research (A*STAR), Singapore.
2
Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
3
Singapore Immunology Network, Agency for Science, Technology, and Research (A*STAR), Singapore.
4
Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
5
Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom.
6
Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; and.
7
Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Abstract

Bile acids (BAs) are surfactant molecules that regulate the intestinal absorption of lipids. Thus, the modulation of BAs represents a potential therapy for nonalcoholic fatty liver disease (NAFLD), which is characterized by hepatic accumulation of fat and is a major cause of liver disease worldwide. Cyp8b1 is a critical modulator of the hydrophobicity index of the BA pool. As a therapeutic proof of concept, we aimed to determine the impact of Cyp8b1 inhibition in vivo on BA pool composition and as protection against NAFLD. Inhibition of Cyp8b1 expression in mice led to a remodeling of the BA pool, which altered its signaling properties and decreased intestinal fat absorption. In a model of cholesterol-induced NAFLD, Cyp8b1 knockdown significantly decreased steatosis and hepatic lipid content, which has been associated with an increase in fecal lipid and BA excretion. Moreover, inhibition of Cyp8b1 not only decreased hepatic lipid accumulation, but also resulted in the clearance of previously accumulated hepatic cholesterol, which led to a regression in hepatic steatosis. Taken together, our data demonstrate that Cyp8b1 inhibition is a viable therapeutic target of crucial interest for metabolic diseases, such as NAFLD.-Chevre, R., Trigueros-Motos, L., Castaño, D., Chua, T., Corlianò, M., Patankar, J. V., Sng, L., Sim, L., Juin, T. L., Carissimo, G., Ng, L. F. P., Yi, C. N. J., Eliathamby, C. C., Groen, A. K., Hayden, M. R., Singaraja, R. R. Therapeutic modulation of the bile acid pool by Cyp8b1 knockdown protects against nonalcoholic fatty liver disease in mice.

KEYWORDS:

NAFLD therapeutics; intestinal cholesterol absorption; liver targeting; siRNA delivery; steatosis

PMID:
29481310
DOI:
10.1096/fj.201701084RR
[Indexed for MEDLINE]

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