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Ursodeoxycholic Acid Suppresses Lipogenesis in Mouse Liver: Possible Role of the Decrease in β-Muricholic Acid, a Farnesoid X Receptor Antagonist

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Lipids

Abstract

The farnesoid X receptor (FXR) is a major nuclear receptor of bile acids; its activation suppresses sterol regulatory element-binding protein 1c (SREBP1c)-mediated lipogenesis and decreases the lipid contents in the liver. There are many reports showing that the administration of ursodeoxycholic acid (UDCA) suppresses lipogenesis and reduces the lipid contents in the liver of experimental animals. Since UDCA is not recognized as an FXR agonist, these effects of UDCA cannot be readily explained by its direct activation of FXR. We observed that the dietary administration of UDCA in mice decreased the expression levels of SREBP1c and its target lipogenic genes. Alpha- and β-muricholic acids (MCA) and cholic acid (CA) were the major bile acids in the mouse liver but their contents decreased upon UDCA administration. The hepatic contents of chenodeoxycholic acid and deoxycholic acid (DCA) were relatively low but were not changed by UDCA. UDCA did not show FXR agonistic or antagonistic potency in in vitro FXR transactivation assay. Taking these together, we deduced that the above-mentioned change in hepatic bile acid composition induced upon UDCA administration might cause the relative increase in the FXR activity in the liver, mainly by the reduction in the content of β-MCA, a farnesoid X receptor antagonist, which suggests a mechanism by which UDCA suppresses lipogenesis and decreases the lipid contents in the mouse liver.

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Abbreviations

ACC:

Acetyl-CoA carboxylase

CA:

Cholic acid

CDCA:

Chenodeoxycholic acid

CE:

Cholesteryl ester

DCA:

Deoxycholic acid

DGAT:

Diacylglycerol acyltransferase

DMEM:

Dulbecco’s minimum essential medium

CYP:

Cytochrome P450

FXR:

Farnesoid X receptor

HDCA:

Hyodeoxycholic acid

FAS:

Fatty acid synthase

LCーMS:

Liquid chromatographyーmass spectrometry

LXR:

Liver X receptor

MCA:

Muricholic acid

MUFA:

Monounsaturated fatty acid

PL:

Phospholipid

RXR:

Retinoid X receptor

SHP:

Small heterodimer partner

SCD:

Stearoyl-CoA desaturase

SMILE:

Small heterodimer partner-interacting leucine zipper protein

SREBP1c:

Sterol regulatory element-binding protein 1c

TG:

Triglyceride

UDCA:

Ursodeoxycholic acid

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Acknowledgements

This work was supported in part by a Grant-in-Aid for the 2015 Co-operative Research Project (Ippan Kenkyu) from the Cooperative Research Project from the Joint Usage/Research Center (Joint Usage/Research Center for Science-Based Natural Medicine), Institute of Natural Medicine, University of Toyama in 2015 (to Y. I. and K. F.) and by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to S.W.) (Research Project Numbers: 23590873 and 26460903).

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Authors and Affiliations

  1. Division of Nutritional Biochemistry, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan

    Kyosuke Fujita & Shiro Watanabe

  2. Faculty of Pharmaceutical Science, Hiroshima International University, Kure, Hiroshima, 737–0112, Japan

    Yusuke Iguchi & Mizuho Une

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  1. Kyosuke Fujita
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  2. Yusuke Iguchi
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Correspondence to Shiro Watanabe.

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Fujita, K., Iguchi, Y., Une, M. et al. Ursodeoxycholic Acid Suppresses Lipogenesis in Mouse Liver: Possible Role of the Decrease in β-Muricholic Acid, a Farnesoid X Receptor Antagonist. Lipids 52, 335–344 (2017). https://doi.org/10.1007/s11745-017-4242-5

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