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Tauroursodeoxycholic Acid Attenuates Progression of Steatohepatitis in Mice Fed a Methionine–Choline-Deficient Diet

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Abstract

Background and Aim

Endoplasmic reticulum (ER) stress has been implicated in the development of nonalcoholic steatohepatitis. A methionine–choline-deficient (MCD) diet induces robust ER stress response and steatohepatitis, but the effects of ER stress modulation on the course of steatohepatitis remain uncertain. The present study evaluated whether reducing ER stress using the chemical chaperone tauroursodeoxycholic acid (TUDCA) could limit hepatocyte lipoapoptosis and progression of MCD diet-induced steatohepatitis.

Methods

HuH7 cells stably transfected with sodium taurocholate cotransporting polypeptide (HuH-Ntcp cells) and palmitate (PA) were used. Experimental steatohepatitis was induced in male C57BL/6 mice using an MCD diet, and three different doses of TUDCA (500, or 1,000 mg/kg, once daily; or 500 mg/kg twice daily) were administered by gavage from the start of the MCD diet regimen or after 4 weeks.

Results

TUDCA reduced PA-induced ER stress as manifested by decreased eIF2α phosphorylation, XBP1 splicing and expression of BiP, ATF4, and CHOP in HuH-Ntcp cells. TUDCA also decreased PA-induced JNK phosphorylation, Puma up-regulation and Bax activation, which in turn suppressed caspase-dependent hepatocyte lipoapoptosis. Mice given TUDCA did not show a significant decrease in the intrahepatic triglyceride contents and steatosis. However, TUDCA treatment significantly reduced hepatic damage compared to controls for both early and late treatment groups. TUDCA treatment reduced the expression of ER stress markers and pro-apoptotic proteins, leading to decreased apoptosis and oxidative stress. Finally, TUDCA reduced histological fibrosis along with the down-regulation of pro-fibrotic gene expression in both early and late treatment groups.

Conclusions

These results show that TUDCA attenuates the progression of MCD diet-induced steatohepatitis by reducing ER stress.

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Acknowledgments

This study was supported by grants from the SNUH Research Fund (No. 03-2012-0220), and in part by Daewoong research fund (No. 06-2011-0070).

Conflict of interest

None.

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Authors and Affiliations

  1. Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, Korea

    Eun-Ju Cho, Jung-Hwan Yoon, Jeong-Hoon Lee, Su Jong Yu, Yoon Jun Kim, Chung Yong Kim & Hyo-Suk Lee

  2. Department of Internal Medicine, Healthcare Research Institute, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul, Korea

    Min-Sun Kwak

  3. Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi-do, Korea

    Eun Sun Jang

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  1. Eun-Ju Cho
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Correspondence to Jung-Hwan Yoon.

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Cho, EJ., Yoon, JH., Kwak, MS. et al. Tauroursodeoxycholic Acid Attenuates Progression of Steatohepatitis in Mice Fed a Methionine–Choline-Deficient Diet. Dig Dis Sci 59, 1461–1474 (2014). https://doi.org/10.1007/s10620-014-3217-0

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  • DOI: https://doi.org/10.1007/s10620-014-3217-0

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