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Importance of detoxifying enzymes in differentiating fibrotic development between SHRSP5/Dmcr and SHRSP rats

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Environmental Health and Preventive Medicine Aims and scope

Abstract

Objectives

High-fat and -cholesterol diet (HFC) induced fibrotic steatohepatitis in stroke-prone spontaneously hypertensive rat (SHRSP) 5/Dmcr, the fifth substrain from SHRSP, by dysregulating bile acid (BA) kinetics. This study aimed to clarify the histopathological and BA kinetic differences in HFC-induced fibrosis between SHRSP5/Dmcr and SHRSP.

Methods

Ten-week-old male SHRSP5/Dmcr and SHRSP were randomly allocated to groups and fed with either control diet or HFC for 2 and 8 weeks. The liver histopathology, biochemical features, and molecular signaling involved in BA kinetics were measured.

Results

HFC caused more severe hepatocyte ballooning, macrovesicular steatosis and fibrosis in SHRSP5/Dmcr than in SHRSP. It was noted that fibrosis was disproportionately formed in retroperitoneal side of both strains. As for BA kinetics, HFC greatly increased the level of Cyp7a1 and Cyp7b1 to the same degree in both strains at 8 weeks, while multidrug resistance-associated protein 3 was greater in SHRSP5/Dmcr than SHRSP. The diet decreased the level of bile salt export pump by the same degree in both strains, while constitutive androstane receptor, pregnane X receptor, and UDP-glucuronosyltransferase activity more prominent in SHRSP5/Dmcr than SHRSP at 8 weeks. In the fibrosis-related genes, only expression of collagen, type I, alpha 1 mRNA was greater in SHRSP5/Dmcr than SHRSP.

Conclusions

The greater progression of fibrosis in SHRSP5/Dmcr induced by HFC may be due to greater suppression of UDP-glucuronosyltransferase activity detoxifying toxicants, such as hydrophobic BAs.

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Abbreviations

αSMA:

Alpha smooth muscle actin

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

BA:

Bile acid

BSEP:

Bile salt export pump

CA:

Cholic acid

CAR:

Constitutive androstane receptor

CDCA:

Chenodeoxycholic acid

COL1a1:

Collagen, type I, alpha 1

CV:

Central vein

CYP27A1:

Cholesterol 27-hydroxylase

CYP7A1:

Cholesterol 7α-hydroxylase

CYP7B1:

Oxysterol 7α-hydroxylase

CYP8B1:

Sterol 12α-hydroxylase

EVG:

Elastic Van Gieson

FXR:

Farnesoid X receptor

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

GGT:

Γ-Glutamyl transpeptidase

H&E:

Hematoxylin and eosin

HFC:

High-fat and -cholesterol diet

MRP:

Resistance-associated protein

MMP-2:

Matrix metalloproteinase-2

NAFLD:

Nonalcoholic fatty liver disease

NASH:

Nonalcoholic steatohepatitis

PDGFβR:

Platelet-derived growth factor receptor, β polypeptide

PXR:

Pregnane X receptor

SHRSP:

Stroke-prone spontaneously hypertensive rat

SULT:

Sulfotransferase

TC:

Total cholesterol

UGT:

UDP-glucuronosyltransferase

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Acknowledgments

The work has been supported by Grants-in-Aid for Scientific Research (B. 23390161, C. 25460797), Grants-in-Aid for Young Scientists (B. 22790543, Start-up. 21890098) and Uehara Memorial Foundation in 2009 (Japan).

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Authors and Affiliations

  1. Department of Public Health, Fujita Health University School of Medicine, Dengakugakubo 1-98, Kutsukake-cho, Toyoake, 470-1192, Japan

    Hisao Naito

  2. Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Hisao Naito, Xiaofang Jia, Husna Yetti, Yukie Yanagiba, Hazuki Tamada, Kazuya Kitamori, Yumi Hayashi, Dong Wang, Masashi Kato & Tamie Nakajima

  3. College of Human Life and Environment, Kinjo Gakuin University, Nagoya, Japan

    Hazuki Tamada & Kazuya Kitamori

  4. Department of Legal Medicine and Bioethics, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Akira Ishii

  5. College of Life and Health Sciences, Chubu University, Kasugai, Japan

    Tamie Nakajima

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  1. Hisao Naito
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  2. Xiaofang Jia
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Naito, H., Jia, X., Yetti, H. et al. Importance of detoxifying enzymes in differentiating fibrotic development between SHRSP5/Dmcr and SHRSP rats. Environ Health Prev Med 21, 368–381 (2016). https://doi.org/10.1007/s12199-016-0539-x

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  • DOI: https://doi.org/10.1007/s12199-016-0539-x

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