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

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

doi:10.1007/s12199-016-0539-x

Abstract

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. Ten-week-old male SHRSP5/Dmcr and SHRSP were randomly allocated to groups and fed with either control diet or HFC for 2 and 8weeks. The liver histopathology, biochemical features, and molecular signaling involved in BA kinetics were measured. 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 8weeks, 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 8weeks. In the fibrosis-related genes, only expression of collagen, type I, alpha 1 mRNA was greater in SHRSP5/Dmcr than SHRSP. 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.

Highlights

Nonalcoholic fatty liver disease (NAFLD) is recognized as one of the most common liver diseases in the world
As for bile acid (BA) kinetics, High-fat and -cholesterol diet (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 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

Summary

Introduction

Nonalcoholic fatty liver disease (NAFLD) is recognized as one of the most common liver diseases in the world. Cholesterol in the liver is metabolized to bile acids (BAs) mainly by the catalytic action of cholesterol 7ahydroxylase (CYP7A1) and cholesterol 27-hydroxylase (CYP27A1), followed by sterol 12a-hydroxylase (CYP8B1) and oxysterol 7a-hydroxylase (CYP7B1) [4] In these processes, the primary BAs, cholic acid (CA) and chenodeoxycholic acid (CDCA) are produced. The conjugated BAs excrete into the bile canaliculi via bile salt export pump (BSEP), an adenosine triphosphate-binding cassette transporter localized in the canalicular hepatocyte membrane. In addition to this pathway, the canalicular multidrug resistance-associated protein (MRP) 2 and basolateral MRP3 are capable of transporting glucuronidated and sulfated BAs into bile canaliculi and blood, respectively [4, 6]. Cholesterol and the resultant metabolites, BAs, and accumulations, are essential for regulating hepatotoxicity [7,8,9]

Objectives

Results

Discussion

Conclusion