Development of novel rat model for high-fat and high-cholesterol diet-induced steatohepatitis and severe fibrosis progression in SHRSP5/Dmcr

Kazuya Kitamori,Kunihiro Sonoda,Yukio Yamori,Yuko Yasui,Katsumi Ikeda,Tamie Nakajima,Hazuki Tamada,Daisuke Miyazawa,Naomi Yasui,Satoru Tsuchikura,Miya Kobayashi,Hisao Naito,Takashi Moriya

doi:10.1007/s12199-011-0235-9

Abstract

Patients with nonalcoholic fatty liver disease are increasing worldwide, and preventive measures are an urgent need and primary concern today. This study aimed to develop and clarify the usefulness of the SHRSP5/Dmcr rat, derived from a stroke-prone spontaneously hypertensive rat, as a novel animal model for time-course analysis of steatohepatitis and the severe fibrosis progression often observed in the disease. Ten-week-old male SHRSP5/Dmcr rats were divided into six groups: half were fed a high-fat and high-cholesterol-containing diet (HFC diet), and the others the control, stroke-prone (SP) diet for 2, 8, and 14weeks. The HFC diet significantly increased serum transaminase and gamma glutamyl transpeptidase activities, tumor necrosis factor alpha levels, and serum and hepatic total cholesterol levels over time. In contrast, this diet decreased serum albumin, glucose, and adiponectin levels throughout or the later stage of the feeding period, but did not influence serum insulin levels. Histopathologically, the HFC diet increased microvesicular steatosis, and focal or spotty necrosis with lymphocyte infiltrations were observed in the liver at 2weeks, macrovesicular steatosis, ballooned hepatocytes with Mallory-Denk body formation in some, and multilobular necrosis and fibrosis at 8weeks. Interestingly, this fibrosis formed a honeycomb network at 14weeks. These changes are very similar to those observed in patients with non-alcoholic steatohepatitis. SHRSP5/Dmcr rats appear to be a useful model for analyzing the time-dependent changes of HFC diet-induced steatohepatitis and fibrosis progression.

Highlights

Aim This study aimed to develop and clarify the usefulness of the SHRSP5/Dmcr rat, derived from a stroke-prone spontaneously hypertensive rat, as a novel animal model for time-course analysis of steatohepatitis and the severe fibrosis progression often observed in the disease
Non-alcoholic fatty liver disease (NAFLD) includes a progressive liver disorder from non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH) without a history of alcohol abuse, which is increasingly observed as a comorbidity of the metabolic syndrome phenotype [1]
Hepatic total cholesterol (TC) levels of the rats fed the HFC diet were considerably higher than those in the SP diet, and the levels increased with the increasing duration of the feeding. We demonstrated that such a diet, referred to as the HFC diet, caused severe lipid accumulation and mild inflammation with an NAFLD activity scores (NAS) evaluation around 5.0 in 2 weeks in the liver of SHRSP5/Dmcr rats

Summary

Introduction

Non-alcoholic fatty liver disease (NAFLD) includes a progressive liver disorder from non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH) without a history of alcohol abuse, which is increasingly observed as a comorbidity of the metabolic syndrome phenotype [1]. During the progression of NAFLD, hepatocyte steatosis and necrosis, infiltration of inflammatory cells, and fibrosis consistently appear, and the fibrosis results in hepatic cirrhosis or, in tumor formation. Of 73 patients with NASH, 25% developed cirrhosis [2]; of 82 of those with NASH, 7% hepatocellular carcinoma [3]. 9% of 382 patients with NASH were diagnosed with hepatocellular carcinoma [4]. The percentage of NASH in patients with NAFLD was approximately 60% [5]. Thirty-six percent of the patients with NAFLD were found to have severe fibrosis by biopsy [6]

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