Estrogen Deficiency Potentiates Thioacetamide-Induced Hepatic Fibrosis in Sprague-Dawley Rats.

Yong Hee Lee,Yoo Jung Park,Hyung Sik Kim,Kyeong Seok Kim,Sam Kacew,Jae Hyeon Park,Ji Yeon Son,Kwang Youl Lee,Keon Wook Kang,In Su Kim,Byung Mu Lee,Kyu-Bong Kim,Hae Ri Kim

doi:10.3390/ijms20153709

Abstract

Hepatic fibrosis is characterized by persistent deposition of extracellular matrix proteins and occurs in chronic liver diseases. The aim of the present study is to investigate whether estrogen deficiency (ED) potentiates hepatic fibrosis in a thioacetamide (TAA)-treated rat model. Fibrosis was induced via intraperitoneal injection (i.p.) of TAA (150 mg/kg/day) for four weeks in ovariectomized (OVX) female, sham-operated female, or male rats. In TAA-treated OVX rats, the activities of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and γ-glutamyl transferase (GGT) were significantly increased compared to those in TAA-treated sham-operated OVX rats or TAA-treated male rats. Furthermore, α-smooth muscle actin (α-SMA) expression was significantly increased compared to that in TAA-treated sham-operated rats. This was accompanied by the appearance of fibrosis biomarkers including vimentin, collagen-I, and hydroxyproline, in the liver of TAA-treated OVX rats. In addition, ED markedly reduced total glutathione (GSH) levels, as well as catalase (CAT) and superoxide dismutase (SOD) activity in TAA-treated OVX rats. In contrast, hepatic malondialdehyde (MDA) levels were elevated in TAA-treated OVX rats. Apoptosis significantly increased in TAA-treated OVX rats, as reflected by elevated p53, Bcl-2, and cleaved caspase 3 levels. Significant increases in interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) concentrations were exhibited in TAA-treated OVX rats, and this further aggravated fibrosis through the transforming growth factor-β (TGF-β)/Smad pathway. Our data suggest that ED potentiates TAA-induced oxidative damage in the liver, suggesting that ED may enhance the severity of hepatic fibrosis in menopausal women.

Highlights

Liver fibrosis is characterized by persistent deposition of extracellular matrix (ECM) proteins and it occurs in most types of chronic liver disease, including fibrosis and cirrhosis [1]
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TAA-induced hepatic fibrosis is accompanied by increasing inflammation and oxidative stress in rats [37]

Summary

Introduction

Liver fibrosis is characterized by persistent deposition of extracellular matrix (ECM) proteins and it occurs in most types of chronic liver disease, including fibrosis and cirrhosis [1]. The gender difference in prevalence of cirrhosis is increasing, with men showing a higher incidence than women [3]. The prevalence of non-alcoholic fatty liver disease (NAFLD) is lower in pre-menopausal women during the reproductive period than in men, but comparable in post-menopausal women and men [4]. Post-menopausal women might exhibit more severe hepatic disease progression and an elevated incidence of hepatic fibrosis. These findings may be explained by the protective effects of estrogen against hepatic fibrogenesis. It has been clearly demonstrated that the protective effects of hormone replacement therapy against fibrogenesis in hepatitis virus related liver disease appears to be mediated by estrogen [5]. Exactly how gender and reproductive state impact the severity of fibrosis in patients with NAFLD remains largely unknown [2,6,7]

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