R. verniciflua and E. ulmoides Extract (ILF-RE) Protects against Chronic CCl₄-Induced Liver Damage by Enhancing Antioxidation.

Hwa-Young Lee,Geum-Hwa Lee,Han-Jung Chae,Young Yoon

doi:10.3390/nu11020382

Abstract

This study aimed to characterize the protective effects of R. verniciflua extract (ILF-R) and E. ulmoides extract (ILF-E), the combination called ILF-RE, against chronic CCl4-induced liver oxidative injury in rats, as well as to investigate the mechanism underlying hepatoprotection by ILF-RE against CCl4-induced hepatic dysfunction. Chronic hepatic stress was induced via intraperitoneal (IP) administration of a mixture of CCl4 (0.2 mL/100 g body weight) and olive oil [1:1(v/v)] twice a week for 4 weeks to rats. ILF-RE was administered orally at 40, 80, and 120 mg/kg to rats for 4 weeks. Alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyl transpeptidase (GGT), and lipid peroxidation assays were performed, and total triglyceride, cholesterol, and LDL-cholesterol levels were quantified. Furthermore, ER stress and lipogenesis-related gene expression including sterol regulatory element-binding transcription factor 1 (SREBP-1), fatty acid synthase (FAS), and P-AMPK were assessed. ILF-RE markedly protected against liver damage by inhibiting oxidative stress and increasing antioxidant enzyme activity including glutathione (GSH), glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase. Furthermore, hepatic dyslipidemia was regulated after ILF-RE administration. Moreover, hepatic lipid accumulation and its associated lipogenic genes, including those encoding SREBP-1 and FAS, were regulated after ILF-RE administration. This was accompanied by regulation of ER stress response signaling, suggesting a mechanism underlying ILF-RE-mediated hepatoprotection against lipid accumulation. The present results indicate that ILF-RE exerts hepatoprotective effects against chronic CCl4-induced dysfunction by suppressing hepatic oxidative stress and lipogenesis, suggesting that ILF-RE is a potential preventive/therapeutic natural product in treating hepatoxicity and associated dysfunction.

Highlights

The liver is a vital metabolic organ in various animal species for biotransformation and detoxification of endogenous and exogenous harmful substances [1,2]
Treatment with ILF-RE inhibited the sterol regulatory element-binding transcription factor 1 (SREBP-1) signaling axis during ER stress, stress, elucidating the effect of CCl4 administration on the expression of SREBP-1 and CHOP, pelucidating the effect of CCl4 administration on the expression of SREBP-1 and CHOP, p-PERK, PERK, and p-eIF2α during ER stress signaling. These results indicate that ILF-RE may and p-eIF2α during ER stress signaling. These results indicate that ILF-RE may inhibit inhibit lipogenesis and probably improves the ER folding status to ameliorate hepatic lipid lipogenesis and probably improves the ER folding status to ameliorate hepatic lipid accumulation accumulation upon CCl4 treatment
The present study shows that chronic CCl4 -induced liver injury, defined as an increase in the levels of serum markers of hepatic damage and abnormal hepatic lipid accumulation, was attenuated in the presence of ILF-RE

Summary

Introduction

The liver is a vital metabolic organ in various animal species for biotransformation and detoxification of endogenous and exogenous harmful substances [1,2]. The mechanism underlying oxidative stress-induced liver damage involves imbalance of oxidation and antioxidant systems, thereby generating excessive free radicals and reducing antioxidant capacity [2]. Carbon tetrachloride (CCl4 ), an industrial solvent, is a potent hepatotoxic agent used extensively in animal models to induce acute and chronic liver injury [4]. CCl4 itself does not have cytotoxic effects on the liver; its metabolites ·CCl3 and ·OOCCl3 in hepatic parenchyma cells formed by cytochrome P450 -dependent monooxygenases cause hepatotoxicity [5]. Notwithstanding extensive advancements in modern pharmacotherapies to treat liver diseases, these drugs are occasionally inadequate and have adverse effects, especially when administered for a long period. Development of new, more effective, and safer functional foods has important implications in treating liver disease

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