Ethyl pyruvate supplemented in drinking water ameliorates experimental nonalcoholic steatohepatitis

Xiujing Sun,Shengtao Zhu,Xueyu Dong,Runar J Strand-Amundsen,Tor Inge Tonnessen,Runkuan Yang

doi:10.1016/j.biopha.2021.111392

Abstract

Inflammation and oxidative stress play a significant role in the pathogenesis of nonalcoholic steatohepatitis (NASH). Ethyl pyruvate (EP) is a novel anti-inflammatory agent and a potent reactive oxygen species (ROS) scavenger. Therefore, EP supplemented in drinking water may alleviate experimental NASH in this study (even though 0.3% of EP cannot attenuate the simple non-aggressive fatty liver). The methionine-choline-deficient (MCD) diet was given to the C57BL/6 male mice for 3 weeks to induce NASH. The NASH animals were randomized into 3 treatment groups: animals in the MCD alone group were treated with normal drinking water alone; animals in the delayed EP group were given 3% (v/v) of EP supplemented in normal drinking water, the treatment started 10 days after MCD diet feeding; animals in the early EP therapy group were treated the same as the delayed EP group except that EP treatment started the same day when MCD diet was given; the control mice were fed with normal chow and treated with normal drinking water (n = 10 for each group). Compared to MCD group with normal drinking water, early EP treatment significantly decreased serum ALT and improved NASH histopathology; delayed EP therapy only attenuated NASH in 50% (5/10) of the animals. The beneficial effects were associated with decreased hepatic TNF-a and IL-6 mRNA expression on early 5 days, inhibited NF-kB activation, reduced liver tissue malondialdehyde levels, and decreased intestinal bacterial translocation (BT). In conclusion: EP supplemented in drinking water attenuates experimental NASH.

Highlights

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease [1]
Compared to MCD fed animals treated with normal drinking water, early Ethyl pyruvate (EP) treatment significantly decreased serum ALT levels (n = 10, p = 0.0019, * indicates p < 0.05 vs. the control group; †indicates p < 0.05 vs. the MCD group) but did not markedly reduce serum AST concentrations in the early EP therapy group (n = 10, p ≥ 0.05)
In the late EP therapy group, 50% of mice (5/ 10) responded well to the delayed EP treatment; the other 50% of mice (5/10) did not response to the delayed EP treatment; the delayed treatment did not significantly reduce serum ALT/AST in the whole late EP treatment group (n = 10, p ≥ 0.05) (Fig. 1)

Summary

Introduction

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease [1]. The hallmark of NAFLD is excessive fatty accu mulation in the hepatocyte, which may be an isolated event (non-alco holic fatty liver, NAFL) or accompanied by evident inflammation and cell injury with or without fibrosis (NASH) [3]. NASH is the active and aggressive form of NAFLD [2,3], this common liver disease affects about 3–5.7% of the adult population [4]. Substantial evidence shows that oxidative stress is a primary and necessary event for the disease progression and inhibition of the stress-activated transcription factor NF-κB can prevent the development of NASH [5]. Gut bacteria may play a major causative role in the development of Abbreviations: NASH, nonalcoholic steatohepatitis; EP, ethyl pyruvate; ROS, reactive oxygen species; MCD, methionine-choline-deficient; MDA, malondialdehyde; BT, bacterial translocation; NAFLD, non-alcoholic fatty liver disease; HCC, hepatocellular carcinoma; MLN, mesenteric lymph nodes

Methods

Results

Conclusion