Basic Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. May 28, 2019; 25(20): 2450-2462
Published online May 28, 2019. doi: 10.3748/wjg.v25.i20.2450
Trimethylamine N-oxide attenuates high-fat high-cholesterol diet-induced steatohepatitis by reducing hepatic cholesterol overload in rats
Ze-Hua Zhao, Feng-Zhi Xin, Da Zhou, Ya-Qian Xue, Xiao-Lin Liu, Rui-Xu Yang, Qin Pan, Jian-Gao Fan
Ze-Hua Zhao, Feng-Zhi Xin, Da Zhou, Xiao-Lin Liu, Rui-Xu Yang, Qin Pan, Jian-Gao Fan, Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
Ya-Qian Xue, CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
Jian-Gao Fan, Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Shanghai 200092, China
Author contributions: Zhao ZH, Pan Q, and Fan JG contributed to the experimental design; Zhao ZH, Xin FZ, Zhou D, Xue YQ, Liu XL, and Yang RX contributed to the acquisition and analysis of data; Fan JG and Zhou D obtained the funding; Zhao ZH and Fan JG wrote the manuscript.
Supported by: National Key R and D Program of China, No. 2017YFC0908903; National Natural Science Foundation of China, No. 81873565, No. 81470840, and No. 81800510; and Shanghai Sailing Program, No. 18YF1415900.
Institutional review board statement: This study was approved by the institutional review board of Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine.
Institutional animal care and use committee statement: The study was approved by the Institutional Animal Care and Use Committee of Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The ARRIVE Guidelines have been adopted.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Jian-Gao Fan, MD, PhD, Chief Doctor, Professor, Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, 1665 Kong Jiang Road, Shanghai 200092, China. fanjiangao@xinhuamed.com.cn
Telephone: +86-21-2507-7340 Fax: +86-21-2507-7340
Received: March 28, 2019
Peer-review started: March 28, 2019
First decision: April 11, 2019
Revised: May 7, 2019
Accepted: May 8, 2019
Article in press: May 8, 2019
Published online: May 28, 2019
Processing time: 61 Days and 20.4 Hours
Abstract
BACKGROUND

Trimethylamine N-oxide (TMAO) has been shown to be involved in cardiovascular disease (CVD). However, its role in nonalcoholic steatohepatitis (NASH) is unknown.

AIM

To determine the effect of TMAO on the progression of NASH.

METHODS

A rat model was induced by 16-wk high-fat high-cholesterol (HFHC) diet feeding and TMAO was administrated by daily oral gavage for 8 wk.

RESULTS

Oral TMAO intervention attenuated HFHC diet-induced steatohepatitis in rats. Histological evaluation showed that TMAO treatment significantly alleviated lobular inflammation and hepatocyte ballooning in the livers of rats fed a HFHC diet. Serum levels of alanine aminotransferase and aspartate aminotransferase were also decreased by TMAO treatment. Moreover, hepatic endoplasmic reticulum (ER) stress and cell death were mitigated in HFHC diet-fed TMAO-treated rats. Hepatic and serum levels of cholesterol were both decreased by TMAO treatment in rats fed a HFHC diet. Furthermore, the expression levels of intestinal cholesterol transporters were detected. Interestingly, cholesterol influx-related Niemann-Pick C1-like 1 was downregulated and cholesterol efflux-related ABCG5/8 were upregulated by TMAO treatment in the small intestine. Gut microbiota analysis showed that TMAO could alter the gut microbial profile and restore the diversity of gut flora.

CONCLUSION

These data suggest that TMAO may modulate the gut microbiota, inhibit intestinal cholesterol absorption, and ameliorate hepatic ER stress and cell death under cholesterol overload, thereby attenuating HFHC diet-induced steatohepatitis in rats. Further studies are needed to evaluate the influence on CVD and define the safe does of TMAO treatment.

Keywords: Gut microbiota; Trimethylamine N-oxide; Nonalcoholic steatohepatitis; Endoplasmic reticulum stress; Cholesterol

Core tip: The function of trimethylamine N-oxide (TMAO) in nonalcoholic steatohepatitis (NASH) remains unexplored. We investigated the effect of oral TMAO administration on the progression of NASH in a rat model induced with a high-fat high-cholesterol (HFHC) diet. This study demonstrated for the first time that the gut microbial metabolite TMAO restores gut microbiota diversity, inhibits intestinal cholesterol absorption, and reduces hepatic cholesterol overload, thus attenuating cholesterol-induced endoplasmic reticulum stress and hepatocyte cell death. These functions facilitate the protection of TMAO against HFHC diet-induced steatohepatitis in rats.