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
ARTICLE HIGHLIGHTS
Research background

The gut microbial metabolites have been shown to be mediators in the gut-liver axis and play important role in non-alcoholic fatty liver disease. Trimethylamine N-oxide (TMAO) is a gut microbial metabolite derived from dietary choline and L-carnitine and is implied to be involved in the pathogenesis of cardiovascular disease.

Research motivation

Although the gut microbiota has long been found to play important roles in maintaining health, its function and regulation pathways are largely unknown. The gut microbial metabolites are considered to mediate the interaction between the gut commensal bacteria and the host. Exploring the function of gut microbial metabolites may help develop novel therapeutic approaches.

Research objectives

The main objective of the present study was to explore the function of TMAO in the progression of NASH and identify the targets and mechanisms underlying the effect of TMAO.

Research methods

A rat model of NASH was induced by high-fat high-cholesterol (HFHC) diet feeding for 16 wk. TMAO was orally administrated daily for 8 wk. Histological analysis was performed to evaluate the effect of TMAO on steatohepatitis. Hepatic and serum lipid profiles were measured. Endoplasmic reticulum (ER) stress-related pathways were detected by Western blot and expression levels of intestinal cholesterol transporters were detected by qRT-PCR. 16s rDNA sequencing was preformed to examine the effect of TMAO on gut microbial profile.

Research results

Oral TMAO administration significantly improved the histological and serological alterations in HFHC diet-induced steatohepatitis. Hepatic ER stress and cell death were ameliorated by TMAO treatment. Both hepatic and serum levels of cholesterol were decreased by TMAO intervention. The expression levels of intestinal cholesterol transporters were altered by TMAO treatment. And the diversity of gut microbial profile was restored by TMAO treatment.

Research conclusions

Under HFHC diet feeding conditions, TMAO inhibits intestinal cholesterol absorption, attenuates hepatic cholesterol overload, and alleviates ER stress mediated liver injury, which leads to the protective role of TMAO in HFHC diet-induced steatohepatitis in rats.

Research perspectives

The minimal effective dose of TMAO treatment needs to be defined to avoid the potential harmful effect of TMAO on the cardiovascular system in future studies.