Basic Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. May 14, 2020; 26(18): 2203-2220
Published online May 14, 2020. doi: 10.3748/wjg.v26.i18.2203
Folic acid attenuates high-fat diet-induced steatohepatitis via deacetylase SIRT1-dependent restoration of PPARα
Feng-Zhi Xin, Ze-Hua Zhao, Rui-Nan Zhang, Qin Pan, Zi-Zhen Gong, Chao Sun, Jian-Gao Fan
Feng-Zhi Xin, Ze-Hua Zhao, Rui-Nan Zhang, Qin Pan, Chao Sun, Jian-Gao Fan, Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
Zi-Zhen Gong, Jian-Gao Fan, Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Shanghai 200092, China
Zi-Zhen Gong, Shanghai Institute for Pediatric Research, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
Zi-Zhen Gong, Department of Pediatric Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
Author contributions: Xin FZ, Zhang RN, and Fan JG contributed to the experimental design; Xin FZ, Zhao ZH, Gong ZZ, and Sun C contributed to the acquisition and analysis of data; Fan JG and Zhang RN obtained the funding; and Xin FZ and Fan JG wrote the manuscript.
Supported by National Key R& D Program of China, No. 2017YFC0908903; National Natural Science Foundation of China, No. 81873565, No. 81470840, and No. 81700503.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of SHRM (SHRM-IACUC-015).
Conflict-of-interest statement: The authors declare that there is no conflict of interest related to this study.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (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, Director, 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 Kongjiang Road, Shanghai 200092, China. fanjiangao@xinhuamed.com.cn
Received: December 31, 2019
Peer-review started: December 31, 2019
First decision: January 19, 2020
Revised: March 27, 2020
Accepted: April 17, 2020
Article in press: April 17, 2020
Published online: May 14, 2020
ARTICLE HIGHLIGHTS
Research background

Non-alcoholic fatty liver disease has become a global burden, but there is still a lack of convinced drug therapy strategies for non-alcoholic steatohepatitis (NASH). As one of essential water-soluble vitamins for the human body, folic acid may become one of the drug targets for treatment of NASH, but the specific mechanism is not fully understood.

Research motivation

As one of essential vitamins absorbed by the intestine mainly, food-sourced folic acid improved high-fat diet (HFD)-induced steatohepatitis in previous studies, but further mechanism of folic acid on host hepatic lipid metabolism and the effect of folic acid on lipid one-carbon metabolism and gut microbiota remains rarely understood.

Research objectives

We aimed to evaluated the effect of folic acid on HFD-fed rat models and further clarify the mechanism of folic acid on hepatic lipid metabolism and gut microbiota.

Research methods

An HFD-induced rat model of NASH was used in the present study. Treatment of folic acid by oral administration lasted for 8 wk. Hepatic lipid metabolism was evaluated by real-time quantitative polymerase chain reaction (qRT-PCR). Expression levels of silence information regulation factor 1 (SIRT1) and peroxisome proliferator-activated receptor alpha (PPARα) were measured by Western blot analysis in HFD-induced rat models and palmitic acid-induced Huh7 cells. SIRT1 siRNA was transfected in Huh7 cells to examine whether folic acid restored PPARα levels through a SIRT1-dependent mechanism. Genes and proteins related to hepatic one-carbon metabolism were detected by qRT-PCR and Western blot. 16S rDNA sequencing was used to evaluate the effect of folic acid on gut microbiota profile.

Research results

Administration of folic acid ameliorated HFD-induced steatohepatitis. Folic acid repaired impaired hepatic lipid β-oxidation and hepatic one-carbon metabolism. SIRT1 and PPARα levels were restored by folic acid treatment. The restoration effect of PPARα by folic acid was blocked after SIRT1 knockdown in vitro. Furthermore, folic acid restored the diversity and altered the overall structure of gut microbiota profile.

Research conclusions

Folic acid restores PPARα levels via a SIRT1-dependent mechanism, ameliorates HFD-induced impaired hepatic lipid metabolism and hepatic one-carbon metabolism, and improves the diversity of gut microbiota, thus acting a protective role in HFD-induced NASH in rats.

Research perspectives

Folic acid may become one of drug targets for treatment of NASH. Research about folic acid in epigenetic regulation may further clarify the mechanism of folic acid on NASH.