Basic Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Mar 28, 2019; 25(12): 1492-1501
Published online Mar 28, 2019. doi: 10.3748/wjg.v25.i12.1492
Ursodeoxycholic acid ameliorates hepatic lipid metabolism in LO2 cells by regulating the AKT/mTOR/SREBP-1 signaling pathway
Jie Hu, Wei Hong, Kan-Nan Yao, Xiao-Hong Zhu, Zhi-Yun Chen, Lei Ye
Jie Hu, Xiao-Hong Zhu, Lei Ye, Department of Infectious Diseases, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, Zhejiang Province, China
Wei Hong, Kan-Nan Yao, Zhi-Yun Chen, the Second Central Laboratory, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, Zhejiang Province, China
Author contributions: Hu J and Ye L designed the research; Yao KN and Hong W performed the research; Chen ZY and Zhu XH contributed new reagents or analytic tools; Yao KN and Chen ZY analyzed the data; Hu J and Hong W wrote the paper.
Supported by the Natural Science Foundation of Zhejiang Province, China, No. LQ19H290001.
Conflict-of-interest statement: There is no conflict of interest in this study.
Data sharing statement: No additional data are available.
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: Lei Ye, MAMS, Doctor, Department of Infectious Diseases, The First Affiliated Hospital of Zhejiang Chinese Medical University, No. 54, Youdian Road, Hangzhou 310006, Zhejiang Province, China. huj520@163.com
Telephone: +86-571-86919345 Fax: +86-571-86919345
Received: November 27, 2018
Peer-review started: November 27, 2018
First decision: January 11, 2019
Revised: January 29, 2019
Accepted: January 30, 2019
Article in press: January 30, 2019
Published online: March 28, 2019
Processing time: 121 Days and 22.7 Hours
Abstract
BACKGROUND

Nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disease, can progress into nonalcoholic steatohepatitis (NASH), cirrhosis, and even hepatocellular carcinoma. Bile acids such as ursodeoxycholic acid (UDCA) play an essential role in the pathogenesis of NAFLD by regulating the level of sterol regulatory element-binding protein (SREBP) 1c, but the underlying regulatory mechanism remains elusive. Increased evidence indicates that the AKT/mTOR/SREBP-1 signaling pathway is a key pathway to regulate hepatic cellular lipid metabolism. UDCA may regulate the AKT/mTOR/SREBP-1 signaling pathway to ameliorate hepatic lipid metabolism.

AIM

To investigate the functional mechanism of UDCA in an oleic acid (OA)-induced cellular model of NAFLD.

METHODS

The cellular model of NAFLD was established using OA and treated with UDCA. First, the best concentration of UDCA was selected. For the best time-dependent assay, cells were stimulated with OA only or co-treated with OA and 2 mmol/L UDCA for 24 h, 48 h, and 72 h. Oil red O staining was used to observe the accumulation of intracellular lipids, while the intracellular contents of triglyceride, alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT), and aspartate aminotransferase (AST) were detected by enzymatic methods. Meanwhile, the expression levels of AKT/mTOR/SREBP-1 signaling pathway-related proteins were detected by real-time PCR and Western blot.

RESULTS

In the NAFLD cell model established with LO2 cells induced using OA, lipid accumulation was obvious. UDCA significantly inhibited lipid accumulation at different concentrations (especially 2 mmol/L) and decreased cell growth ability at different time points. The biochemical parameters like ALT, AST, and GGT were significant improved by UDCA. UDCA treatment vividly repressed the activation of AKT, mTOR, and CRTC2 and the expression of nSREBP-1 in LO2 cells induced with OA.

CONCLUSION

Our findings demonstrate the effect of UDCA in improving NAFLD. UDCA attenuates OA-induced hepatic steatosis mainly by regulation of AKT/mTOR/SREBP-1 signal transduction.

Keywords: Ursodeoxycholic acid; Hepatic lipid metabolism; AKT/mTOR/SREBP-1; Hepatic steatosis

Core tip: Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver disease. Many studies show that the disorder of hepatic lipid metabolism is the major pathogenesis. Increased evidence indicates that the AKT/mTOR/SREBP-1 signaling pathway is a key pathway to regulate hepatocellular lipid metabolism. At present, there are few studies on the mechanism of NAFLD with regard to hepatic lipid metabolism. We aimed to investigate the functional mechanism of ursodeoxycholic acid (UDCA) in the oleic acid-induced cellular model of NAFLD. The possible molecular mechanism and related targets of regulating hepatic lipid metabolism were explored, and the correlation between the occurrence of NAFLD and the AKT/mTOR/SREBP-1 signaling pathway was explored. We provided more sufficient experimental basis for clinical application of UDCA in the treatment of NAFLD.