Published online Mar 28, 2019. doi: 10.3748/wjg.v25.i12.1492
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
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.
To investigate the functional mechanism of UDCA in an oleic acid (OA)-induced cellular model of NAFLD.
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.
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.
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.
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.