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
Ursodeoxycholic acid (UDCA) plays an essential role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD), but the underlying regulatory mechanism remains elusive. Increased evidence indicates that the AKT/mTOR/SREBP-1 signaling pathway is a key pathway to regulate cellular hepatic lipid metabolism. UDCA may regulate the AKT/mTOR/SREBP-1 signaling pathway to ameliorate hepatic lipid metabolism. However, no report has discussed the regulatory effects of UDCA on lipid metabolism in vitro.
Although UDCA has been widely used in the treatment of NAFLD, the mechanism remains unclear. Understanding and regulating the AKT/mTOR/SREBP-1 signaling pathway using UDCA will be an important area for future research.
This study aimed to explore the protective effects of UDCA on NAFLD by regulating the AKT/mTOR/SREBP-1 signaling pathway. This will provide a therapeutic target for future clinical applications of UDCA to prevent and improve hepatic lipid metabolism disorders related diseases.
First, we established a cellular model of NAFLD using LO2 cells induced with oleic acid (OA). Second, we used a MTT assay to determine the optimal concentration of OA for inducing hepatocyte steatosis and the best treatment duration of UDCA. Third, oil red O staining was used to observe the formation of intracellular lipid droplets, and subsequently we analyzed the intracellular levels of biochemical indexes with UDCA treatment by enzymatic methods. Finally, we examined the effects of UDCA on the expression levels of the AKT/mTOR/SREBP-1 signaling pathway related proteins by real-time PCR and Western blot.
UDCA inhibited the lipid accumulation of LO2 cells induced with OA. UDCA decreased cell growth ability under the treatment of OA in a dose- and time-dependent manner. UDCA treatment significantly improved the biochemical parameters like alanine aminotransferase, gamma-glutamyl transpeptidase, and aspartate aminotransferase. UDCA suppressed the OA-induced upregulation of AKT, mTOR, CRTC2, and nSREBP-1 expression in LO2 cells.
UDCA administration improves OA induced growth inhibition of LO2 cells and relieves OA induced lipid accumulation. UDCA has a protective effect in improving hepatic steatosis and amending liver function in our in vitro experiments. We may provide the first evidence of the AKT/mTOR/SREBP-1 signaling pathway regulated by UDCA in OA-induced LO2 cells as an in vitro model of NAFLD. Our hypothesis was confirmed using LO2 cells treated with OA. We present a novel theory here that UDCA can ameliorate hepatic lipid metabolism via the AKT/mTOR/SREBP-1 signaling pathway. Thus, UDCA and other bile acids may have novel clinical applications to ameliorate hepatic lipid metabolism for NAFLD in future.
Our findings provide evidence that UDCA has the effect of ameliorating hepatic lipid metabolism. This study has some limitations and further studies using animals and further in vitro research with agonists and inhibitors of mTOR as tools should be performed.