Published online May 14, 2020. doi: 10.3748/wjg.v26.i18.2203
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
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.
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.
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.
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.
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.
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.
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.