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
Folic acid has been shown to improve non-alcoholic steatohepatitis (NASH), but its roles in hepatic lipid metabolism, hepatic one-carbon metabolism, and gut microbiota are still unknown.
To demonstrate the role of folic acid in lipid metabolism and gut microbiota in NASH.
Twenty-four Sprague-Dawley rats were assigned into three groups: Chow diet, high-fat diet (HFD), and HFD with folic acid administration. At the end of 16 wk, the liver histology, the expression of hepatic genes related to lipid metabolism, one-carbon metabolism, and gut microbiota structure analysis of fecal samples based on 16S rRNA sequencing were measured to evaluate the effect of folic acid. Palmitic acid-exposed Huh7 cell line was used to evaluate the role of folic acid in hepatic lipid metabolism.
Folic acid treatment attenuated steatosis, lobular inflammation, and hepatocellular ballooning in rats with HFD-induced steatohepatitis. Genes related to lipid de novo lipogenesis, β-oxidation, and lipid uptake were improved in HFD-fed folic acid-treated rats. Furthermore, peroxisome proliferator-activated receptor alpha (PPARα) and silence information regulation factor 1 (SIRT1) were restored by folic acid in HFD-fed rats and palmitic acid-exposed Huh7 cell line. The restoration of PPARα by folic acid was blocked after transfection with SIRT1 siRNA in the Huh7 cell line. Additionally, folic acid administration ameliorated depleted hepatic one-carbon metabolism and restored the diversity of the gut microbiota in rats with HFD-induced steatohepatitis.
Folic acid improves hepatic lipid metabolism by upregulating PPARα levels via a SIRT1-dependent mechanism and restores hepatic one-carbon metabolism and diversity of gut microbiota, thereby attenuating HFD-induced NASH in rats.
Core tip: The roles of folic acid in hepatic lipid metabolism, hepatic one-carbon metabolism, and gut microbiota in high-fat diet (HFD)-induced steatohepatitis are still unknown. This study confirmed that folic acid ameliorated HFD-induced steatohepatitis by restoring PPARα levels via a SIRT1 dependent mechanism. Moreover, folic acid restored depleted hepatic one-carbon metabolism and the diversity of gut microbiota. All these findings further clarified the improvement effect of folic acid on HFD-induced steatohepatitis and suggested that folic acid may become a therapeutic drug to treat non-alcoholic fatty liver disease in the future.