Theabrownin alleviates nonalcoholic fatty liver disease by inhibiting the intestinal farnesoid X receptor–ceramide axis

Abstract Theabrownin (TB), which is derived from Pu‐erh tea and previously recognized as an intestinal farnesoid X receptor (FXR) antagonist, is known to have favorable effects on metabolic diseases such as hyperlipidemia and obesity. However, the mechanisms underlying the beneficial effects of TB in nonalcoholic fatty liver disease (NAFLD) require further exploration. This study aimed to use an NAFLD mouse model to evaluate changes in hepatic steatosis via the intestinal FXR–ceramide (Cer) axis following treatment with TB. The results indicated that TB alleviated hepatic steatosis and reduced total Cer levels in NAFLD mice. In particular, the levels of Cer(d18:1/16:0) in the intestine and liver were significantly reduced, which is considered to play a vital role in aggravating NAFLD. Furthermore, the transcriptional expression of Cer synthetase was markedly downregulated following treatment with TB or FXR antagonist, but this expression was reversed following treatment with a specific intestinal FXR agonist. These results indicate that TB alleviates NAFLD by reducing Cer levels via the inhibition of the intestinal FXR–Cer synthetase pathway.