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Mechanism of kaempferol ameliorating hepatic lipid deposition induced by high fat diet based on endoplasmic reticulum stress-FXR pathway
Received date: 2025-04-08
Online published: 2025-08-28
Objective To investigate the protective effects of Kaempferol （KAE） against hepatic lipid deposition induced by a high-fat diet， as well as the underlying mechanisms. Methods C57BL/6J male mice were fed a high-fat diet for 22 weeks to establish a chronic nonalcoholic steatohepatitis （NASH） model. KAE was administered during the last 8 weeks as an interventional agent to evaluate its effects. Liver lipid deposition was assessed， and the expression levels of endoplasmic reticulum （ER） stress-related proteins， activation of the Farnesoid X Receptor （FXR） signaling pathway， and the expression of lipid synthesis-related genes were analyzed. In vitro， palmitic acid （PA） was used to stimulate AML-12 cells to induce lipid accumulation. Additionally， siRNA targeting FXR was transfected into AML-12 cells to investigate the role of the ER stress-FXR signaling pathway in mediating the effects of KAE. Results The intervention of kaempferol inhibited the rapid weight gain induced by a high-fat diet， reduced serum total cholesterol， triglyceride levels， and ALT activity， effectively alleviated large-scale lipid aggregation in the liver， thereby exerting a protective effect against hepatic lipid deposition in NASH. Mechanistically， KAE decreased hepatic ER stress， promoted the expression of FXR and its activation marker SHP， thereby suppressing the expression of FASN and reducing hepatic lipid synthesis. In vitro， KAE treatment significantly reversed the inhibitory effect of excessive ER stress on FXR activity， as evidenced by the upregulation of FXR activity leading to decreased FASN expression and reduced steatosis in AML-12 cells. Moreover， FXR knockdown markedly abolished the protective effects of KAE on lipid deposition in AML-12 cells exposed to PA， by eliminating the promoting effect of KAE on SHP expression and the SHP-mediated suppression of SREBP1c. Conclusions KAE treatment alleviated ER stress， thereby enhancing FXR/SHP signaling and subsequently suppressing lipid synthesis to reduce hepatic lipid accumulation. These findings suggest that KAE holds therapeutic potential for the management of hepatic steatosis in NASH.
Shinan ZHOU , Lu LIANG , Wenyan ZHONG , Jingjing CHEN , Li. XIAO . Mechanism of kaempferol ameliorating hepatic lipid deposition induced by high fat diet based on endoplasmic reticulum stress-FXR pathway[J]. The Journal of Practical Medicine, 2025 , 41(16) : 2481 -2488 . DOI: 10.3969/j.issn.1006-5725.2025.16.007
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