基于内质网应激-FXR途径探讨山柰酚改善高脂饮食诱导的肝脏脂质沉积的机制

doi:10.3969/j.issn.1006-5725.2025.16.007

Abstract

Abstract:

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.

Key words: kaempferol, endoplasmic reticulum stress, farnesoid x receptor, non-alcoholic steatohepatitis, lipid deposition

CLC Number:

R363

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.

Figures/Tables 5

Tab.1

Fig.1

Fig.2

Fig.3

Fig.4

References 30

[1]	ENGIN A. Nonalcoholic Fatty Liver Disease and Staging of Hepatic Fibrosis［J］. Adv Exp Med Biol， 2024， 1460：539-574. doi:10.1007/978-3-031-63657-8_18 doi: 10.1007/978-3-031-63657-8_18
[2]	TENG M L， NG C H， HUANG D Q， et al. Global incidence and prevalence of nonalcoholic fatty liver disease［J］. Clin Mol Hepatol， 2023， 29（）：S32-S42. doi:10.3350/cmh.2022.0365 doi: 10.3350/cmh.2022.0365
[3]	WEI S， WANG L， EVANS P C， et al. NAFLD and NASH： etiology， targets and emerging therapies［J］. Drug Discov Today， 2024， 29（3）：103910. doi:10.1016/j.drudis.2024.103910 doi: 10.1016/j.drudis.2024.103910
[4]	AJOOLABADY A， KAPLOWITZ N， LEBEAUPIN C， et al. Endoplasmic reticulum stress in liver diseases［J］. Hepatology， 2023， 77（2）：619-639. doi:10.1002/hep.32562 doi: 10.1002/hep.32562
[5]	李霞，李映，何伟，等.糖蛋白130在急性肝损伤中负性调控内质网应激作用及机制［J］.实用医学杂志，2022，38（12）：1499-1505.
[6]	PARTHASARATHY G， MALHI H. Assessment of Lipotoxic Endoplasmic Reticulum （ER） Stress in Nonalcoholic Steatohepatitis （NASH）［J］. Methods Mol Biol， 2022， 2455：243-254. doi:10.1007/978-1-0716-2128-8_19 doi: 10.1007/978-1-0716-2128-8_19
[7]	MERENDA T， JUSZCZAK F， FERIER E， et al. Natural compounds proposed for the management of non-alcoholic fatty liver disease［J］. Nat Prod Bioprospect， 2024， 14（1）：24. doi:10.1007/s13659-024-00445-z doi: 10.1007/s13659-024-00445-z
[8]	YAO Y X， YU Y J， DAI S， et al. Kaempferol efficacy in metabolic diseases： Molecular mechanisms of action in diabetes mellitus， obesity， non-alcoholic fatty liver disease， steatohepatitis， and atherosclerosis［J］. Biomed Pharmacother， 2024， 175：116694. doi:10.1016/j.biopha.2024.116694 doi: 10.1016/j.biopha.2024.116694
[9]	SHIN S K， KWON E Y. Kaempferol ameliorates metabolic syndrome by inhibiting inflammation and oxidative stress in high-fat diet-induced obese mice［J］. Nutr Res Pract， 2024， 18（3）：325-344. doi:10.4162/nrp.2024.18.3.325 doi: 10.4162/nrp.2024.18.3.325
[10]	XIANG H， SHAO M， LU Y， et al. Kaempferol Alleviates Steatosis and Inflammation During Early Non-Alcoholic Steatohepatitis Associated With Liver X Receptor α-Lysophosphatidylcholine Acyltransferase 3 Signaling Pathway［J］. Front Pharmacol， 2021， 12：690736. doi:10.3389/fphar.2021.690736 doi: 10.3389/fphar.2021.690736
[11]	TIE F， DING J， HU N， et al. Kaempferol and Kaempferide Attenuate Oleic Acid-Induced Lipid Accumulation and Oxidative Stress in HepG2 Cells［J］. Int J Mol Sci， 2021， 22（16）：8847. doi:10.3390/ijms22168847 doi: 10.3390/ijms22168847
[12]	WANG H， CHEN L， ZHANG X， et al. Kaempferol protects mice from d-GalN/LPS-induced acute liver failure by regulating the ER stress-Grp78-CHOP signaling pathway［J］. Biomed Pharmacother， 2019， 111：468-475. doi:10.1016/j.biopha.2018.12.105 doi: 10.1016/j.biopha.2018.12.105
[13]	CAO R， CAO C， HU X， et al. Kaempferol attenuates carbon tetrachloride （CCl（4））-induced hepatic fibrosis by promoting ASIC1a degradation and suppression of the ASIC1a-mediated ERS［J］. Phytomedicine， 2023， 121：155125. doi:10.1016/j.phymed.2023.155125 doi: 10.1016/j.phymed.2023.155125
[14]	XIE X， LIAO Y， LIN Z， et al. Patchouli alcohol alleviates metabolic dysfunction-associated steatohepatitis via inhibiting mitochondria-associated endoplasmic reticulum membrane disruption-induced hepatic steatosis and inflammation in rats［J］. Int Immunopharmacol， 2024， 138：112634. doi:10.1016/j.intimp.2024.112634 doi: 10.1016/j.intimp.2024.112634
[15]	XIONG X， WANG X， LU Y， et al. Hepatic steatosis exacerbated by endoplasmic reticulum stress-mediated downregulation of FXR in aging mice［J］. J Hepatol， 2014， 60（4）：847-854. doi:10.1016/j.jhep.2013.12.003 doi: 10.1016/j.jhep.2013.12.003
[16]	ISRAELSEN M， FRANCQUE S， TSOCHATZIS E A， et al. Steatotic liver disease［J］. Lancet， 2024， 404（10464）：1761-1778. doi:10.1016/s0140-6736(24)01811-7 doi: 10.1016/s0140-6736(24)01811-7
[17]	XIA S W， WANG Z M， SUN S M， et al. Endoplasmic reticulum stress and protein degradation in chronic liver disease［J］. Pharmacol Res， 2020， 161：105218. doi:10.1016/j.phrs.2020.105218 doi: 10.1016/j.phrs.2020.105218
[18]	CHEN H， TAN H， WAN J， et al. PPAR-γ signaling in nonalcoholic fatty liver disease： Pathogenesis and therapeutic targets［J］. Pharmacol Ther， 2023， 245：108391. doi:10.1016/j.pharmthera.2023.108391 doi: 10.1016/j.pharmthera.2023.108391
[19]	LI X， XU Z， WANG S， et al. Emodin ameliorates hepatic steatosis through endoplasmic reticulum-stress sterol regulatory element-binding protein 1c pathway in liquid fructose-feeding rats［J］. Hepatol Res， 2016， 46（3）：E105-E117. doi:10.1111/hepr.12538 doi: 10.1111/hepr.12538
[20]	VARGHESE D S， OOMMEN D， JOHN A， et al. GRP78/BiP alleviates oxLDL-induced hepatotoxicity in familial hypercholesterolemia caused by missense variants of LDLR in a HepG2 cellular model［J］. Lipids Health Dis， 2023， 22（1）：69. doi:10.1186/s12944-023-01835-x doi: 10.1186/s12944-023-01835-x
[21]	WANG D， LAO L， PANG X， et al. Asiatic acid from Potentilla chinensis alleviates non-alcoholic fatty liver by regulating endoplasmic reticulum stress and lipid metabolism［J］. Int Immunopharmacol， 2018， 65：256-267. doi:10.1016/j.intimp.2018.10.013 doi: 10.1016/j.intimp.2018.10.013
[22]	GIOIELLO A， ROSATELLI E， CERRA B. Patented Farnesoid X receptor modulators： A review （2019 - present）［J］. Expert Opin Ther Pat， 2024， 34（7）：547-564. doi:10.1080/13543776.2024.2314296 doi: 10.1080/13543776.2024.2314296
[23]	牛春燕，石永强，陈跃.非酒精性脂肪性肝病的新兴靶向治疗药物研究进展［J］.实用医学杂志，2022，38（11）：1439-1442.
[24]	CHEN S， SUN S， FENG Y， et al. Diosgenin attenuates nonalcoholic hepatic steatosis through the hepatic FXR-SHP-SREBP1C/PPARα/CD36 pathway［J］. Eur J Pharmacol， 2023， 952：175808. doi:10.1016/j.ejphar.2023.175808 doi: 10.1016/j.ejphar.2023.175808
[25]	HAGA S， YIMIN， OZAKI M. Relevance of FXR-p62/SQSTM1 pathway for survival and protection of mouse hepatocytes and liver， especially with steatosis［J］. BMC Gastroenterol， 2017， 17（1）：9. doi:10.1186/s12876-016-0568-3 doi: 10.1186/s12876-016-0568-3
[26]	KIM K H， CHOI S， ZHOU Y， et al. Hepatic FXR/SHP axis modulates systemic glucose and fatty acid homeostasis in aged mice［J］. Hepatology， 2017， 66（2）：498-509. doi:10.1002/hep.29199 doi: 10.1002/hep.29199
[27]	ADORINI L， TRAUNER M. FXR agonists in NASH treatment［J］. J Hepatol， 2023， 79（5）：1317-1331. doi:10.1016/j.jhep.2023.07.034 doi: 10.1016/j.jhep.2023.07.034
[28]	KREMOSER C. FXR agonists for NASH： How are they different and what difference do they make？［J］. J Hepatol， 2021， 75（1）：12-15. doi:10.1016/j.jhep.2021.03.020 doi: 10.1016/j.jhep.2021.03.020
[29]	MOHAMMADPOUR-ASL S， ROSHAN-MILANI B， ROSHAN-MILANI S， et al. Endoplasmic reticulum stress PERK-ATF4-CHOP pathway is involved in non-alcoholic fatty liver disease in type 1 diabetic rats： The rescue effect of treatment exercise and insulin-like growth factor I［J］. Heliyon， 2024， 10（5）：e27225. doi:10.1016/j.heliyon.2024.e27225 doi: 10.1016/j.heliyon.2024.e27225
[30]	HAN C Y， RHO H S， KIM A， et al. FXR Inhibits Endoplasmic Reticulum Stress-Induced NLRP3 Inflammasome in Hepatocytes and Ameliorates Liver Injury［J］. Cell Rep， 2018， 24（11）：2985-2999. doi:10.1016/j.celrep.2018.07.068 doi: 10.1016/j.celrep.2018.07.068

基因	序列 (5’ to 3’)
TNF?ɑ	正向	CCTGTAGCCCACGTCGTAG
	反向	GGGAGTAGACAAGGTACAACCC
IL?1β	正向	GAAATGCCACCTTTTGACAGTG
	反向	CTGGATGCTCTCATCAGGACA
GAPDH	正向	TCAAGAAGGGTGGTGAAGG
	反向	TCAAAGGGTGGAGGGGGGGGGTGGTT

Mechanism of kaempferol ameliorating hepatic lipid deposition induced by high fat diet based on endoplasmic reticulum stress-FXR pathway

RichHTML

PDF (PC)

Knowledge

Abstract

Cite this article

share this article

Figures/Tables 5

References 30

Related Articles 7

Recommended Articles

Metrics

Comments

[1]	Shan LUO,Ying FENG,Dandan FAN,Wenxin ZHENG,Xingrong GUO,Xuzhi. RUAN. ANGPTL8 knockout reduces lipopolysaccharide⁃induced hepatic lipid deposition [J]. The Journal of Practical Medicine, 2024, 40(9): 1197-1203.
[2]	Changsong MA,Shuai HUANG,Qingde WA,Weizhi CHEN,Yang WANG,Xitao LINGHU,Yubo. TANG. Mechanism of ginkgolide B antagonizing vascular endothelial injury by inhibiting endoplasmic reticulum stress [J]. The Journal of Practical Medicine, 2023, 39(24): 3175-3181.
[3]	Jie DING,Siqi LIU,Yiying WANG,Lin WANG,Chenghong SHI,Fang WANG,Guoji CHANG,Lijuan HUA,Huayi CHEN,Shenghao LI,Qingqing. WANG. Gentiopicroside promotes autophagy to alleviate nonalcoholic steatohepatitis in rats via up⁃regulating the expression of LC3Ⅱ [J]. The Journal of Practical Medicine, 2023, 39(16): 2022-2028.
[4]	WEI Liying, ZHANG Jinghong. . 1，25 ⁃Dihydroxyvitamin D3 ameliorates neutrophilic asthma in mice and inhibits endoplasmic reticulum stress by upregulating Nrf2 expression [J]. The Journal of Practical Medicine, 2022, 38(16): 2013-2023.
[5]	LI Xia, LI Ying, HE Wei, DENG Jie, JIANG Xiaoling, JIANG Jinliang, JIANG Zhigang, CHENG Qiji⁃ ao, LIU Xia, HE Yihuai.. Study on the role and mechanism of gp130 negatively regulating endoplasmic reticulum stress in acute liver injury [J]. The Journal of Practical Medicine, 2022, 38(12): 1499-1505.
[6]	WEN Hailing, MENG Xiangxi, YANG Jingzhe, XIAO Changshuan.. Loganin inhibits the apoptosis of intestinal epithelial cells in burned rats and protects the intestinal muco⁃ sal structure through the ERS pathway [J]. The Journal of Practical Medicine, 2022, 38(11): 1353-1358.
[7]	ZHANG Chunyang, GUO Zhenwei, HE Xiaobing, ZHOU Xinyu.. Role and mechanism of endoplasmic reticulum stress protein GRP78 in inflammatory activation of astro⁃ cytes after intracerebral hemorrhage [J]. The Journal of Practical Medicine, 2021, 37(24): 3132-3142.