Quercetin improves hepatic lipid accumulation by up-regulating lipolysis and lipophagy pathways

Yan ZHANG; Yilin YANG; Jiaqi YUAN; Mantian MI; Yu QIN

doi:10.16016/j.2097-0927.202401003

您当前的位置：

首页 >

文章列表页 >

Quercetin improves hepatic lipid accumulation by up-regulating lipolysis and lipophagy pathways

Basic Medicine | 更新时间：2026-01-09

- Quercetin improves hepatic lipid accumulation by up-regulating lipolysis and lipophagy pathways
- Journal of Army Medical University Vol. 46, Issue 20, Pages: 2301-2312(2024)
- 作者机构：
  
  400038 重庆，陆军军医大学(第三军医大学)军事预防医学系营养与食品安全研究中心，重庆市医学营养研究中心，重庆市营养与健康重点实验室
- 作者简介：
- 基金信息：
  
  the General Program of National Natural Science Foundation of China(81973037)
- DOI：10.16016/j.2097-0927.202401003
  CLC： Q591.5;R285.5;R575.5
- Received：02 January 2024，
  
  Revised：2024-06-29，
  
  Published：30 October 2024
- 稿件说明：
移动端阅览
Yan ZHANG, Yilin YANG, Jiaqi YUAN, et al. Quercetin improves hepatic lipid accumulation by up-regulating lipolysis and lipophagy pathways[J]. Journal of Army Medical University, 2024, 46(20): 2301-2312.
DOI：

Yan ZHANG, Yilin YANG, Jiaqi YUAN, et al. Quercetin improves hepatic lipid accumulation by up-regulating lipolysis and lipophagy pathways[J]. Journal of Army Medical University, 2024, 46(20): 2301-2312. DOI： 10.16016/j.2097-0927.202401003.

摘要

目的

明确槲皮素(quercetin，QUE)通过调控脂解及脂噬途径改善肝细胞脂质蓄积的效应及作用机制。

方法

利用棕榈酸(palmitic acid，PA)诱导人正常HHL-5肝细胞株(human hepatocyte cell line 5

HHL-5)建立脂肪变性肝细胞模型，使用不同浓度槲皮素(5、10、20和40 μmol/L)干预脂肪变性的HHL-5细胞24 h

实验分为(

=3)：对照组、PA组、PA+QUE5组、PA+QUE10组、PA+QUE20组、PA+QUE40组。为明确自噬对QUE作用的影响，利用3-甲基腺嘌呤(3-methyladenine，3-MA)阻断自噬，将HHL-5细胞分为(

=3)：对照组、PA组、PA+QUE40组、3-MA组、PA+3-MA组和PA+3-MA+QUE40组。2种不同实验分组均检测细胞内甘油三酯含量、脂滴蓄积情况、脂解和脂噬相关分子表达情况及共定位水平、自噬底物P62的表达水平。

结果

与对照组比较，PA组肝细胞的甘油三酯含量和脂质蓄积程度明显升高，脂解相关分子脂肪甘油三酯脂肪酶(adipose triglycerides lipase，ATGL)和比较基因识别因子58(comparative gene identification-58，CGI58)，以及脂噬相关分子Ras相关蛋白7(Ras-related protein 7

RAB7)和微管相关蛋白1B轻链3(microtubule-associated protein 1 light chain 3

LC3β)的蛋白表达水平、平均荧光强度及共定位程度均明显降低，而P62表达增强(

＜0.05)。与PA组相比，PA+QUE40组的甘油三酯含量和脂质蓄积程度显著降低，脂解和脂噬相关分子的蛋白表达水平、平均荧光强度及共定位程度也明显增加，而P62明显降低(

＜0.05)。在脂肪变性肝细胞中加入3-MA抑制自噬后，QUE对脂肪变性肝细胞的脂质蓄积的改善作用以及对脂解和脂噬相关分子的调控作用基本被抵消。

结论

槲皮素可促进脂解和脂噬途径相关分子的表达及相互作用，从而减轻脂肪变性HHL-5细胞内的脂质蓄积，但以上作用可被自噬阻断剂3-MA削弱。

Abstract

Objective

To investigate the effect and mechanism of quercetin (QUE) in improving lipid accumulation in hepatocytes by regulating lipolysis and lipophagy pathway.

Methods

The human hepatocyte cell line 5 (HHL-5) was induced by palmitic acid (PA) to establish a steatogenic hepatocyte model. Quercetin at different concentrations (5

20 and 40 μmol/L) has been utilized to interfere with HHL-5 cells for 24 h

and the experiment was divided into six groups: control group

PA group

PA+QUE5 group

PA+QUE10 group

PA+QUE20 groupand PA+QUE40 group. In order to determine the influence of lipophagy on QUE effect

3-methyladenine (3-MA) was used to block autophagy

and HHL-5 cells were divided into the control

PA+QUE40

3-MA

PA+3-MA and PA+3-MA+QUE40 groups. The contents of triglyceride (TG)

accumulations of lipid droplets

expression of lipolysis and lipophagy related molecules

and degree of co-localization

and expression level of substrate of autophagy P62 were detected in above 2 types of experimental groups.

Results

Compared with the control group

the TG content and the lipid accumulation were significantly increased

the protein levels

average fluorescence intensities and colocalization degree of lipolysis related molecules adipose triglycerides lipase(ATGL) and comparative gene identification-58(CGI58)

and lipophagy related molecules Ras-related protein 7(RAB7) and microtubule-associated protein 1 light chain 3 beta (LC3β) were significantly decreased

while the expression of P62 was enhanced in HHL-5 cells in the PA group (all

0.05). Compared with the PA group

the triglyceride content and the degree of lipid accumulation in the PA+QUE40 group were significantly decreased

and the protein expression level

average fluorescence intensity and co-localization degree of lipolysis and lipophagy related molecules were significantly increased

while P62 was significantly decreased (

0.05). When 3-MA was added to the s

teatogenic hepatocytes to inhibit autophagy

the improvement effect of QUE on lipid accumulation and the regulation of lipolysis and liphagy related molecules in steatogenic hepatocytes were neutralized.

Conclusion

QUE alleviates lipid accumulation in HHL-5 cells by promoting the expression and interaction of molecules related to lipolysis and lipophagy pathways. However

these effects can be weakened by the autophagy inhibitor 3-MA.

关键词

Keywords

references

YOUNOSSI Z M, GOLABI P, PAIK J M, et al . The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review[J ] . Hepatology, 2023, 77(4): 1335-1347. DOI: 10.1097/HEP.0000000000000004.

CHO C H, PATEL S, RAJBHANDARI P. Adipose tissue lipid metabolism: lipolysis[J]. Curr Opin Genet Dev, 2023, 83: 102114. DOI: 10.1016/j.gde.2023.102114.

SATHYANARAYAN A, MASHEK M T, MASHEK D G. ATGL promotes autophagy/lipophagy via SIRT1 to control hepatic lipid droplet catabolism[J]. Cell Rep, 2017, 19(1): 1-9. DOI: 10.1016/j.celrep.2017.03.026.

FENG S, SUN Z A, JIA X, et al . Lipophagy: molecular mechanisms and implications in hepatic lipid metabolism[J ] . Front Biosci, 2023, 28(1): 6. DOI: 10.31083/j.fbl2801006.

KOBORI M, MASUMOTOS, AKIMOTO Y, et al . Chronic dietary intake of quercetin alleviates hepatic fat accumulation associated with consumption of a Western-style diet in C57/BL6J mice[J ] . Mol Nutr Food Res, 2011, 55(4): 530-540. DOI: 10.1002/mnfr.201000392.

ZHU X H, XIONG T, LIU P Y, et al . Quercetin ameliorates HFD-induced NAFLD by promoting hepatic VLDL assembly and lipophagy via the IRE1a/XBP1s pathway[J ] . Food Chem Toxicol, 2018, 114: 52-60. DOI: 10.1016/j.fct.2018.02.019.

PORRAS D, NISTAL E, MARTÍNEZ-FLÓREZ S, et al . Functional interactions between gut microbiota transplantation, quercetin, and high-fat diet determine non-alcoholic fatty liver disease development in germ-free mice[J ] . Mol Nutr Food Res, 2019, 63(8): e1800930. DOI: 10.1002/mnfr.201800930.

ZHANG M, XIE Z K, GAO W N, et al . Quercetin regulates hepatic cholesterol metabolism by promoting cholesterol-to-bile acid conversion and cholesterol efflux in rats[J ] . Nutr Res, 2016, 36(3): 271-279. DOI: 10.1016/j.nutres.2015.11.019.

MOMCHILOVA A, NIKOLAEV G, PANKOV S, et al . Effect of quercetin and fingolimod, alone or in combination, on the sphingolipid metabolism in HepG2 cells[J ] . Int J Mol Sci, 2022, 23(22): 13916. DOI: 10.3390/ijms232213916.

GUAN H, ZHANG W Y, LIU H, et al . Quercetin induces apoptosis in HepG2 cells via directly interacting with YY1 to disrupt YY1-p53 interaction[J ] . Metabolites, 2023, 13(2): 229. DOI: 10.3390/metabo13020229..

MOON J, DO H J, KIM O Y, et al . Antiobesity effects of quercetin-rich onion peel extract on the differentiation of 3T3-L1 preadipocytes and the adipogenesis in high fat-fed rats[J ] . Food Chem Toxicol, 2013, 58: 347-354. DOI: 10.1016/j.fct.2013.05.006.

OHMAE S, AKAZAWA S, TAKAHASHI T, et al . Quercetin attenuates adipogenesis and fibrosis in human skeletal muscle[J ] . Biochem Biophys Res Commun, 2022, 615: 24-30. DOI: 10.1016/j.bbrc.2022.05.033.

GNONI A,DI CHIARA STANCA B, GIANNOTTI L, et al . Quercetin reduces lipid accumulation in a cell model of NAFLD by inhibiting de novo fatty acid synthesis through the acetyl-CoA carboxylase 1/AMPK/PP2A axis[J ] . Int J Mol Sci, 2022, 23(3): 1044. DOI: 10.3390/ijms23031044..

FUKAYA M, SATO Y, KONDO S, et al . Quercetin enhances fatty acid β-oxidation by inducing lipophagy in AML12 hepatocytes[J ] . Heliyon, 2021, 7(6): e07324. DOI: 10.1016/j.heliyon.2021.e07324.

SCHOTT M B, WELLER S G, SCHULZE R J, et al . Lipid droplet size directs lipolysis and lipophagy catabolism in hepatocytes[J ] . J Cell Biol, 2019, 218(10): 3320-3335. DOI: 10.1083/jcb.201803153.

WANG Z Y, XUE C Y, WANG X, et al . Quercetin 3-O-glucuronide-rich lotus leaf extract promotes a Brown-fat-phenotype in C 3 H 10 T 1/2 mesenchymal stem cells[J ] . Food Res Int, 2023, 163: 112198. DOI: 10.1016/j.foodres.2022.112198..

KONG L, ZHANG W K, LIU S S, et al . Quercetin, engelitin and caffeic acid of Smilax China L. polyphenols, stimulate 3T3-L1 adipocytes to brown-like adipocytes via β3-AR/AMPK signaling pathway[J ] . Plant Foods Hum Nutr, 2022, 77(4): 529-537. DOI: 10.1007/s11130-022-00996-x..

SEO Y S, KANG O H, KIM S B, et al . Quercetin prevents adipogenesis by regulation of transcriptional factors and lipases in OP9 cells[J ] . Int J Mol Med, 2015, 35(6): 1779-1785. DOI: 10.3892/ijmm.2015.2185.

BABA T, TOTH D J, SENGUPTA N, et al . Phosphatidylinositol 4,5-bisphosphate controls Rab7 and PLEKHM1 membrane cycling during autophagosome-lysosome fusion[J ] . EMBO J, 2019, 38(8): e100312. DOI: 10.15252/embj.2018100312.

KRAFT C, PETER M, HOFMANN K. Selective autophagy: ubiquitin-mediated recognition and beyond[J]. Nat Cell Biol, 2010, 12(9): 836-841. DOI: 10.1038/ncb0910-836.

LIN H K, GUO X P, LIU J J, et al . Improving lipophagy by restoring Rab7 cycle: protective effects of quercetin on ethanol-induced liver steatosis[J ] . Nutrients, 2022, 14(3): 658. DOI: 10.3390/nu14030658.

KAUSHIK S, CUERVO A M. Degradation of lipid droplet-associated proteins by chaperone-mediated autophagy facilitates lipolysis[J]. Nat Cell Biol, 2015, 17(6): 759-770. DOI: 10.1038/ncb3166.

GUO Y, MAH E, BRUNO R S. Quercetin bioavailability is associated with inadequate plasma vitamin C status and greater plasma endotoxin in adults[J]. Nutrition, 2014, 30 (11/12): 1279-1286. DOI: 10.1016/j.nut.2014.03.032.

KAUSHIK S, CUERVO A M. AMPK-dependent phosphorylation of lipid droplet protein PLIN2 triggers its degradation by CMA[J]. Autophagy, 2016, 12(2): 432-438. DOI: 10.1080/15548627.2015.1124226.

MARTINEZ-LOPEZ N, GARCIA-MACIA M, SAHU S, et al . Autophagy in the CNS and periphery coordinate lipophagy and lipolysis in the brown adipose tissue and liver[J ] . Cell Metab, 2016, 23(1): 113-127. DOI: 10.1016/j.cmet.2015.10.008.

LUO D L, CHEN S S, WANG X X, et al . Unraveling the mechanism of quercetin alleviating perfluorooctane sulfonate-induced apoptosis in grass carp ( Ctenopharyngodon idellus) hepatocytes: AMPK/mTOR-mediated mitophagy[J ] . Aquat Toxicol, 2023, 265: 106769. DOI: 10.1016/j.aquatox.2023.106769..

YANG T T, WANG Y Y, CAO X Y, et al . Targeting mTOR/YY1 signaling pathway by quercetin through CYP7A1-mediated cholesterol-to-bile acids conversion alleviated type 2 diabetes mellitus induced hepatic lipid accumulation[J ] . Phytomedicine, 2023, 113: 154703. DOI: 10.1016/j.phymed.2023.154703.

UNGURIANU A, ZANFIRESCU A, MARGINǍ D. Exploring the therapeutic potential of quercetin: a focus on its sirtuin-mediated benefits[J]. Phytother Res, 2024, 38(5): 2361-2387. DOI: 10.1002/ptr.8168.

WAN Q Z, TANG L S, JIN K L, et al . Quercetin and tanshinone prevent mitochondria from oxidation and autophagy to inhibit KGN cell apoptosis through the SIRT1/SIRT3-FOXO3a axis[J ] . Cell Mol Biol, 2024, 70(2): 257-263. DOI: 10.14715/cmb/2024.70.2.36.

Views

180

下载量

CSCD

Alert me when the article has been cited

提交

Tools

Publicity Resources

Resveratrol promotes hepatic lipid decomposition by regulating ATGL/CGI58 and Rab7/LC3β through perilipin 2

Target prediction and preliminary validation of quercetin in treatment of endometriosis

Quercetin inhibits ferroptosis to alleviate intestinal ischemia-reperfusion injury

Quercetin protects H9C2 cells against hypoxia injury through MAPK/ERK1/2 signal pathway

Effects and mechanism of quercetin on neuropathic pain in chronic constriction injury rats

Related Author

糜漫天

秦玉

张艳

杨依林

ZHANG Yi

WU Lulu

TANG Li

CUI Jiao

Related Institution

the Second Affiliated Hospital of Hunan University of Chinese Medicine

the Central Hospital of Wuhan， Tongji Medical College， Huazhong University of Science and Technology

Rocket Force Medical Center of PLA

First Clinical Medical College of Lanzhou University

Department of Anesthesiology and Surgery， the First Hospital of Lanzhou University

⁰