Genistein upregulates LDLR levels via JNK-mediated activation of SREBP-2

Kartawijaya, Medicia; Han, Hye Won; Kim, Yunhye; Lee, Seung Min

doi:10.3402/fnr.v60.31120

Cited by 16 publications

(15 citation statements)

References 41 publications

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“…Furthermore, the cause of familial hypercholesterolemia has been proved to be the LDLR gene mutation‐induced reduction of LDLR activity (Bertolini, Pisciotta, Fasano, Rabacchi, & Calandra, ). Previous study showed that isoflavones could exert hypolipidemic effects through increasing the mRNA and protein levels of LDLR and HMGCR via the activation of SREBP‐2 (Mullen, Brown, Osborne, & Shay, ; Kartawijaya et al., ). In consistent with the previous researches, our data showed that genistein significantly increased both the mRNA and the protein levels of SREBP‐2 even only at the dosage of 0.01 µM.…”

Section: Discussionmentioning

confidence: 99%

“…We previously showed that genistein had benefits on plasma and hepatic lipid metabolism in high-fat-diet induced nonalcoholic steatohepatitis (NASH) rats through modulating the key transcription factors, including SREBP, PPAR, and AMPK (Liu, Zhong, Yin, & Jiang, 2017). Several mechanisms have been reported to explain the effect of genistein on lowering plasma cholesterol, including cholesterol synthesis, cholesterol esterification, fatty acid synthesis and fatty acid oxidation in vitro and in vivo (Borradaile, de Dreu, Wilcox, Edwards, & Huff, 2002;Shin et al, 2007;Kartawijaya et al, 2016). Nevertheless, the effects of genistein on cholesterol absorption and cholesterol efflux have not been identified yet.…”

Section: Introductionmentioning

confidence: 99%

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Effect of Genistein on Cholesterol Metabolism‐Related Genes in HepG2 Cell

Zheng

Yin

et al. 2019

Journal of Food Science

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It has been reported that genistein could improve metabolic syndromes. Our study aimed to investigate the effects and potential mechanisms of genistein on improving cholesterol metabolism in HepG2 cell. HepG2 cells were cultured with 0, 0.01, 1.00, 10.00, and 50.00 µM genistein for 24 hr. The current results showed a dose‐dependent manner between genistein and intracellular contents of total cholesterol (TC), high‐density lipoprotein‐cholesterol (HDL‐C), and cellular apolipoprotein A1 (Apo‐A1) secretion. TC was increased by 25.69%, meanwhile HDL‐C and Apo‐A1 were decreased by 56.00% and 25.93%, respectively, when the dosage of genistein was 1.00 µM. Genistein dose‐dependently upregulated the protein and mRNA levels of sterol regulatory element binding proteins‐2 (SREBP‐2), as well as the mRNA levels of low‐density lipoprotein receptor (LDLR) and 3‐hydroxy‐3‐methyl glutaryl coenzyme A reductase (HMGCR), by 145.91%, 72.29%, 310.23%, and 123.08%, respectively, when we gave 1.00 µM genistein, indicating that intracellular cholesterol synthesis and absorption of exogenous cholesterol were increased. In addition, the mRNA levels of peroxisome proliferator‐activated receptor‐γ (PPARγ) and liver X receptor (LXRα), lowered by 58.23% and 34.86% at 0.01 µM genistein, were reduced in a dose‐dependent manner. LXRα and ATP‐binding cassette transporter A1 (ABCA1) protein levels were significantly (P < 0.05) decreased by 50.35% and 11.60% at 1.00 µM genistein, which indicated that cellular cholesterol efflux was inhibited. Taken together, our results suggested that genistein at dosage of more than 1.00 µM was able to increase the intracellular cholesterol levels by up regulating SREBP‐2/LDLR/HMGCR pathway and suppressing PPARγ/LXRα/ABCA1 pathway. Practical Application In this study, genistein appeared to be effective in reducing plasma cholesterol levels due to increase the intracellular cholesterol levels by upregulating cholesterol absorption through SREBP‐2/LDLR/HMGCR pathway, and also downregulating cholesterol efflux via PPARγ/LXRα/ABCA1 pathway in vitro. In addition, plasma cholesterol is regarded as the key indicator of atherosclerosis; therefore, we believe that our findings could be used for further exploration on a possible therapeutic application of genistein for atherosclerosis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effect of Genistein on Cholesterol Metabolism‐Related Genes in HepG2 Cell

Zheng

Yin

et al. 2019

Journal of Food Science

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“…LDLR is the protein responsible for the uptake of extracellular LDL-cholesterol and plays an important role in maintaining the cholesterol metabolism. Additionally, LDLR genes are also regulated by the same transcription factor SREBP-2 (Kartawijaya et al, 2016;Rice et al, 2014). Thus, the role of the SREBP-2-LDLR pathway in the hypercholesterolemic effect of BPA is needed to be further studied.…”

Section: Discussionmentioning

confidence: 99%

Bisphenol A induces cholesterol biosynthesis in HepG2 cells via SREBP-2/HMGCR signaling pathway

Zhang

Zou

et al. 2019

J. Toxicol. Sci.

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-Bisphenol A (BPA), an environmental chemical to which humans are commonly exposed, has been shown to increase cholesterol level but the molecular mechanism is not clear. Since cholesterol biosynthesis plays an important role in elevating cholesterol level, the aim of the present study is to explore the effects of BPA on cholesterol biosynthesis in HepG2 cells and its possible mechanisms. HepG2 cells were treated with different concentrations of BPA for 24 hr, the total cholesterol level and the activity of 3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) were measured using commercial enzymatic assay kits, and the mRNA and protein expression levels of sterol regulatory element binding protein-2(SREBP-2) and HMGCR were analyzed by qPCR, Western blotting and immunofluorescence, respectively. After treating HepG2 cells with different concentrations (0.1 nM~10 µM) of BPA for 24 hr, we found that BPA at the environmentally relevant concentrations of 1 nM and 10 nM significantly increased the total cholesterol content, the activity and expression of HMGCR in HepG2 cells, but at 100 nM, 1 µM and 10 µM doses, BPA had no stimulatory effect on cholesterol biosynthesis. The whole doseresponse relationship follows non-monotonic dose responses, such as an inverted U-shape. Using human SREBP-2 small interfering RNA, we further discovered that the stimulatory effects of BPA on cholesterol biosynthesis and HMGCR expression could be prevented by blockade of the SREBP-2 pathway. This study provides important implications for understanding the potential lipotoxicity of BPA exposure, and it also indicates that low-dose BPA induces hepatic cholesterol biosynthesis through upregulating the SREBP-2/HMGCR signaling pathway.

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“…SREBP-1c (SREBF-1) and its target gene FAS could regulate the biosynthesis of fatty acids, further influencing the biosynthesis of TGs (Dentin et al, 2005). SREBP-2 (SREBF-2) and its related gene LDLR involved in cholesterol uptake (Kartawijaya et al, 2016). The target PPARa and its related genes LXRa, CYP7A1, and ABCA1 played a regulatory role in the process in the transformation of cholesterol into bile acids and cholesterol efflux (Wang et al, 2001;Basso et al, 2003;Cao et al, 2012;Ramakrishna et al, 2017).…”

Section: C-t-p Networkmentioning

confidence: 99%

Investigation of the Lipid-Lowering Mechanisms and Active Ingredients of Danhe Granule on Hyperlipidemia Based on Systems Pharmacology

Chen

Yan

et al. 2020

Front. Pharmacol.

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Objective: Investigate the active ingredients and underlying hypolipidemic mechanisms of Danhe granule (DHG). Methods: The lipid-lowering effect of DHG was evaluated in hyperlipidemic hamsters induced by a high-fat diet. The ingredients absorbed into the blood after oral administration of DHG in hamsters were identified by ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF/MS). A systems pharmacology approach incorporating target prediction and network construction, gene ontology (GO) enrichment and pathway analysis was performed to predict the active compounds and map the compounds-targets-disease network. Real-time polymerase chain reaction (RT-PCR) and Western blot were utilized to analyze the mRNA and protein expression levels of predicted targets. Results: DHG remarkably lowered the levels of serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-c), and arteriosclerosis index (AI), at the same time, elevated the levels of serum high-density lipoprotein cholesterol (HDL-c) and HDL-c/TC ratio in hyperlipidemic hamsters. Sixteen ingredients absorbed into blood after oral administration of DHG were identified as the possible components interacted with targets. Moreover, 65 potential targets were predicted after targets intersection and compounds-targets-disease network mapping. Then, compounds-targets-pathways network mapping revealed that six active compounds (emodin, naringenin, etc.) compounds could interact with 10 targets such as sterol regulatory element binding protein (SREBP) 1c, SREBP-2 and peroxisome proliferation-activated receptor (PPAR) a, regulate three lipid metabolism-related pathways including SREBP control of lipid synthesis pathway, PPAR signaling pathway and nuclear receptors in lipid metabolism and toxicity pathway, and further affect lipid metabolic processes including fatty acid biosynthesis, low-density lipoprotein receptor (LDLR)-mediated cholesterol uptake, bile acid biosynthesis, and cholesterol efflux. Experimental results indicated that DHG significantly increased SREBP-2, LDLR, PPARa, liver X receptor alpha (LXRa),

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Genistein upregulates LDLR levels via JNK-mediated activation of SREBP-2

Cited by 16 publications

References 41 publications

Effect of Genistein on Cholesterol Metabolism‐Related Genes in HepG2 Cell

Effect of Genistein on Cholesterol Metabolism‐Related Genes in HepG2 Cell

Bisphenol A induces cholesterol biosynthesis in HepG2 cells via SREBP-2/HMGCR signaling pathway

Investigation of the Lipid-Lowering Mechanisms and Active Ingredients of Danhe Granule on Hyperlipidemia Based on Systems Pharmacology

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