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Molecular mechanisms underlying the cholesterol-lowering effect of Ginkgo biloba extract in hepatocytes: a comparative study with lovastatin.

Xie ZQ, Liang G, Zhang L, Wang Q, Qu Y, Gao Y, Lin LB, Ye S, Zhang J, Wang H, Zhao GP, Zhang QH - Acta Pharmacol. Sin. (2009)

Bottom Line: In addition, GBE decreased cholesterol influx, whereas lovastatin increased cholesterol influx.GBE treatment induced significant increases in the expression of cholesterogenic genes and genes involved in cholesterol metabolism, such as SREBF2, as determined by cDNA microarray and real-time RT-PCR.Specifically, we demonstrated that GBE exhibited dual effects on the cellular cholesterol pool by modulating both HMG-CoA reductase activity and inhibiting cholesterol influx.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.

ABSTRACT

Aim: To explore the molecular mechanisms underlying the cholesterol-lowering effect of a Ginkgo biloba extract (GBE).

Methods: Enzyme activity, cholesterol flux and changes in gene expression levels were assessed in cultured hepatocytes treated with GBE or lovastatin.

Results: GBE decreased the total cholesterol content in cultured hepatocytes and inhibited the activity of HMG-CoA reductase, as determined by an in vitro enzyme activity assay. In addition, GBE decreased cholesterol influx, whereas lovastatin increased cholesterol influx. GBE treatment induced significant increases in the expression of cholesterogenic genes and genes involved in cholesterol metabolism, such as SREBF2, as determined by cDNA microarray and real-time RT-PCR. Furthermore, INSIG2, LDLR, LRP1, and LRP10 were differentially regulated by GBE and lovastatin. The data imply that the two compounds modulate cholesterol metabolism through distinct mechanisms.

Conclusion: By using a gene expression profiling approach, we were able to broaden the understanding of the molecular mechanisms by which GBE lowers cellular cholesterol levels. Specifically, we demonstrated that GBE exhibited dual effects on the cellular cholesterol pool by modulating both HMG-CoA reductase activity and inhibiting cholesterol influx.

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Related in: MedlinePlus

Ideogram illustration of the gene regulation networks underlying the cholesterol-lowering effect of GBE and lovastatin treatment in HepG2 cells. (A) GBE treatment. (B) Lovastatin treatment. The genes in green were down-regulated, while the genes in red were over-expressed, the yellow color represents genes that were not significantly changed, the red arrows indicated stimulation, the green line with block represents negative regulation. The following theme is proposed: lovastatin lowers cellular cholesterol content by inhibiting de novo biosynthesis by modulating the expression of the rate limiting enzyme, HMGCR, and inducing adaptive responses, such as the over expression of genes involved in cholesterol endogenous biosynthesis and cholesterol influx, and the down-regulation of genes related to cholesterol catabolism into bile acids, which are required for the maintenance of the homeostasis of cellular cholesterol. With respect to molecular mechanisms downstream of GBE treatment, in addition to inhibiting HMGCR, cholesterol influx was also inhibited and related gene expression changes were demonstrated.
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fig6: Ideogram illustration of the gene regulation networks underlying the cholesterol-lowering effect of GBE and lovastatin treatment in HepG2 cells. (A) GBE treatment. (B) Lovastatin treatment. The genes in green were down-regulated, while the genes in red were over-expressed, the yellow color represents genes that were not significantly changed, the red arrows indicated stimulation, the green line with block represents negative regulation. The following theme is proposed: lovastatin lowers cellular cholesterol content by inhibiting de novo biosynthesis by modulating the expression of the rate limiting enzyme, HMGCR, and inducing adaptive responses, such as the over expression of genes involved in cholesterol endogenous biosynthesis and cholesterol influx, and the down-regulation of genes related to cholesterol catabolism into bile acids, which are required for the maintenance of the homeostasis of cellular cholesterol. With respect to molecular mechanisms downstream of GBE treatment, in addition to inhibiting HMGCR, cholesterol influx was also inhibited and related gene expression changes were demonstrated.

Mentions: Genes involved in cholesterol influx, such as the LDL receptor (LDLR), the scavenger receptor class B member 1 (SCARB1) and Niemann-Pick C1-like protein 1 (NPC1L1), were all upregulated by GBE and lovastatin. However, LDL-related protein 1 (LRP1) was downregulated. Lovastatin upregulated LDLR, but downregulated LRP1 expression to a greater extent than GBE (Figure 4C). Cholesterol efflux-related genes, such as transporter genes, ATP-binding cassette 1 (ABCA1), ATP-binding cassette 5 (ABCG5), ATP-binding cassette 8 (ABCG8), microsomal triglyceride transfer protein (MTTP) and apolipoprotein B 100 (APOB100), were not significantly regulated. However, the cholesterol efflux gene apolipoprotein A–I (APOA1) was upregulated by both GBE and lovastatin (Figure 3D, Figure 6).


Molecular mechanisms underlying the cholesterol-lowering effect of Ginkgo biloba extract in hepatocytes: a comparative study with lovastatin.

Xie ZQ, Liang G, Zhang L, Wang Q, Qu Y, Gao Y, Lin LB, Ye S, Zhang J, Wang H, Zhao GP, Zhang QH - Acta Pharmacol. Sin. (2009)

Ideogram illustration of the gene regulation networks underlying the cholesterol-lowering effect of GBE and lovastatin treatment in HepG2 cells. (A) GBE treatment. (B) Lovastatin treatment. The genes in green were down-regulated, while the genes in red were over-expressed, the yellow color represents genes that were not significantly changed, the red arrows indicated stimulation, the green line with block represents negative regulation. The following theme is proposed: lovastatin lowers cellular cholesterol content by inhibiting de novo biosynthesis by modulating the expression of the rate limiting enzyme, HMGCR, and inducing adaptive responses, such as the over expression of genes involved in cholesterol endogenous biosynthesis and cholesterol influx, and the down-regulation of genes related to cholesterol catabolism into bile acids, which are required for the maintenance of the homeostasis of cellular cholesterol. With respect to molecular mechanisms downstream of GBE treatment, in addition to inhibiting HMGCR, cholesterol influx was also inhibited and related gene expression changes were demonstrated.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4007179&req=5

fig6: Ideogram illustration of the gene regulation networks underlying the cholesterol-lowering effect of GBE and lovastatin treatment in HepG2 cells. (A) GBE treatment. (B) Lovastatin treatment. The genes in green were down-regulated, while the genes in red were over-expressed, the yellow color represents genes that were not significantly changed, the red arrows indicated stimulation, the green line with block represents negative regulation. The following theme is proposed: lovastatin lowers cellular cholesterol content by inhibiting de novo biosynthesis by modulating the expression of the rate limiting enzyme, HMGCR, and inducing adaptive responses, such as the over expression of genes involved in cholesterol endogenous biosynthesis and cholesterol influx, and the down-regulation of genes related to cholesterol catabolism into bile acids, which are required for the maintenance of the homeostasis of cellular cholesterol. With respect to molecular mechanisms downstream of GBE treatment, in addition to inhibiting HMGCR, cholesterol influx was also inhibited and related gene expression changes were demonstrated.
Mentions: Genes involved in cholesterol influx, such as the LDL receptor (LDLR), the scavenger receptor class B member 1 (SCARB1) and Niemann-Pick C1-like protein 1 (NPC1L1), were all upregulated by GBE and lovastatin. However, LDL-related protein 1 (LRP1) was downregulated. Lovastatin upregulated LDLR, but downregulated LRP1 expression to a greater extent than GBE (Figure 4C). Cholesterol efflux-related genes, such as transporter genes, ATP-binding cassette 1 (ABCA1), ATP-binding cassette 5 (ABCG5), ATP-binding cassette 8 (ABCG8), microsomal triglyceride transfer protein (MTTP) and apolipoprotein B 100 (APOB100), were not significantly regulated. However, the cholesterol efflux gene apolipoprotein A–I (APOA1) was upregulated by both GBE and lovastatin (Figure 3D, Figure 6).

Bottom Line: In addition, GBE decreased cholesterol influx, whereas lovastatin increased cholesterol influx.GBE treatment induced significant increases in the expression of cholesterogenic genes and genes involved in cholesterol metabolism, such as SREBF2, as determined by cDNA microarray and real-time RT-PCR.Specifically, we demonstrated that GBE exhibited dual effects on the cellular cholesterol pool by modulating both HMG-CoA reductase activity and inhibiting cholesterol influx.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.

ABSTRACT

Aim: To explore the molecular mechanisms underlying the cholesterol-lowering effect of a Ginkgo biloba extract (GBE).

Methods: Enzyme activity, cholesterol flux and changes in gene expression levels were assessed in cultured hepatocytes treated with GBE or lovastatin.

Results: GBE decreased the total cholesterol content in cultured hepatocytes and inhibited the activity of HMG-CoA reductase, as determined by an in vitro enzyme activity assay. In addition, GBE decreased cholesterol influx, whereas lovastatin increased cholesterol influx. GBE treatment induced significant increases in the expression of cholesterogenic genes and genes involved in cholesterol metabolism, such as SREBF2, as determined by cDNA microarray and real-time RT-PCR. Furthermore, INSIG2, LDLR, LRP1, and LRP10 were differentially regulated by GBE and lovastatin. The data imply that the two compounds modulate cholesterol metabolism through distinct mechanisms.

Conclusion: By using a gene expression profiling approach, we were able to broaden the understanding of the molecular mechanisms by which GBE lowers cellular cholesterol levels. Specifically, we demonstrated that GBE exhibited dual effects on the cellular cholesterol pool by modulating both HMG-CoA reductase activity and inhibiting cholesterol influx.

Show MeSH
Related in: MedlinePlus