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


CONCLUSIONS
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.
Xie
Zuo-quan
ZQ
State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
Liang
Gai
G
Zhang
Lu
L
Wang
Qi
Q
Qu
Yi
Y
Gao
Yang
Y
Lin
Li-bo
LB
Ye
Sai
S
Zhang
Ji
J
Wang
Hui
H
Zhao
Guo-ping
GP
Zhang
Qing-hua
QH
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D002784:Cholesterol / Q000032:analysis* / Q000096:biosynthesis / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D020441:Ginkgo biloba; D022781:Hepatocytes / Q000737:chemistry / Q000187:drug effects*; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D008148:Lovastatin / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D010936:Plant Extracts / Q000494:pharmacology*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D000924:Anticholesteremic Agents; D010936:Plant Extracts; D002784:Cholesterol; D008148:Lovastatin; D006903:Hydroxymethylglutaryl CoA Reductases
Pharmacol Ther. 2002 Nov-Dec;96(2-3):67-202
12453566
J Lipid Res. 1979 Jul;20(5):588-93
158623
FEBS Lett. 2006 Jun 26;580(15):3571-81
16750200
Acta Pharmacol Sin. 2008 Sep;29(9):1042-50
18718173
Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12027-32
14512514
Nucleic Acids Res. 2002 Feb 15;30(4):e15
11842121
J Nutr Biochem. 2004 Dec;15(12):749-56
15607648
Blood. 2006 Feb 15;107(4):1582-90
16249384
Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):12753-8
12242332
Atherosclerosis. 2007 Jun;192(2):438-44
17397850
Toxicol Appl Pharmacol. 2006 Feb 1;210(3):225-35
15975614
Biochem Biophys Res Commun. 2006 Jun 2;344(2):562-70
16620784
Mol Cell. 2000 Sep;6(3):517-26
11030332
Curr Opin Lipidol. 2004 Jun;15(3):287-95
15166784
J Lipid Res. 2006 Feb;47(2):421-30
16264196
Biochimie. 2004 Nov;86(11):839-48
15589694
J Herb Pharmacother. 2004;4(4):13-26
15927922
Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12197-202
12213959
Proc Natl Acad Sci U S A. 2005 May 24;102(21):7653-8
15894607
J Cell Biochem. 2002;85(3):572-82
11967997
Anal Bioanal Chem. 2007 Sep;389(1):171-8
17534610
J Cardiovasc Nurs. 2002 Jul;16(4):21-32
12597260
Curr Alzheimer Res. 2007 Jul;4(3):253-62
17627482
Acta Pharmacol Sin. 2006 Sep;27(9):1137-45
16923333
Phytother Res. 2001 Aug;15(5):449-51
11507743
Biosci Biotechnol Biochem. 1995 Apr;59(4):595-601
7772823
Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6577-80
11381109
Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5116-21
11309499
FEBS J. 2009 Mar;276(5):1450-8
19187224
Acta Pharmacol Sin. 2004 Oct;25(10):1306-11
15456532
J Biochem Mol Biol. 2007 Sep 30;40(5):678-83
17927900