Journal
JOURNAL OF LIPID RESEARCH
Volume 45, Issue 1, Pages 106-112Publisher
ELSEVIER
DOI: 10.1194/jlr.M300179-JLR200
Keywords
apolipoprotein; liver; mitogen-activated protein kinase; early growth response factor 1; hepatocyte nuclear factor-3 beta
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Funding
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [K08HL003209] Funding Source: NIH RePORTER
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We have previously shown that 17-beta-estradiol (E-2) and genistein increase the expression of apolipoprotein A-I (apoA-I), the major protein component of HDL, in Hep G2 cells. To elucidate the mechanism mediating the increase in apoA-I gene expression by these compounds, plasmid constructs containing serial deletions of the apoA-I promoter region were generated. The smallest region maintaining response to E2 and genistein spanned the -220 to -148 sequence, and the estrogen antagonist 10182,780 completely inhibited the E2 and genistein effect. Nuclear extracts from cells treated with E2 and genistein showed increased binding to site B oligonucleotide (-169 to -146), and nuclear extracts from genistein-treated cells showed increased binding to an early growth response factor I (Egr-1) oligonucleotide compared to control cells. An increase in the concentrations of Egr-1 and hepatocyte nuclear factor-3beta was observed in nuclear extracts of cells treated with both compounds compared to control cells. Treatment with a specific inhibitor of mitogen-activated protein (MAP) kinase, but not with other inhibitors, abolished the stimulation of apoA-I gene expression by E2 and genistein. EM These results indicate that the MAP kinase pathway is involved in the regulation of apoA-I gene expression by genistein and E2, possibly through downstream regulation of transcription factors binding to the promoter region.
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