Estrogen Suppresses Transcription of Lipoprotein Lipase Gene

Abstract

Estrogen exerts a variety of effects not only on female reproductive organs but also on nonreproductive organs, including adipose tissue. Estrogen inhibits obesity triggered by ovariectomy in rodents. We studied the mechanism underlying this estrogen-dependent inhibition of obesity. Estrogen markedly decreased the amounts of fat accumulation and lipoprotein lipase (LPL) mRNA as well as triglyceride accumulation in genetically manipulated 3T3-L1 adipocytes stably expressing the estrogen receptor (ER). A pLPL(1980)-CAT construct, along with an ER expression vector, was introduced into differentiated 3T3-L1 cells, and CAT activities were determined. ER, mostly ligand-dependently, inhibited the basal LPL promoter activity by 7-fold. We searched the LPL promoter for an estrogen-responsive suppressive element by employing a set of 5-deletion mutants of the pLPL-CAT reporter. Although there was no classical estrogen response element, it was demonstrated that an AP-1-like TGAATTC sequence located at (؊1856/؊1850) was responsible for the suppression of the LPL gene transcription by estrogen. An electrophoretic mobility shift assay probed with the TGAATTC sequence demonstrated formation of a specific DNAnuclear protein complex. Interestingly, this complex was not affected by the addition of any antibodies against ER, c-Jun, c-Fos, JunB, or JunD. Because this TGAATTC element responded to phorbol ester and overexpression of CREB-binding protein abrogated the suppressive effect of estrogen on the LPL promoter, we conclude that a unique protein that is related to the AP-1 transcription factor families may be involved in the complex that binds to the TGAATTC element.

Exposure of KS483 Cells to Estrogen Enhances Osteogenesis and Inhibits Adipogenesis

“…These results are in agreement with observations in animal models of ovariectomy, ER␣ knockout and aromatase-deficient (8,9,11,12) and estrogen-deficient women. (38) KS483 is a fetal mouse calvaria-derived clonal cell line committed to the osteoblast lineage.…”

“…(19) Two types of ERs, namely, ER␣ and ER␤, mediate the biological effects of estrogen in target tissues including bone (1,20,21) and adipose tissue. (8,11,12) Both receptors can form heterodimers within the target cells and ER␤ modulates ER␣ transcriptional activity. (22,23) Furthermore, ER␤2, a splice variant of ER␤, can function as a negative regulator of estrogen action.…”

“…(15)(16)(17)(18) In addition, adipocyte protein 2 (aP2) and LPL also are markers for adipocytes. (2,7,8) For osteoblasts, core-binding factor ␣-1 (Cbfa1) is essential for osteoblast differentiation. (14) Other specific osteoblast markers include osteocalcin and parathyroid hormone/parathyroid hormonerelated protein receptor (PTH/PTHrP-R).…”

Estrogen Induces the Akt-dependent Activation of Endothelial Nitric-oxide Synthase in Vascular Endothelial Cells

“…Akt can then phosphorylate substrates such as glycogen synthase kinase-3, 6-phosphofructo-2-kinase, and BAD. More recently, it was found that eNOS is also an Akt substrate and is activated by Akt-dependent phosphorylation to release NO in endothelial cells (31-34).The actions of estrogen can be mediated by the classical nuclear receptors, ER␣ and ER␤ (35,36) or through other putative membrane receptors. By definition, rapid effects of estrogen that involve nongenomic mechanisms are independent of transcriptional activation by the nuclear ERs.…”

“…The actions of estrogen can be mediated by the classical nuclear receptors, ER␣ and ER␤ (35,36) or through other putative membrane receptors. By definition, rapid effects of estrogen that involve nongenomic mechanisms are independent of transcriptional activation by the nuclear ERs.…”