Regulation of Cholesterol Responsive Genes in Ovary Cells:  Impact of Cholesterol Delivery Systems

Medicherla, Satyanarayana; Azhar, Salman; Cooper, Allen D.; Reaven, Eve

doi:10.1021/bi952137l

Cited by 22 publications

(23 citation statements)

References 64 publications

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“…HMG-CoA reductase catalyzes the conversion of HMG-CoA to mevalonate, which is considered to be the major point of regulation in the synthesis of cholesterol. In Leydig as well as granulosa cells, hCG/cAMP treatment enhances HMG-CoA reductase activity and causes a concomitant increase in steroid production (Hou et al 1990, Medicherla et al 1996.…”

Section: Discussionmentioning

confidence: 99%

Mono-(2-ethylhexyl) phthalate stimulates basal steroidogenesis by a cAMP-independent mechanism in mouse gonadal cells of both sexes

Gunnarsson

Leffler²,

Ekwurtzel³

et al. 2008

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Phthalates are widely used as plasticizers in a number of daily-life products. In this study, we investigated the influence of mono-(2-ethylhexyl) phthalate (MEHP), the active metabolite of the frequently used plasticizer di-(2-ethylhexyl) phthalate (DEHP), on gonadal steroidogenesis in vitro. MEHP (25-100 mM) stimulated basal steroid synthesis in a concentration-dependent manner in immortalized mouse Leydig tumor cells (MLTC-1). The stimulatory effect was also detected in KK-1 granulosa tumor cells. MEHP exposure did not influence cAMP or StAR protein levels and induced a gene expression profile of key steroidogenic proteins different from the one induced by human chorionic gonadotropin (hCG). Simultaneous treatment with MEHP and a p450scc inhibitor (aminoglutethimide) indicated that MEHP exerts its main stimulatory effect prior to pregnenolone formation. MEHP (10-100 mM) up-regulated hormone-sensitive lipase and 3-hydroxy-3-methylglutaryl coenzyme A reductase, suggesting that MEHP increases the amount of cholesterol available for steroidogenesis. Our data suggest that MEHP, besides its known inhibitory effect on hCG action, can directly stimulate gonadal steroidogenesis in both sexes through a cAMP-and StAR-independent mechanism. The anti-steroidogenic effect of DEHP has been proposed to cause developmental disorders such as hypospadias and cryptorchidism, whereas a stimulation of steroid synthesis may prematurely initiate the onset of puberty and theoretically affect the hypothalamic-pituitary-gonadal axis. Reproduction (2008) 135 693-703

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Section: Discussionmentioning

confidence: 99%

Mono-(2-ethylhexyl) phthalate stimulates basal steroidogenesis by a cAMP-independent mechanism in mouse gonadal cells of both sexes

Gunnarsson

Leffler²,

Ekwurtzel³

et al. 2008

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“…Guojun Bu and Alan Schwartz (Washington University School of Medicine, St. Louis, MO) generously supplied the partial cDNA clones for rat LRP and RAP (38). The cDNA probes for LDL (B/E) receptor, rat HMG-CoA reductase, and 18S rRNA were obtained as described previously (5,6). All other reagents used were of analytical grade.…”

Section: Methodsmentioning

confidence: 99%

“…A nonendocytic process known as the scavenger receptor class B type I (SR-BI)/"selective" CE uptake pathway appears to be the principal uptake mechanism for the bulk delivery of cholesterol (1)(2)(3)(4). However, under in vitro cell culture conditions, the classical endocytic [LDL or Apolipoprotein B/apolipoprotein E (B/ E)] receptor pathway also becomes unmasked in steroidogenic cells, and in addition to HDL-CE taken in by selective uptake, exogenously provided human or rat LDL can be internalized by the traditional B/E pathway (5,6). This study was initiated to explore the role of still another member of the LDL receptor superfamily, the low density lipoprotein receptor-related protein (LRP) (7)(8)(9), in the lipoproteinderived cholesterol uptake process.…”

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confidence: 99%

“…To further assess the role of the LRP pathway in the delivery of lipoprotein cholesterol for steroidogenesis, we took advantage of a well-studied hormone-primed rat ovarian granulosa cell model (32). This cell model has very limited lipoprotein-CE uptake by either the selective or endocytic (LDL receptor) pathway before stimulation with trophic hormones or cAMP analogs (5,6,33,34). However, when cultured with trophic hormones or the second messenger analog N 6 ,O 29 -dibutyryl adenosine 39,59-cyclic monophosphate (Bt 2 cAMP), the cells become luteinized, express high levels of both LDL receptor (5,6) and SR-BI (35) proteins, and in the presence of lipoproteins take up massive amounts of CEs via the selective pathway.…”

mentioning

confidence: 99%

“…This cell model has very limited lipoprotein-CE uptake by either the selective or endocytic (LDL receptor) pathway before stimulation with trophic hormones or cAMP analogs (5,6,33,34). However, when cultured with trophic hormones or the second messenger analog N 6 ,O 29 -dibutyryl adenosine 39,59-cyclic monophosphate (Bt 2 cAMP), the cells become luteinized, express high levels of both LDL receptor (5,6) and SR-BI (35) proteins, and in the presence of lipoproteins take up massive amounts of CEs via the selective pathway. The cells respond with a 1,000-to 2,000-fold increase in secretion of progestins compared with cells grown under basal conditions (32).…”

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LDL and cAMP cooperate to regulate the functional expression of the LRP in rat ovarian granulosa cells

Azhar

Medicherla

Shen

et al. 2006

Journal of Lipid Research

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Rat ovarian granulosa rely heavily on lipoproteinderived cholesterol for steroidogenesis, which is principally supplied by the LDL receptor-and scavenger receptor class B type I (SR-BI)-mediated pathways. In this study, we characterized the hormonal and cholesterol regulation of another member of the LDL receptor superfamily, low density lipoprotein receptor-related protein (LRP), and its role in granulosa cell steroidogenesis. Coincubation of cultured granulosa cells with LDL and N 6,O 29 -dibutyryl adenosine 39,59-cyclic monophosphate (Bt 2 cAMP) greatly increased the mRNA/protein levels of LRP. Bt 2 cAMP and Bt 2 cAMP plus human (h)LDL also enhanced SR-BI mRNA levels. However, there was no change in the expression of receptor-associated protein, a chaperone for LRP, or another lipoprotein receptor, LRP8/apoER2, in response to Bt 2 cAMP plus hLDL, whereas the mRNA expression of LDL receptor was reduced significantly. The induced LRP was fully functional, mediating increased uptake of its ligand, a 2 -macroglobulin. The level of binding of another LRP ligand, chylomicron remnants, did not increase, although the extent of remnant degradation that could be attributed to the LRP doubled in cells with increased levels of LRP. The addition of lipoproteintype LRP ligands such as chylomicron remnants and VLDL to the incubation medium significantly increased the progestin production under both basal and stimulated conditions. In summary, our studies demonstrate a role for LRP in lipoprotein-supported ovarian granulosa cell steroidogenesis.-Azhar, S

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Enhancement of Mdr2 Gene Transcription Mediates the Biliary Transfer of Phosphatidylcholine Supplied by An Increased Biosynthesis in the Pravastatin–Treated Rat

et al. 1999

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An increase of biliary lipid secretion is known to occur in the rat under sustained administration of statin-type 3-hydroxy-3-methylglutaryl (HMG) coenzyme A (CoA) reductase inhibitors. The present study has addressed critical mechanisms of hepatic lipid synthesis and phosphatidylcholine (PC) biliary transport in the rat fed with a 0.075% pravastatin diet for 3 weeks. After treatment, biliary secretion of PC and cholesterol increased to 233% and 249% of controls, while that of bile salts was unchanged. Activity of cytidylyltransferase (CT), a major regulatory enzyme in the CDP-choline pathway of PC synthesis, was raised in both microsomal and cytosolic fractions (226% and 150% of controls), and there was an increase to 187% in the mass of active enzyme as determined by Western blot of microsomal protein using an antibody specific to CT. Cytosolic activity of choline kinase, another enzyme of the CDP-choline pathway, also increased to 175% of controls. In addition, there was an over eightfold increase in the HMG CoA reductase activity and mRNA. Thus, an increased PC and cholesterol synthetic supply to hepatocytes appeared as a basic mechanism for the biliary hypersecretion of these lipids. Notwithstanding the increased synthesis, hepatic PC content was unchanged, suggesting an enhanced transfer of this lipid into bile. Indeed, there was a sevenfold increase of multidrug resistance gene 2 (mdr2) gene mRNA coding for a main PC canalicular translocase. Thus, hypersecretion of biliary PC in the model studied can be explained by an up-regulation of mdr2 gene transcription and its P-glycoprotein product mediating the biliary transfer of PC supplied by an increased biosynthesis. (HEPATOLOGY 1999; 29:1825-1832.)

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Regulation of Cholesterol Responsive Genes in Ovary Cells: Impact of Cholesterol Delivery Systems

Cited by 22 publications

References 64 publications

Mono-(2-ethylhexyl) phthalate stimulates basal steroidogenesis by a cAMP-independent mechanism in mouse gonadal cells of both sexes

Mono-(2-ethylhexyl) phthalate stimulates basal steroidogenesis by a cAMP-independent mechanism in mouse gonadal cells of both sexes

LDL and cAMP cooperate to regulate the functional expression of the LRP in rat ovarian granulosa cells

Enhancement of Mdr2 Gene Transcription Mediates the Biliary Transfer of Phosphatidylcholine Supplied by An Increased Biosynthesis in the Pravastatin–Treated Rat

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