Cholesterol supply and SREBPs modulate transcription of the Niemann-Pick C-1 gene in steroidogenic tissues

Gévry, Nicolas; Schoonjans, Kristina; Guay, Frédéric; Murphy, Bruce D.

doi:10.1194/jlr.m700554-jlr200

Cited by 34 publications

(21 citation statements)

References 36 publications

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“…The expression level of NPC1 was reduced in cholesterol-replete placentas, as demonstrated in other tissues (70), and as such would not enhance transport from lysosomes. Though the mechanism of regulation is thought to be via SREBP-2, a different regulatory mechanism exists in the rapidly growing placenta since SREBP-2 levels are not affected significantly in the cholesterol-replete placenta (54).…”

Section: Placentamentioning

confidence: 82%

Transport of maternal cholesterol to the fetus is affected by maternal plasma cholesterol concentrations in the Golden Syrian hamster

Burke

Colvin

Myatt

et al. 2009

Journal of Lipid Research

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The fetus has a high requirement for cholesterol and synthesizes cholesterol at elevated rates. Recent studies suggest that fetal cholesterol also can be obtained from exogenous sources. The purpose of the current study was to examine the transport of maternal cholesterol to the fetus and determine the mechanism responsible for any cholesterol-driven changes in transport. Studies were completed in pregnant hamsters with normal and elevated plasma cholesterol concentrations. Cholesterol feeding resulted in a 3.1-fold increase in the amount of LDL-cholesterol taken up by the fetus and a 2.4-fold increase in the amount of HDL-cholesterol taken up. LDL-cholesterol was transported to the fetus primarily by the placenta, and HDL-cholesterol was transported by the yolk sac and placenta. Several proteins associated with sterol transport and efflux, including those induced by activated liver X receptor, were expressed in hamster and human placentas: NPC1, NPC1L1, ABCA2, SCP-x, and ABCG1, but not ABCG8. NPC1L1 was the only protein increased in hypercholesterolemic placentas. Thus, increasing maternal lipoprotein-cholesterol concentrations can enhance transport of maternal cholesterol to the fetus, leading to 1) increased movement of cholesterol down a concentration gradient in the placenta, 2) increased lipoprotein secretion from the yolk sac (shown previously), and possi- Cholesterol is essential for normal fetal development. Possibly the most noted role of cholesterol is as a structural component of membranes. Sterols are also the precursor for bile acids, steroid hormones, and oxysterols, which are all synthesized by the fetus and regulate various cellular processes. Cholesterol is also required for activation of sonic hedgehog (Shh), a protein involved in brain development, and for propagation of the Shh signal (1, 2). Cholesterol is obtained endogenously by de novo synthesis and exogenously by transfer of maternal cholesterol to the fetus. Interestingly, maternal plasma triglyceride and cholesterol concentrations increase during pregnancy in humans (3, 4), possibly an adaptation to maternal and fetal needs. However, whether these changes in maternal lipoprotein concentrations result in increased transport of maternal cholesterol to the fetus is unclear.Since the fetus does not come in direct contact with the maternal circulation, maternal cholesterol destined for the fetus must initially be taken up by the placenta and yolk sac prior to transport and delivery to the fetus. Indeed, the placenta and yolk sac take up maternal LDL-and HDLcholesterol at relatively elevated rates compared with other peripheral tissues (5). LDL is taken up by the LDL receptor (LDLR), which is expressed abundantly in the placenta but expressed at low levels, if at all, in the yolk sac (5, 6). LDL-derived sterol is transported to the lysosome/endosome pathway where the ester bond is hydrolyzed (7). The unesterified cholesterol is then transported by NiemannThese studies were supported by grants HD34089 (LAW) and GM31651 (FS) from the...

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Section: Placentamentioning

confidence: 82%

Transport of maternal cholesterol to the fetus is affected by maternal plasma cholesterol concentrations in the Golden Syrian hamster

Burke

Colvin

Myatt

et al. 2009

Journal of Lipid Research

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“…The increased expression of HMGR in the SCARB1 Ϫ / Ϫ ovary was interpreted to be an intracellular feedback response to the reduction in intracellular cholesterol in the transgenic ovaries ( 31 ). The mouse bearing spontaneous mutation in the Niemann-Pick C1 gene is unable to process LDL cholesterol but displays circulating progesterone concentrations that do not differ from WT mice ( 32 ).…”

Section: Downloaded Frommentioning

confidence: 99%

“…As all three sources were believed to have been compromised in the present study, it must be concluded that cholesterol stored in the CL in the form of cholestryl esters was the source of the substrate for progesterone synthesis. The feedback system for cholesterol homeostasis is regulated by the abundance of the transcriptionally active form of sterol-regulatory element binding protein (SREBP) ( 31 ). An important transcriptional target of SREBP is the liver alone ( 13 ).…”

Section: Downloaded Frommentioning

confidence: 99%

Scavenger receptor-B1 and luteal function in mice

Jiménez

Binelli

Bertolin

et al. 2010

Journal of Lipid Research

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This article is available online at http://www.jlr.org augmentation of the supply is by importation of lipoprotein-bound cholesterol ( 1 ). Low-density lipoproteins enter cells by receptor-mediated endocytosis of the LDL complex and the LDL receptor (LDLR) ( 2 ). High-density lipoproteins interact with a membrane protein known as scavenger receptor-B1 (SCARB1) to effect the selective uptake of cholesterol esters from the HDL molecule into cells and the bidirectional transfer of free cholesterol ( 3 ). The relative contribution of LDL and HDL to the steroidogenic substrate pool varies among species and may vary among tissues within a species. One of the most active steroidogenic tissues is the corpus luteum (CL), formed from the components of the follicle following ovulation ( 4 ). In humans, circulating LDL is believed to be the major source of cholesterol for luteal steroid synthesis, but it has been shown that luteinized human granulosa cells can derive cholesterol esters from selective uptake via the HDL pathway ( 5 ). The HDL pathway appears to predominate in the CL of rodents ( 1 ), and SCARB1 is expressed in theca and luteal cells of the rat ovary ( 6 ). SCARB1 expression in primary cultures of rat granulosa cells is tightly coupled with the uptake of cholesterol esters, again suggesting that it is the major pathway for importation in this tissue ( 7 ). There is a low level of expression of SCARB1 in mouse granulosa cells ( 8 ), and recent studies of luteinization in the pig demonstrated similar low expression of SCARB1 in the granulosa cells of the follicle ( 9 ). The latter study revealed extensive upregulation of SCARB1 in the CL following ovulation, with a high level of expression persisting through the luteal phase. In the macaque, the ovulatory stimulus causes a rapid increase in expression of both SCARB1 and LDLR, but only LDL can augment steroidogenesis after 24 h in vitro ( 10 ). The cholesterol substrate required for most tissues to accomplish steroidogenesis exceeds the capacity for de novo synthesis of this sterol, and the principal means of Abstract

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“…However, subsequent studies performed in vitro using human fibroblasts, mouse fibroblasts, and porcine granulosa cells indicated that the NPC1 or Npc1 gene is downregulated at the transcriptional level by feedback inhibition of the sterol regulatory element-binding protein (SREBP) pathway (20,21). These studies also indicated that the NPC1 or Npc1 gene promoter region in humans, mice, and pigs possesses both sterol regulatory element (SRE)-like sequences and classic SRE sequences and is therefore capable of interacting with all 3 forms of mature (m)-SREBP proteins to regulate transcription of the NPC1 or Npc1 gene.…”

Section: Introductionmentioning

confidence: 98%

The Niemann-Pick C1 Gene Is Downregulated in Livers of C57BL/6J Mice by Dietary Fatty Acids, but Not Dietary Cholesterol, through Feedback Inhibition of the SREBP Pathway3

Jelínek

Castillo

Richardson

et al. 2012

The Journal of Nutrition

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The Niemann-Pick C1 (NPC1) gene is associated with human obesity. Mouse models with decreased Npc1 gene dosage are susceptible to weight gain when fed a high-fat diet, but not a low-fat diet, consistent with an Npc1 gene-diet interaction. The objectives of this study were to define regulation of the Npc1 gene and to investigate the Npc1 gene-diet interaction responsible for weight gain. The experimental design involved feeding C57BL/6J male mice a low-fat diet (with 0.00, 0.10, or 1.00% cholesterol) or a high-fat diet (with 0.02% cholesterol) until 30 wk to determine regulation of the Npc1 gene in liver. The key results showed that the Npc1 gene was downregulated by dietary fatty acids (54%, P = 0.022), but not by dietary cholesterol, through feedback inhibition of the sterol regulatory element-binding protein (SREBP) pathway. However, the dietary fatty acids secondarily increased liver cholesterol, which also inhibits the SREBP pathway. Similarly, the Npc1 gene was downregulated in peritoneal fibroblasts isolated from C57BL/6J weanling male mice not exposed to the experimental diets and incubated in media supplemented with purified oleic acid (37%, P = 0.038) but not in media supplemented with purified cholesterol. These results are important because they suggest a novel mechanism for the interaction of fatty acids with the Npc1 gene to influence energy balance and to promote weight gain. Moreover, the responsiveness of the Npc1 gene to fatty acids is consistent with studies that suggest that the encoded NPC1 protein has a physiologic role in regulating both cholesterol and fatty acid metabolism.

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Cholesterol supply and SREBPs modulate transcription of the Niemann-Pick C-1 gene in steroidogenic tissues

Cited by 34 publications

References 36 publications

Transport of maternal cholesterol to the fetus is affected by maternal plasma cholesterol concentrations in the Golden Syrian hamster

Transport of maternal cholesterol to the fetus is affected by maternal plasma cholesterol concentrations in the Golden Syrian hamster

Scavenger receptor-B1 and luteal function in mice

The Niemann-Pick C1 Gene Is Downregulated in Livers of C57BL/6J Mice by Dietary Fatty Acids, but Not Dietary Cholesterol, through Feedback Inhibition of the SREBP Pathway3

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