Sterol synthesis and low density lipoprotein clearance in vivo in the pregnant rat, placenta, and fetus. Sources for tissue cholesterol during fetal development.

Belknap, William M.; Dietschy, John M.

doi:10.1172/jci113829

Cited by 109 publications

(57 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The high cholesterol synthesis may be related to the needs of a still-growing organism. Third, in the later stages of pregnancy, when circulating estrogen levels reach the highest point (26), there was a dramatic decrease of expression of all enzymes, possibly because at day 17 of pregnancy, the fetus acquires the ability to produce its own cholesterol (27). Finally, and most relevantly, in the absence of a cycle due to age or surgical menopause, expression of most of the genes studied was not oscillatory and was generally set to accumulate the mRNAs at levels significantly higher than those at proestrus.…”

Section: Discussionmentioning

confidence: 99%

Tetradian oscillation of estrogen receptor α is necessary to prevent liver lipid deposition

Villa

Torre²,

Stell³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

117

View full text Add to dashboard Cite

In the liver of female mice, the transcriptional activity of estrogen receptor (ER) α oscillates in phase with the 4-d-long estrous cycle. Here systemic, genome-wide analysis demonstrates that ER tetradian oscillation is necessary to generate pulses of expression in genes for fatty acid and cholesterol synthesis. This ER-dependent metabolic programming changes with pregnancy and after cessation of ovarian function due to age or surgical menopause, suggesting that ER signaling is optimized to coordinate liver functions with the energetic requirements of each reproductive stage. Alterations of amplitude and frequency of the tetradian cycle, as observed after surgical menopause, age, or specific ablation of the hepatic Igf-1 gene, are associated with liver fat deposition. Appropriate hormone replacement therapy reinstating the oscillatory activity of liver ER prevents the effect of surgical menopause on fat deposition in liver.energy metabolism | estrogen action | steroid hormone physiology | selective estrogen receptor modulators E strogen receptor (ER) α (or ESR1 or NR3A) is a transcription factor regulated by estrogens and nonestrogenic substances. ERα is highly expressed in reproductive organs and is indispensable for female reproductive functions (1). ERα is also present in most nonreproductive organs, where its role is currently object of intense investigation because of the large number of dysfunctions associated with the postmenopause and affecting the metabolic, cardiovascular, and immune systems (2-5).Application of the ER responsive element (ERE)-Luc reporter mouse, a transgenic mouse in which the luciferase reporter is driven by a promoter carrying multiple ERE copies (6), identified the liver as the organ in which ERs are most transcriptionally active (7,8). Further studies demonstrated that hepatic ERα transcriptional activity oscillates with the estrous cycle (tetradian oscillation) and is regulated by several compounds, including growth factors and nutritional proteins (9). This latter mechanism is instrumental for the synthesis of the circulating insulin-like growth factor 1 (IGF-1) necessary for the progression of the estrous cycle (9).These studies pointed to the hepatic ERα as a sensor of nutrient availability and a switch able to block the reproductive cycle in the event of malnutrition. On the other hand, a large body of evidence indicates that ERs are important regulators of several aspects of liver energy metabolism. Phenotypic analysis of mutant mice, including ERα (ERKO), ERβ, and aromatase KO mice, demonstrated that ERs play a pivotal role in the regulation of many processes related to the control of energy homeostasis, including energy expenditure, insulin sensitivity, and fat distribution (1, 10-13). In addition, investigation of the genetic programs controlled by hepatic ERs performed by comparing the transcriptomes of vehicle-and 17β-estradiol (E 2 )-treated ovariectomized (ovx) mice (14) established the potential for ER to recognize and regulate the transcription of numerous genes in...

show abstract

Section: Discussionmentioning

confidence: 99%

Tetradian oscillation of estrogen receptor α is necessary to prevent liver lipid deposition

Villa

Torre²,

Stell³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

117

View full text Add to dashboard Cite

show abstract

“…As in the adult, this cholesterol is supplied by either de novo synthesis within the fetal compartment or by transfer from the maternal compartment to the fetus through uptake of cholesterol carried in lipoproteins. Previous studies have shown that sterol synthesis is markedly increased in the developing fetus including a preimplantation embryo (27)(28)(29). In addition, transport of maternal LDL and HDL to the fetal yolk sac is drastically increased (30).…”

Section: Discussionmentioning

confidence: 99%

“…It is conceivable that the placental system is too immature to fully compensate for the complete deficiency of the de novo cholesterol synthesis around this developmental stage. Belknap and Dietschy (27) have shown that the de novo cholesterol synthesis remains highly active during the whole midgestational period and that the contents of newly synthesized sterols are maximal at E17 in the rat fetus. Similar failure to catch up with the increasing demand may underlie the lethality of mice lacking apoB (11,12,39) or microsomal triglyceride transfer protein (13), because both mutants die at the same developmental stage.…”

Section: Discussionmentioning

confidence: 99%

Embryonic Lethality and Defective Neural Tube Closure in Mice Lacking Squalene Synthase

Tozawa¹,

Ishibashi²,

Osuga³

et al. 1999

Journal of Biological Chemistry

123

View full text Add to dashboard Cite

Squalene synthase (SS) catalyzes the reductive headto-head condensation of two molecules of farnesyl diphosphate to form squalene, the first specific intermediate in the cholesterol biosynthetic pathway. We used gene targeting to knock out the mouse SS gene. The mice heterozygous for the mutation (SS؉/؊) were apparently normal. SS؉/؊ mice showed 60% reduction in the hepatic mRNA levels of SS compared with SS؉/؉ mice. Consistently, the SS enzymatic activities were reduced by 50% in the liver and testis. Nevertheless, the hepatic cholesterol synthesis was not different between SS؉/؊ and SS؉/؉ mice, and plasma lipoprotein profiles were not different irrespective of the presence of the low density lipoprotein receptor, indicating that SS is not a rate-limiting enzyme in the cholesterol biosynthetic pathway. The mice homozygous for the disrupted SS gene (SS؊/؊) were embryonic lethal around midgestation. E9.5-10.5 SS؊/؊ embryos exhibited severe growth retardation and defective neural tube closure. The lethal phenotype was not rescued by supplementing the dams either with dietary squalene or cholesterol. We speculate that cholesterol is required for the development, particularly of the nervous system, and that the chorioallantoic circulatory system is not mature enough to supply the rapidly growing embryos with maternal cholesterol at this developmental stage.

show abstract

“…At 11.5 days post-conception (dpc), studies were performed; hamsters have a gestational period of 15.5 days. [31,33].…”

Section: Animals and Dietsmentioning

confidence: 99%

Inability to fully suppress sterol synthesis rates with exogenous sterol in embryonic and extraembyronic fetal tissues

Yao

Jenkins

Horn

et al. 2007

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

View full text Add to dashboard Cite

SUMMARYThe requirement for cholesterol is greater in developing tissues (fetus, placenta, and yolk sac) as compared to adult tissues. Here, we compared cholesterol-induced suppression of sterol synthesis rates in the adult liver to the fetal liver, fetal body, placenta, and yolk sac of the Golden Syrian hamster. Sterol synthesis rates were suppressed maximally in non-pregnant adult livers when cholesterol concentrations were increased. In contrast, sterol synthesis rates were suppressed only marginally in fetal livers, fetal bodies, placentas, and yolk sacs when cholesterol concentrations were increased. To begin to elucidate the mechanism responsible for the blunted response of sterol synthesis rates in fetal tissues to exogenous cholesterol, the ratio of sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP) to Insig-1 was measured in these same tissues since the ratio of SCAP to the Insigs can impact SREBP processing. The fetal tissues had anywhere from a 2-to 6-fold greater ratio of SCAP to Insig-1 than did the adult liver, suggesting constitutive processing of the SREBPs. As expected, the level of mature, nuclear SREBP-2 was not different in the fetal tissues with different levels of cholesterol whereas it was different in adult livers. These findings indicate that the suppression of sterol synthesis to exogenous sterol is blunted in developing tissues and the lack of response appears to be mediated at least partly through relative levels of Insigs and SCAP.

show abstract

Sterol synthesis and low density lipoprotein clearance in vivo in the pregnant rat, placenta, and fetus. Sources for tissue cholesterol during fetal development.

Cited by 109 publications

References 30 publications

Tetradian oscillation of estrogen receptor α is necessary to prevent liver lipid deposition

Tetradian oscillation of estrogen receptor α is necessary to prevent liver lipid deposition

Embryonic Lethality and Defective Neural Tube Closure in Mice Lacking Squalene Synthase

Inability to fully suppress sterol synthesis rates with exogenous sterol in embryonic and extraembyronic fetal tissues

Contact Info

Product

Resources

About