Sex-specific effects of in vitro fertilization on adult metabolic phenotypes and hepatic transcriptomic and proteomic pathways in mouse

AbstractAlthough in vitro fertilization (IVF) is associated with adverse perinatal outcomes, an increasing concern is the long-term health implications. We augmented our IVF mouse model to longitudinally investigate cardiometabolic outcomes in offspring from optimal neonatal litter sizes. We found that IVF-conceived females had higher body weight and cholesterol levels compared to naturally-conceived females, whereas IVF-conceived males had higher levels of triglycerides and insulin, and increased body fat composition. Through transcriptomics and proteomics of adult liver, we identified sexually-dimorphic dysregulation of the sterol regulatory element binding protein (SREBP) pathways that are associated with the sex-specfic phenotypes. We also found that global loss of DNA methylation in placenta was linked to higher cholesterol levels in IVF-conceived females. Our findings indicate that IVF procedures have long-lasting sex-specific effects on metabolic health of offspring and lay the foundation to utilize the placenta as a predictor of long-term outcomes.

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Protein in culture and endogenous lipid interact with embryonic stages in vitro to alter calf birthweight after embryo vitrification and warming

Reproduction Fertility and Development ◽

10.1071/rd16213 ◽

2017 ◽

Vol 29 (10) ◽

pp. 1932 ◽

Cited By ~ 5

Author(s):

E. Gómez ◽

S. Carrocera ◽

S. Uzbekova ◽

D. Martín ◽

A. Murillo ◽

...

Keyword(s):

Stress Responses ◽

Regulatory Element ◽

Pregnancy Rates ◽

Hormone Sensitive Lipase ◽

Expression Of Genes ◽

Element Binding Protein ◽

Sterol Regulatory Element ◽

Hormone Sensitive

Short-term protein removal in vitro improves long-term blastocyst competence to survive vitrification. We investigated the mechanisms and effects underlying protein removal. Day-6 morulae and early blastocysts were cultured individually with and without protein for 24 h. Development and lipid content were analysed in expanded blastocysts derived from morulae (M-XB) and from early blastocysts (EB-XB). Expression of genes involved in lipid metabolism, stress responses and apoptosis was analysed in fresh and vitrified–warmed M-XB produced with and without protein. Pregnancy rates, birth rates and birthweight (BW) were recorded after transfer of embryos. Day-7 EB-XB production rates (with, 66.9 ± 6.2 and without, 68.8 ± 6.0 protein) were higher than M-XB rates (with, 21.4 ± 4.6 and without, 9.4 ± 4.6 protein; P < 0.005). EB-XB showed fewer lipids than M-XB (P = 0.03). In fresh M-XB, expression of sterol regulatory element binding protein (SREBP1) was lower with (4.1 ± 2.2) than without (13.6 ± 2.2) protein, contrary to results obtained for Patatin-like phospholipase domain containing 2, Hormone-sensitive lipase and Bcl-2–associated X protein (P < 0.05). Protein did not affect pregnancy rates and birth phenotypes (P > 0.05). However, BW was higher (P < 0.01) in calves born from vitrified M-XB (48.6 ± 3.4 kg) than from EB-XB (39.8 ± 2.9 kg). Such effects were more pronounced in females (P < 0.001). Calves from fresh embryos did not show BW differences. These results indicate that embryonic kinetics and vitrification impact birth phenotypes, at least in females. Alterations might involve exogenous protein and mobilisation of lipid stocks.

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Peculiarities of pregnancy and delivery course in women after the application of assisted reproductive technologies against obesity (Based on the retrospective analysis)

HEALTH OF WOMAN ◽

10.15574/hw.2018.132.122 ◽

2018 ◽

pp. 122-126

Author(s):

I.A. Zhabchenko ◽

◽

O.R. Sudmak ◽

Keyword(s):

In Vitro Fertilization ◽

Pregnant Women ◽

Retrospective Analysis ◽

Perinatal Outcomes ◽

Reproductive Technologies ◽

Ischemic Lesion ◽

Vitro Fertilization ◽

Pregnancy And Delivery

The objective: to study the structure and frequency of complications of pregnancy, deliveries and perinatal outcomes in three groups of women: women with infertility and obesity, treated by application of in vitro fertilization (hereinafter IVF), pregnant women after IVF application with normal body weight, and pregnant women on the background of obesity which did not have an infertility in past history. Materials and methods. A retrospective analysis of 221 case histories of pregnancies and labors in women who were treated and gave birth in the Pregnancy and delivery pathology Department of SI «Institute of Pediatrics, Obstetrics and Gynecology named after Acad. O. M. Lukyanova of NAMS of Ukraine» for 2012 – 2016 years was carried out. Results. The overwhelming majority of pregnant women after IVF on the background of obesity are primaparas, who have a complicated obstetric history, hormonal changes in the form of progesterone deficiency predominantly and chronic inflammatory processes. Pregnancy with a combination of infertility, treated by the means of IVF application, and obesity, in most cases is accompanied by a long-term threat of termination of pregnancy (48.8%), threatening preterm deliveries (56%), placental dysfunction (41.5%), premature rupture of the amniotic membranes (41.5%), other problems during pregnancy, at the same time, every second woman (58.5%) had a combination of several complications, and required a long-term and repeated inpatient treatment (53.7%). The specific gravity of surgical delivery was 90%, and 16.2% of such deliveries were complicated by pathological blood loss. The number of preterm deliveries was 17.1%, with perinatal losses up to 11.3‰. Among full-term newborns 21.3% of newborns had malnutrition of the I degree and 17% of them had hypoxic-ischemic lesion of CNS. Conclusion. The course of pregnancy, delivery and the postpartum period in the studied contingent of women has a significant frequency of complications, mainly the coinciding ones, which affects on the consequences of perinatal outcomes and requires further study of this problem and the development of differentiated algorithms for antenatal observation. Key words: pregnancy, obesity, in vitro fertilization, complications, delivery, newborn.

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Tissue-Specific Effects of Central Leptin on the Expression of Genes Involved in Lipid Metabolism in Liver and White Adipose Tissue

Endocrinology ◽

10.1210/en.2007-0933 ◽

2007 ◽

Vol 148 (12) ◽

pp. 5604-5610 ◽

Cited By ~ 74

Author(s):

Nilda Gallardo ◽

Elena Bonzón-Kulichenko ◽

Teresa Fernández-Agulló ◽

Eduardo Moltó ◽

Sergio Gómez-Alonso ◽

...

Keyword(s):

Adipose Tissue ◽

Lipid Metabolism ◽

White Adipose Tissue ◽

Binding Protein ◽

Regulatory Element ◽

Epididymal Adipose Tissue ◽

Key Enzymes ◽

Specific Effects ◽

Element Binding Protein ◽

Sterol Regulatory Element

Leptin reduces adiposity and exerts antisteatotic effects on nonadipose tissues. However, the mechanisms underlying leptin effects on lipid metabolism in liver and white adipose tissue have not been fully clarified. Here, we have studied the effects of central leptin administration on key enzymes and transcription factors involved in lipid metabolism in liver and epididymal adipose tissue. Intracerebroventricular leptin infusion for 7 d did not change leptin plasma levels but decreased triacylglyceride content in liver, epididymal adipose tissue, and plasma. In both tissues this treatment markedly decreased the expression of key enzymes of the de novo fatty acid (FA) synthesis such as acetyl-coenzyme A-carboxylase, FA synthase, and stearoyl-coenzyme A desaturase-1, in parallel with a reduction in mRNA expression of sterol regulatory element binding protein-1c in liver and carbohydrate regulatory element binding protein in adipose tissue. In addition, leptin also decreased phosphoenol-pyruvate carboxykinase-C expression in adipose tissue, an enzyme involved in glyceroneogenesis in this tissue. Central leptin administration down-regulates delta-6-desaturase expression in liver and adipose tissue, in parallel with the decrease of the expression of sterol regulatory element binding protein-1c in liver and peroxisome proliferator activated receptor α in adipose tissue. Finally, leptin treatment, by regulating adipose triglyceride lipase/hormone sensitive lipase/diacylglycerol transferase 1 expression, also established a new partitioning in the FA-triacylglyceride cycling in adipose tissue, increasing lipolysis and probably the FA efflux from this tissue, and favoring in parallel the FA uptake and oxidation in the liver. These results suggest that leptin, acting at central level, exerts tissue-specific effects in limiting fat tissue mass and lipid accumulation in nonadipose tissues, preventing the development of obesity and type 2 diabetes.

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A New Role for Sterol Regulatory Element Binding Protein 1 Transcription Factors in the Regulation of Muscle Mass and Muscle Cell Differentiation

Molecular and Cellular Biology ◽

10.1128/mcb.00690-09 ◽

2009 ◽

Vol 30 (5) ◽

pp. 1182-1198 ◽

Cited By ~ 54

Author(s):

Virginie Lecomte ◽

Emmanuelle Meugnier ◽

Vanessa Euthine ◽

Christine Durand ◽

Damien Freyssenet ◽

...

Keyword(s):

Transcription Factors ◽

Muscle Mass ◽

Target Genes ◽

Binding Protein ◽

Regulatory Element ◽

Element Binding Protein ◽

Sterol Regulatory Element ◽

Myogenic Program

ABSTRACT The role of the transcription factors sterol regulatory element binding protein 1a (SREBP-1a) and SREBP-1c in the regulation of cholesterol and fatty acid metabolism has been well studied; however, little is known about their specific function in muscle. In the present study, analysis of recent microarray data from muscle cells overexpressing SREBP1 suggested that they may play a role in the regulation of myogenesis. We then demonstrated that SREBP-1a and -1c inhibit myoblast-to-myotube differentiation and also induce in vivo and in vitro muscle atrophy. Furthermore, we have identified the transcriptional repressors BHLHB2 and BHLHB3 as mediators of these effects of SREBP-1a and -1c in muscle. Both repressors are SREBP-1 target genes, and they affect the expression of numerous genes involved in the myogenic program. Our findings identify a new role for SREBP-1 transcription factors in muscle, thus linking the control of muscle mass to metabolic pathways.

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Functional antagonism between inhibitor of DNA binding (Id) and adipocyte determination and differentiation factor 1/sterol regulatory element-binding protein-1c (ADD1/SREBP-1c) trans-factors for the regulation of fatty acid synthase promoter in adipocytes

Biochemical Journal ◽

10.1042/bj3440873 ◽

1999 ◽

Vol 344 (3) ◽

pp. 873-880 ◽

Cited By ~ 30

Author(s):

Marthe MOLDES ◽

Muriel BOIZARD ◽

Xavier LE LIEPVRE ◽

Bruno FÈVE ◽

Isabelle DUGAIL ◽

...

Keyword(s):

Fatty Acid ◽

Dna Binding ◽

Fatty Acid Synthase ◽

Regulatory Element ◽

Expression Vectors ◽

Element Binding Protein ◽

Sterol Regulatory Element ◽

Inhibitor Of Dna Binding ◽

Isolated Rat

We show that Id (inhibitor of DNA binding) 2 and Id3, dominant negative members of the helix-loop-helix (HLH) family, interact with the adipocyte determination and differentiation factor 1 (ADD1)/sterol regulatory element-binding protein (SREBP) 1c, a transcription factor of the basic HLH-leucine zipper family that controls the expression of several key genes of adipose metabolism. Gel mobility-shift assays performed with in vitro-translated ADD1, Id2 or Id3 proteins and a fatty acid synthase (FAS) promoter oligonucleotide showed evidence for a marked inhibition of the formation of DNA-ADD1 complexes by Id2 or Id3 proteins. Co-immunoprecipitation studies using in vitro-translated proteins demonstrated further the physical interaction of Id and ADD1/SREBP-1c proteins in the absence of DNA. Using the FAS gene as a model of an ADD1-regulated promoter in transiently transfected isolated rat adipocytes or mature 3T3-L1 adipocytes, a potent inhibition of the activity of the FAS-chloramphenicol acetyltransferase reporter gene was observed by overexpression of Id2 or Id3. Reciprocally, co-transfection of Id3 antisense and ADD1 expression vectors in preadipocytes potentiated the ADD1/SREBP-1c effect on the FAS promoter activity. Finally, in the non adipogenic NIH-3T3 cell line, most of the ADD1-mediated trans-activation of the FAS promoter was counteracted by co-transfection of Id2 or Id3 expression vectors. Previous studies have indicated Id gene expression to be down-regulated during adipogenesis [Moldes, Lasnier, Fève, Pairault and Djian (1997) Mol. Cell. Biol. 17, 1796-1804]. We here demonstrated that there was a dramatic rise of Id2 and Id3 mRNA levels when 3T3-L1 adipocytes or isolated rat fat cells were exposed to lipolytic and anti-lipogenic agents, forskolin and isoproterenol. Taken together, our data show that Id products are functionally involved in modulating ADD1/SREBP-1c transcriptional activity, and thus lipogenesis in adipocytes.

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Insulin activates the rat sterol-regulatory-element-binding protein 1c (SREBP-1c) promoter through the combinatorial actions of SREBP, LXR, Sp-1 and NF-Y cis-acting elements

Biochemical Journal ◽

10.1042/bj20040162 ◽

2004 ◽

Vol 385 (1) ◽

pp. 207-216 ◽

Cited By ~ 104

Author(s):

Lauren M. CAGEN ◽

Xiong DENG ◽

Henry G. WILCOX ◽

Edwards A. PARK ◽

Rajendra RAGHOW ◽

...

Keyword(s):

Binding Protein ◽

Regulatory Element ◽

Ectopic Expression ◽

Rat Hepatocytes ◽

Luciferase Reporter ◽

Luciferase Reporter Gene ◽

Cis Acting ◽

Element Binding Protein ◽

Sterol Regulatory Element

The enhanced synthesis of fatty acids in the liver and adipose tissue in response to insulin is critically dependent on the transcription factor SREBP-1c (sterol-regulatory-element-binding protein 1c). Insulin increases the expression of the SREBP-1c gene in intact liver and in hepatocytes cultured in vitro. To learn the mechanism of this stimulation, we analysed the activation of the rat SREBP-1c promoter and its truncated or mutated congeners driving a luciferase reporter gene in transiently transfected rat hepatocytes. The rat SREBP-1c promoter contains binding sites for LXR (liver X receptor), Sp1, NF-Y (nuclear factor-Y) and SREBP itself. We have found that each of these sites is required for the full stimulatory response of the SREBP-1c promoter to insulin. Mutation of either the putative LXREs (LXR response elements) or the SRE (sterol response element) in the proximal SREBP-1c promoter reduced the stimulatory effect of insulin by about 50%. Insulin and the LXR agonist TO901317 increased the association of SREBP-1 with the SREBP-1c promoter. Ectopic expression of LXRα or SREBP-1c increased activity of the SREBP-1c promoter, and this effect is further enhanced by insulin. The Sp1 and NF-Y sites adjacent to the SRE are also required for full activation of the SREBP-1c promoter by insulin. We propose that the combined actions of the SRE, LXREs, Sp1 and NF-Y elements constitute an insulin-responsive cis-acting unit of the SREBP-1c gene in the liver.

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Importin beta1 mediates the glucose-stimulated nuclear import of pancreatic and duodenal homeobox-1 in pancreatic islet beta-cells (MIN6)

Biochemical Journal ◽

10.1042/bj20031549 ◽

2004 ◽

Vol 378 (1) ◽

pp. 219-227 ◽

Cited By ~ 18

Author(s):

Ghislaine GUILLEMAIN ◽

Gabriela da SILVA XAVIER ◽

Imran RAFIQ ◽

Armelle LETURQUE ◽

Guy A. RUTTER

Keyword(s):

Nuclear Membrane ◽

Nuclear Import ◽

Target Genes ◽

Nuclear Translocation ◽

Regulatory Element ◽

Pancreatic Islet Beta Cells ◽

Element Binding Protein ◽

Elevated Glucose ◽

Sterol Regulatory Element

The transcription factor PDX-1 (pancreatic and duodenal homeobox-1) is essential for pancreatic development and the maintainence of expression of islet β-cell-specific genes. In an previous study [Rafiq, Kennedy and Rutter (1998) J. Biol. Chem. 273, 23241–23247] we demonstrated that PDX-1 may be activated at elevated glucose concentrations by translocation from undefined binding sites in the cytosol and nuclear membrane into the nucleoplasm. In the present study, we show that PDX-1 interacts directly and specifically in vitro with the nuclear import receptor family member, importin β1, and that this interaction is mediated by the PDX-1 homeodomain (amino acids 146–206). Demonstrating the functional importance of the PDX-1–importin β1 interaction, microinjection of MIN6 β-cells with anti-(importin β1) antibodies blocked both the nuclear translocation of PDX-1, and the activation by glucose (30 mM versus 3 mM) of the pre-proinsulin promoter. However, treatment with extracts from pancreatic islets incubated at either low or high glucose concentrations had no impact on the ability of PDX-1 to interact with importin β1 in vitro. Furthermore, importin β1 also interacted with SREBP1c (sterol-regulatory-element-binding protein 1c) in vitro, and microinjection of importin β1 antibodies blocked the activation by glucose of SREBP1c target genes. Since the subcellular distribution of SREBP1c is unaffected by glucose, these findings suggest that a redistribution of importin β1 is unlikely to explain the glucose-stimulated nuclear uptake of PDX-1. Instead, we conclude that the uptake of PDX-1 into the nucleoplasm, as glucose concentrations increase, may be mediated by release of the factor both from sites of retention in the cytosol and from non-productive complexes with importin β1 at the nuclear membrane.

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A Component Formula of Chinese Medicine for Hypercholesterolemia Based on Virtual Screening and Biology Network

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2018/1854972 ◽

2018 ◽

Vol 2018 ◽

pp. 1-11 ◽

Cited By ~ 3

Author(s):

Xiaoqian Huo ◽

Fang Lu ◽

Liansheng Qiao ◽

Gongyu Li ◽

Yanling Zhang

Keyword(s):

Chinese Medicine ◽

Virtual Screening ◽

Regulatory Element ◽

Pharmacophore Model ◽

Lipid Lowering ◽

Hmg Coa Reductase ◽

Element Binding Protein ◽

Sterol Regulatory Element ◽

Coa Reductase

Hypercholesterolemia is a risk factor to atherosclerosis and coronary heart disease II. The abnormal rise of cholesterol in plasma is the main symptom. Cholesterol synthesis pathway is an important pathway of the origin of cholesterol, which is an essential pathway for the therapy of hypercholesterolemia. The 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), squalene synthase (SQS), and sterol regulatory element binding protein-2 (SREBP-2) are closely connected with the synthesis of cholesterol. The inhibition of these targets can reduce the cholesterol in plasma. This study aimed to build a component formula including three Traditional Chinese Medicines (TCM) components with the inhibition activity of these targets by using virtual screening and biological network. Structure-based pharmacophore models of HMG-CoA reductase and SQS and ligand-based pharmacophore model of SREBP-2 were constructed to screen the Traditional Chinese Medicine Database (TCMD). Molecular docking was used for further screening of components of HMG-CoA reductase and SQS. Then, metabolic network was constructed to elucidate the comprehensive interaction of three targets for lipid metabolism. Finally, three potential active compounds were obtained, which are poncimarin, hexahydrocurcumin, and forsythoside C. The source plants of the compounds were also taken into account, which should have known action of lowering hyperlipidemia. The lipid-lowering effect of hexahydrocurcumin was verified by experiment in vitro. The components that originated from TCMs with lipid-lowering efficacy made up a formula with a synergistic effect through the computer aid drug design methods. The research provides a fast and efficient method to build TCM component formula and it may inspire the study of the explanation of TCM formula mechanism.

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Effectors of Rapid Homeostatic Responses of Endoplasmic Reticulum Cholesterol and 3-Hydroxy-3-methylglutaryl-CoA Reductase

Journal of Biological Chemistry ◽

10.1074/jbc.m706967200 ◽

2007 ◽

Vol 283 (3) ◽

pp. 1445-1455 ◽

Cited By ~ 81

Author(s):

Yvonne Lange ◽

Daniel S. Ory ◽

Jin Ye ◽

Michael H. Lanier ◽

Fong-Fu Hsu ◽

...

Keyword(s):

Gene Expression ◽

Endoplasmic Reticulum ◽

Regulatory Element ◽

Cholesterol Content ◽

Cholesterol Levels ◽

Element Binding Protein ◽

Sterol Regulatory Element ◽

Hmgr Activity ◽

Coa Reductase ◽

Cholesterol Precursors

The cholesterol content of the endoplasmic reticulum (ER) and the activity of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) imbedded therein respond homeostatically within minutes to changes in the level of plasma membrane cholesterol. We have now examined the roles of sterol regulatory element-binding protein (SREBP)-dependent gene expression, side chain oxysterol biosynthesis, and cholesterol precursors in the short term regulation of ER cholesterol levels and HMGR activity. We found that SREBP-dependent gene expression is not required for the response to changes in cell cholesterol of either the pool of ER cholesterol or the rate of cholesterol esterification. It was also found that the acute proteolytic inactivation of HMGR triggered by cholesterol loading required the conversion of cholesterol to 27-hydroxycholesterol. High levels of exogenous 24,25-dihydrolanosterol drove the inactivation of HMGR; lanosterol did not. However, purging endogenous 24,25-dihydrolanosterol, lanosterol, and other biosynthetic sterol intermediates by treating cells with NB-598 did not greatly affect either the setting of their ER cholesterol pool or the inactivation of their HMGR. In summary, neither SREBP-regulated genes nor 27-hydroxycholesterol is involved in setting the ER cholesterol pool. On the other hand, 27-hydroxycholesterol, rather than cholesterol itself or biosynthetic precursors of cholesterol, stimulates the rapid inactivation of HMGR in response to high levels of cholesterol.

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Prolyl dihydroxylation of unassembled uS12/Rps23 regulates fungal hypoxic adaptation

eLife ◽

10.7554/elife.28563 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 5

Author(s):

Sara J Clasen ◽

Wei Shao ◽

He Gu ◽

Peter J Espenshade

Keyword(s):

Regulatory Element ◽

Regulatory System ◽

Low Oxygen ◽

Hypoxic Response ◽

Element Binding Protein ◽

Sterol Regulatory Element ◽

Consensus Binding Sequence ◽

Binding Sequence ◽

Protein Transcription

The prolyl-3,4-dihydroxylase Ofd1 and nuclear import adaptor Nro1 regulate the hypoxic response in fission yeast by controlling activity of the sterol regulatory element-binding protein transcription factor Sre1. Here, we identify an extra-ribosomal function for uS12/Rps23 central to this regulatory system. Nro1 binds Rps23, and Ofd1 dihydroxylates Rps23 P62 in complex with Nro1. Concurrently, Nro1 imports Rps23 into the nucleus for assembly into 40S ribosomes. Low oxygen inhibits Ofd1 hydroxylase activity and stabilizes the Ofd1-Rps23-Nro1 complex, thereby sequestering Ofd1 from binding Sre1, which is then free to activate hypoxic gene expression. In vitro studies demonstrate that Ofd1 directly binds Rps23, Nro1, and Sre1 through a consensus binding sequence. Interestingly, Rps23 expression modulates Sre1 activity by changing the Rps23 substrate pool available to Ofd1. To date, oxygen is the only known signal to Sre1, but additional nutrient signals may tune the hypoxic response through control of unassembled Rps23 or Ofd1 activity.

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