Long-Term Administration of Estradiol Decreases Expression of Hepatic Lipogenic Genes and Improves Insulin Sensitivity in ob/ob Mice: A Possible Mechanism Is through Direct Regulation of Signal Transducer and Activator of Transcription 3

Gao, Hui; Bryzgalova, Galyna; Hedman, Erik; Khan, Abdul Waheed; Efendić, Suad; Gustafsson, Jan Åke; Dahlman-Wright, Karin

doi:10.1210/me.2006-0012

Cited by 162 publications

(124 citation statements)

References 30 publications

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“…The microarray analysis successfully identified 47 and 51 genes upand down-regulated by estradiol treatment (Ն2.0-fold, P Ͻ 0.05), and those showing Ն2.5-fold change in gene expression are listed in Table 1. Some of these genes were previously reported as estradiol-responsive (Gao et al, 2006), with changes in expression of 7.1-fold (P Ͻ 0.05) and 9.0-fold (P Ͻ 0.05), respectively, as confirmed by quantitative PCR analysis, suggesting, in part, that our microarray analysis was successful.…”

Section: Resultssupporting

confidence: 72%

“…In mouse liver, microarray analysis revealed that expression of numerous genes is regulated by ethynyl estradiol, including oxidative metabolism and stress, and lipid metabolism and transport genes (Boverhof et al, 2004). Another study also showed that many mouse hepatic genes were regulated by estradiol, including the genes of lipid metabolism and synthesis, such as leptin receptor (LEPR) and stearoyl-CoA desaturase (SCD) (Gao et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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Effect of Estradiol on Gene Expression Profile in Cynomolgus Macaque Liver: Implications for Drug-Metabolizing Enzymes

Uno

Kito²

2011

Drug Metab Dispos

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ABSTRACT:Estrogen regulation of gene expression is essential for physiological function of estrogen-responsive tissues, such as mammary glands, ovaries, and the uterus. In the liver, estrogen is responsible for sex-dependent gene expression of drug-metabolizing enzymes in rodents. However, the influence of estrogen on hepatic gene expression has not been fully investigated in primates, including human. Macaque, including cynomolgus macaque, is an important species for comparative studies aimed at understanding human physiology due to its evolutionary closeness to human. To identify estrogen-responsive genes in primate liver, therefore, hepatic gene expression was compared, by microarray analysis, in ovariectomized cynomolgus macaques treated with estradiol or solvent (control). The analysis identified 98 estradiol-responsive genes; 47 and 51 were up-and down-regulated by estradiol, respectively (>2.0-fold, P < 0.05). Expression of drug-metabolizing enzyme genes was also influenced by estradiol treatment; estradiol enhanced expression of GSTM5 (3.8-fold, P < 0.05) and CYP3A8(4) (2.7-fold, P < 0.01), but lowered expression of CYP4F12 (2.2-fold, P < 0.01), as verified by quantitative polymerase chain reaction. In particular, CYP3A8(4), orthologous to human CYP3A4, is an essential drug-metabolizing enzyme in cynomolgus macaque liver. These results suggest that expression of hepatic genes, including drug-metabolizing enzyme genes, is at least partly regulated by estradiol in cynomolgus macaque.

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Section: Resultssupporting

confidence: 72%

Section: Introductionmentioning

confidence: 99%

Effect of Estradiol on Gene Expression Profile in Cynomolgus Macaque Liver: Implications for Drug-Metabolizing Enzymes

Uno

Kito²

2011

Drug Metab Dispos

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“…Previous studies have reported that E2 suppresses lipogenesis in white adipose tissue and liver in vivo (32,33). However, it is unknown whether the antilipogenic effects of E2 are mediated via activation of adipocyte or hepatocyte ERs or via the central nervous system, similar to leptin signals from the mediobasal hypothalamus that trigger sympathetic outflow to white adipose tissue (34).…”

Section: Discussionmentioning

confidence: 99%

Estrogen receptor activation reduces lipid synthesis in pancreatic islets and prevents β cell failure in rodent models of type 2 diabetes

Tiano

Delghingaro-Augusto²,

et al. 2011

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The failure of pancreatic β cells to adapt to an increasing demand for insulin is the major mechanism by which patients progress from insulin resistance to type 2 diabetes (T2D) and is thought to be related to dysfunctional lipid homeostasis within those cells. In multiple animal models of diabetes, females demonstrate relative protection from β cell failure. We previously found that the hormone 17β-estradiol (E2) in part mediates this benefit. Here, we show that treating male Zucker diabetic fatty (ZDF) rats with E2 suppressed synthesis and accumulation of fatty acids and glycerolipids in islets and protected against β cell failure. The antilipogenic actions of E2 were recapitulated by pharmacological activation of estrogen receptor α (ERα) or ERβ in a rat β cell line and in cultured ZDF rat, mouse, and human islets. Pancreas-specific null deletion of ERα in mice (PERα -/-) prevented reduction of lipid synthesis by E2 via a direct action in islets, and PERα -/-mice were predisposed to islet lipid accumulation and β cell dysfunction in response to feeding with a high-fat diet. ER activation inhibited β cell lipid synthesis by suppressing the expression (and activity) of fatty acid synthase via a nonclassical pathway dependent on activated Stat3. Accordingly, pancreas-specific deletion of Stat3 in mice curtailed ER-mediated suppression of lipid synthesis. These data suggest that extranuclear ERs may be promising therapeutic targets to prevent β cell failure in T2D.

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“…However, an emerging importance of ESR1 in metabolic systems is evident, as a number of ESR1 polymorphisms have been associated with metabolic syndromes like atherosclerosis and type II diabetes (19,29,37,58). Moreover, in hepatic tissue, administration of estradiol downregulates expression of lipogenic genes and improves insulin sensitivity (30). ESR1 was 2.4-fold upregulated with CR (q ϭ 0.03, P ϭ 0.01) and had the highest number of DE target genes compared with any other TF in the four categories of genes in our study (Fig.…”

Section: Esr1 Targets Cr-induced De Genes In Cell Cycle and Apoptoticmentioning

confidence: 99%

Gene expression profiling of the short-term adaptive response to acute caloric restriction in liver and adipose tissues of pigs differing in feed efficiency

Lkhagvadorj¹,

Cai

et al. 2010

American Journal of Physiology-Regulatory, Integrative and Comp

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Residual feed intake (RFI) is a measure of feed efficiency, in which low RFI denotes improved feed efficiency. Caloric restriction (CR) is associated with feed efficiency in livestock species and to human health benefits, such as longevity and cancer prevention. We have developed pig lines that differ in RFI, and we are interested in identifying the genes and pathways that underlie feed efficiency. Prepubertal Yorkshire gilts with low RFI (n ϭ 10) or high RFI (n ϭ 10) were fed ad libitum or fed at restricted intake of 80% of maintenance energy requirements for 8 days. We measured serum metabolites and hormones and generated transcriptional profiles of liver and subcutaneous adipose tissue on these animals. Overall, 6,114 genes in fat and 305 genes in liver were differentially expressed (DE) in response to CR, and 311 genes in fat and 147 genes in liver were DE due to RFI differences. Pathway analyses of CR-induced DE genes indicated a dramatic switch to a conservation mode of energy usage by down-regulating lipogenesis and steroidogenesis in both liver and fat. Interestingly, CR altered expression of genes in immune and cell cycle/apoptotic pathways in fat, which may explain part of the CR-driven lifespan enhancement. In silico analysis of transcription factors revealed ESR1 as a putative regulator of the adaptive response to CR, as several targets of ESR1 in our DE fat genes were annotated as cell cycle/ apoptosis genes. The lipid metabolic pathway was overrepresented by down-regulated genes due to both CR and low RFI. We propose a common energy conservation mechanism, which may be controlled by PPARA, PPARG, and/or CREB in both CR and feed-efficient pigs. microarray; transcriptional profiling; ESR1; residual feed intake; peroxisome proliferator-activated receptor a; peroxisome proliferatoractivated receptor g; cAMP response element binding; protein GENETIC MECHANISMS THAT CONTROL feed intake (FI) and feed efficiency are not well understood. Differences in feed efficiency arise due to factors such as variations in body composition, feeding patterns, digestibility, activity, thermoregulation, and tissue metabolic rates (68). Residual feed intake (RFI) has been broadly accepted as a reliable method of measuring feed efficiency and is defined as the feed consumed above or below what is required for growth and maintenance (47, 54). Pigs with low RFI (LRFI) consume less food than the population average without a significant loss in growth parameters such as body weight and composition, and therefore, they are more feed efficient. Our group has successfully developed pig lines that differ in RFI up to 124 g/day without significant change in the body composition, with an estimated heritability for RFI of 0.33 (12). The physiology underlying RFI differences has been studied mainly in poultry and in beef cattle, in which whole-genome SNP analyses and microarray approaches have been undertaken (6, 9, 74). For example, transcriptomic analysis of liver biopsies from Angus bulls identified 163 differentially expressed genes...

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Long-Term Administration of Estradiol Decreases Expression of Hepatic Lipogenic Genes and Improves Insulin Sensitivity in ob/ob Mice: A Possible Mechanism Is through Direct Regulation of Signal Transducer and Activator of Transcription 3

Cited by 162 publications

References 30 publications

Effect of Estradiol on Gene Expression Profile in Cynomolgus Macaque Liver: Implications for Drug-Metabolizing Enzymes

Effect of Estradiol on Gene Expression Profile in Cynomolgus Macaque Liver: Implications for Drug-Metabolizing Enzymes

Estrogen receptor activation reduces lipid synthesis in pancreatic islets and prevents β cell failure in rodent models of type 2 diabetes

Gene expression profiling of the short-term adaptive response to acute caloric restriction in liver and adipose tissues of pigs differing in feed efficiency

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