Gene expression profiling identifies liver X receptor alpha as an estrogen-regulated gene in mouse adipose tissue

Lundholm, Lovisa; Movérare, Sofia; Steffensen, Knut R.; Nilsson, Maria; Otsuki, Michio; Ohlsson, Claes; Gustafsson, Jan‐Åke; Dahlman-Wright, Karin

doi:10.1677/jme.0.0320879

Cited by 47 publications

(38 citation statements)

References 74 publications

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“…In mice and humans, ERa is the predominant ER expressed in adipose tissues (Lundholm et al 2004), and our previous studies are consistent with direct actions of E 2 via ERa on the adipose depots (Misso et al 2003, Hewitt et al 2004, McInnes et al 2006. Our data show that the intra-abdominal adiposity (omental and infra-renal fat depots) was reduced by the selective activation of ERa in the male ArKO mice.…”

Section: Era-mediated Pathways: Peripheral Effectssupporting

confidence: 90%

A selective estrogen receptor α agonist ameliorates hepatic steatosis in the male aromatase knockout mouse

Chow¹,

Jones²,

Prelle

et al. 2011

Journal of Endocrinology

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Male aromatase knockout mice (ArKO; an estrogen-deficient model) present with male-specific hepatic steatosis that is reversible upon 17b-estradiol replacement. This study aims to elucidate which estrogen receptor (ER) subtype, ERa or ERb, is involved in the regulation of triglyceride (TG) homeostasis in the liver. Nine-month-old male ArKO mice were treated with vehicle, ERa-or ERb-specific agonists via s.c. injection, daily for 6 weeks. Male ArKO mice treated with ERa agonist had normal liver histology and TG contents compared with vehicle-treated ArKO; omental (gonadal) and infra-renal (visceral) fat pad weights were normalized to those of vehicle-treated wild-type (WT). In contrast, ERb agonist treatment did not result in the similar reversal of these ArKO phenotypes. In vehicle-treated ArKO mice, hepatic transcript expression of fatty acid synthase (Fasn) and stearoyl-coenzyme A desaturase 1 (key enzymes in de novo FA synthesis) were significantly elevated compared with vehicle-treated WT, but only Fasn expression was lowered to WT level after ERa agonist treatment. There were no significant changes in the transcript levels of carnitine palmitoyl transferase 1 (required for transfer of FA residues into the mitochondria for b-oxidation) and sterol regulatory element-binding factor 1c (the upstream regulator of de novo FA synthesis). We also confirmed by RT-PCR that only ERa is expressed in the mouse liver. There were no changes in hepatic androgen receptor transcript level across all treatment groups. Our data suggest that estrogens act via ERa to regulate TG homeostasis in the ArKO liver. Since the liver, adipose tissue and arcuate nucleus express mainly ERa, estrogens could regulate hepatic functions via peripheral and central pathways.

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Section: Era-mediated Pathways: Peripheral Effectssupporting

confidence: 90%

A selective estrogen receptor α agonist ameliorates hepatic steatosis in the male aromatase knockout mouse

Chow¹,

Jones²,

Prelle

et al. 2011

Journal of Endocrinology

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“…Data from our laboratory and others show that LXRα is a target for ERα (38) and in liver the synthesis of liver X receptor (LXR) α is regulated by the estrous cycle and is significantly increased in LERKO mice. On the other hand, IGF-1 is known to regulate the activity of HNF4, a transcription factor relevant for fatty acid deposition (39); we believe that the physiological changes in circulating estrogens and IGF-1 favor the different pathways regulating lipid synthesis, which will alternate in response to these two hormones (Fig.…”

Section: Discussionmentioning

confidence: 91%

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

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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...

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“…The two ERs show overlapping, yet distinct, patterns of expression (DahlmanWright et al 2006). Of particular relevance for glucose homeostasis, ERa is the major ER expressed in the liver (Kuiper et al 1997), adipose tissue (Lundholm et al 2004), skeletal muscle (Wiik et al 2003), and pancreatic islets (Geisler et al 2002). ER subtype-specific ligands have been developed, and are increasingly used to further clarify the specific roles of ERa and ERb .…”

Section: Introductionmentioning

confidence: 99%

The estrogen receptor α-selective agonist propyl pyrazole triol improves glucose tolerance in ob/ob mice; potential molecular mechanisms

Lundholm

Bryzgalova

Gao

et al. 2008

Journal of Endocrinology

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The aim of this study was to validate the role of estrogen receptor a (ERa) signaling in the regulation of glucose metabolism, and to compare the molecular events upon treatment with the ERa-selective agonist propyl pyrazole triol (PPT) or 17b-estradiol (E 2 ) in ob/ob mice. Female ob/ob mice were treated with PPT, E 2 or vehicle for 7 or 30 days. Intraperitoneal glucose and insulin tolerance tests were performed, and insulin secretion was determined from isolated islets. Glucose uptake was assayed in isolated skeletal muscle and adipocytes. Gene expression profiling in the liver was performed using Affymetrix microarrays, and the expression of selected genes was studied by real-time PCR analysis. PPTand E 2 treatment improved glucose tolerance and insulin sensitivity. Fasting blood glucose levels decreased after 30 days of PPT and E 2 treatment. However, PPT and E 2 had no effect on insulin secretion from isolated islets. Basal and insulin-stimulated glucose uptake in skeletal muscle and adipose tissue were similar in PPT and vehicle-treated ob/ob mice. Hepatic lipid content was decreased after E 2 treatment. In the liver, treatment with E 2 and PPT increased and decreased the respective expression levels of the transcription factor signal transducer and activator of transcription 3, and of glucose-6-phosphatase. In summary, our data demonstrate that PPTexerts anti-diabetic effects, and these effects are mediated via ERa.

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Gene expression profiling identifies liver X receptor alpha as an estrogen-regulated gene in mouse adipose tissue

Cited by 47 publications

References 74 publications

A selective estrogen receptor α agonist ameliorates hepatic steatosis in the male aromatase knockout mouse

A selective estrogen receptor α agonist ameliorates hepatic steatosis in the male aromatase knockout mouse

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

The estrogen receptor α-selective agonist propyl pyrazole triol improves glucose tolerance in ob/ob mice; potential molecular mechanisms

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