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Jan-Ake Gustafsson

Publications and source records attributed to Jan-Ake Gustafsson.

At least 37 records · Page 2Linked to original sources
PubMed2006

Characterization of human thioredoxin-like-1: potential involvement in the cellular response against glucose deprivation.

The thioredoxin system, composed of thioredoxin (Trx) and thioredoxin reductase (TrxR), emerges as one of the most important thiol-based systems involved in the maintenance of the cellular redox balance. Thioredoxin-like-1 (TXL-1) is a highly conserved protein comprising an N-terminal Trx domain and a C-terminal domain of unknown function. Here we show that TXL-1 is a substrate for the cytosolic selenoprotein TrxR-1. In situ hybridization experiments demonstrates high expression of Txl-1 mRNA in various areas of central nervous system and also in some reproductive organs. Glucose deprivation, but not hydrogen peroxide treatment, reduced the levels of endogenous TXL-1 protein in HEK-293 cell line. Conversely, overexpression of TXL-1 protects against glucose deprivation-induced cytotoxicity. Taken together, the finding that Txl-1 mRNA is highly expressed in tissues which use glucose as a primary energy source and the modulation of TXL-1 levels upon glucose deprivation indicate that TXL-1 might be involved in the cellular response to sugar starvation stress.

Animals↗
PubMed2006

Muscle GLUT4 regulation by estrogen receptors ERbeta and ERalpha.

Estrogen is known to influence glucose homeostasis with dominant effects in the liver, but the role of estrogen receptors in muscle glucose metabolism is unknown. In the present study, we investigated the expression of the two estrogen receptors, ERalpha and ERbeta, and their influence on regulation of the glucose transporter, GLUT4, and its associated structural protein, caveolin-1, in mouse gastrocnemius muscle. Immunohistochemical analysis revealed that ERalpha and ERbeta are coexpressed in the nuclei of most muscle cells, and that their levels were not affected by absence of estradiol [in aromatase-knockout (ArKO) mice]. GLUT4 expression on the muscle cell membrane was not affected by loss of ERbeta but was extremely reduced in ERalpha(-/-) mice and elevated in ArKO mice. RT-PCR confirmed a parallel reduction in GLUT4 mRNA levels in ERalpha(-/-) mice. Upon treatment of ArKO mice with the ERbeta agonist 2,3-bis(4-hydroxyphenyl)propionitrile, GLUT4 expression was reduced. By immunofluorescence and Western blotting, caveolin-1 expression was higher in ArKO mice and lower in ERbeta(-/-) and ERalpha(-/-) mice than in WT littermates. GLUT4 and caveolin-1 were colocalized in WT and ArKO mice but not in ERbeta(-/-) and ERalpha(-/-) mice. These results reveal that ERalpha is a positive regulator of GLUT4 expression, whereas ERbeta has a suppressive role. Both ERbeta and ERalpha are necessary for optimal caveolin-1 expression. Taken together, these results indicate that colocalization of caveolin-1 and GLUT4 is not an absolute requirement for muscle glucose metabolism but that reduction in GLUT4 could be contributing to the insulin resistance observed in ERalpha(-/-) mice.

Animals↗
PubMed2006

Pitavastatin effect on ATP binding cassette A1-mediated lipid efflux from macrophages: evidence for liver X receptor (LXR)-dependent and LXR-independent mechanisms of activation by cAMP.

The promotion of lipid efflux from macrophages is an important ATP binding cassette A1 (ABCA1)-mediated antiatherosclerotic mechanism that prevents peripheral tissues from foam cell accumulation. Statins exert beneficial antiatherosclerotic effects on cardiovascular disease correlated to the cholesterol-lowering properties and the pleiotropic activities. In this work, we investigated the ability of statins to modulate ABCA1-mediated lipid efflux from macrophages, where the protein expression was differently induced. Pitavastatin (0.1-10 microM) and compactin (10 microM) reduced both cholesterol and phospholipid efflux up to 60% from macrophages expressing ABCA1 upon treatment with 8-(4-chlorophenylthio)-cyclic AMP (cpt-cAMP), and this was secondary to a reduction of ABCA1 mRNA and protein content. Conversely, statins did not affect ABCA1 activity when the protein was up-regulated by 22-hydroxycholesterol/9-cis-retinoic acid or through cholesterol loading. Statin inhibition of lipid efflux induced by cpt-cAMP was reversed in the presence of mevalonate, 22-hydroxycholesterol, and cholesterol but not geranyl geraniol. In macrophages obtained from liver X receptor (LXR)-deficient mice, cpt-cAMP still promoted cholesterol efflux, but pitavastatin did not exert any effect. The present work shows that statins may inhibit ABCA1-mediated lipid efflux in macrophages only when ABCA1 protein expression is induced by cpt-cAMP and provides evidence that cAMP may activate ABCA1 independently of an increase of intracellular sterol synthesis but through at least two pathways: one independent of LXR and one involving an intracellular sterol(s) acting as LXR ligand(s). In addition, the lack of inhibitory effect on lipid efflux in cholesterol-loaded macrophages is likely to exclude a potential negative pleiotropic effect by statins.

ATP Binding Cassette Transporter 1↗
PubMed2006

Differential expression of oestrogen receptors in human secondary lymphoid tissues.

Many autoimmune diseases including rheumatoid arthritis (RA), Sjögren's syndrome (SS) and systemic lupus erythematosus (SLE) occur much more frequently in women than in men. There is much evidence that oestrogen is the major cause of this gender difference. Interestingly, oestrogen relieves the symptoms of RA and SS but it exacerbates SLE. This contradictory effect of oestrogen on autoimmune diseases is not well understood. Most of the effects of oestrogen are mediated by two receptors: oestrogen receptor alpha and beta (ERalpha and ERbeta). To determine whether these contradictory effects of oestrogen relate to the involvement of distinct effects of the two ERs, we investigated expression of ERalpha and ERbeta in human secondary lymphoid tissues. We observed that, in tonsils, ERbeta is expressed in lymphocytes of germinal centres (GC) and the follicular mantle zone as well as in granulocytes, while ERalpha is expressed only in activated germinal centres but not in the follicular zone. ERbeta is the predominant ER in human leucocytes from peripheral blood, spleen and in leucocytes infiltrating cancers in both males and females. In addition, in different human lymphoma cell lines including Hodgkin lymphoma, Burkitt lymphoma, and multiple myeloma, ERbeta is abundant while ERalpha is not detectable. Our results indicate that ERbeta is the predominant type of ER in mature lymphocytes. We suggest that ERalpha and ERbeta have distinct roles in secondary lymphoid tissues and that further studies with ERbeta-specific agonists will help to elucidate the role of ERbeta in these tissues.

Adult↗
PubMed2006

Proteomic identification of glucocorticoid receptor interacting proteins.

The glucocorticoid receptor (GR) acts as a ligand dependent transcription factor but can also cross talk with other signaling pathways via protein-protein interactions. In this paper we describe methods to study novel cytosolic GR interacting proteins, using mAb based immunoaffinity chromatography of GR from rat liver cytosol. Co-purifying proteins were identified by 2-DE in combination with MALDI-TOF-MS. Non-liganded/non-activated and in vitro liganded/activated GR, respectively, co-purifies with specific sets of proteins. Of these 34 were conclusively identified, seven have previously been reported to be part of the GR-complex, revealing 27 new possible interacting candidates for the GR-complex. Of the novel GR interacting proteins the major vault protein, TATA binding interacting protein 49a and glycoprotein PP63 were of special interest. Furthermore, using 2-D DIGE we show that the set of proteins interacting with non-liganded GR is distinctly different in protein amount compared to the proteins found with liganded/activated GR. This suggests the presence of different GR complexes in the cell, which was further substantiated by the finding of several separate GR native protein complexes, "GR-receptosomes", using blue native gel electrophoresis. Our findings suggest the existence of several new mechanisms for GR signaling and regulation.

Animals↗
PubMed2006

Expression of the proto-oncoprotein breast cancer nuclear receptor auxiliary factor (Brx) is altered in eutopic endometrium of women with endometriosis.

OBJECTIVE: To evaluate the expression of estrogen receptor alpha (ERalpha), estrogen receptor beta (ERbeta), and breast cancer nuclear receptor auxiliary factor (Brx) in eutopic endometrium of normal women and women with endometriosis. DESIGN: Prospective observational study. SETTING: Tertiary care and research center. PATIENT(S): Twenty-nine women with endometriosis and 35 healthy ovulatory volunteers of similar ages. INTERVENTION(S): Endometrial biopsy. MAIN OUTCOME MEASURE(S): Expression of immunohistochemical staining intensity and localization of ERalpha, ERbeta, and Brx proteins in eutopic endometrium during the menstrual cycle. RESULT(S): Expression of ERalpha and ERbeta was highest in the proliferative phase and was similar in both groups. Brx expression differed between healthy volunteers and those with endometriosis. During the proliferative phase, immunostaining intensity of Brx was greater in both the glandular and the stromal compartments of biopsies from patients with endometriosis compared to healthy volunteers; nuclear stromal Brx staining was more common in patients with endometriosis. CONCLUSION(S): The spatiotemporal expression of Brx was altered in eutopic endometrium of women with endometriosis. These findings suggest a fundamental alteration in the endometrium of women who have endometriosis. The role of Brx in ectopic implantation of endometrium deserves further study.

A Kinase Anchor Proteins↗
PubMed2006

Dihydrotestosterone treatment results in obesity and altered lipid metabolism in orchidectomized mice.

OBJECTIVE: To determine the role of androgen receptor (AR) activation for adipose tissue metabolism. Sex steroids are important regulators of adipose tissue metabolism in men. Androgens may regulate the adipose tissue metabolism in men either directly by stimulation of the AR or indirectly by aromatization of androgens into estrogens and, thereafter, by stimulation of the estrogen receptors. Previous studies have shown that estrogen receptor alpha stimulation results in reduced fat mass in men. RESEARCH METHODS AND PROCEDURES: Orchidectomized mice were treated with the non-aromatizable androgen 5alpha-dihydrotestosterone (DHT), 17beta-estradiol, or vehicle. Vo(2), Vco(2), resting metabolic rate, locomotor activity, and food consumption were measured. Furthermore, changes in hepatic gene expression were analyzed. RESULTS: DHT treatment resulted in obesity, associated with reduced energy expenditure and fat oxidation. In contrast, DHT did not affect food consumption or locomotor activity. Furthermore, DHT treatment resulted in increased high-density lipoprotein-cholesterol and triglyceride levels associated with markedly decreased 7alpha-hydroxylase gene expression, indicating decreased bile acid production. DISCUSSION: We showed that AR activation results in obesity and altered lipid metabolism in orchidectomized mice. One may speculate that AR antagonists might be useful in the treatment of obesity in men.

Adiposity↗
PubMed2006

The Women's Health Initiative. What is on trial: nutrition and chronic disease? Or misinterpreted science, media havoc and the sound of silence from peers?

The first results of the Women's Health Initiative dietary intervention trial were published in the USA in February. This is a colossal intervention designed to see if diets lower in fat and higher in fruits, vegetables and grains than is usual in high-income countries reduce the incidence of breast cancer, colorectal cancer, heart disease and other chronic diseases, in women aged 50-79 years. As interpreted by US government media releases, the results were unimpressive. As interpreted by a global media blitz, the results indicate that food and nutrition has little or nothing to do with health and disease. But the trial was in key respects not reaching its aims, was methodologically controversial, and in any case has not produced the reported null results. What should the public health nutrition profession do about such messes?

Aged↗
PubMed2006

Sex and the liver - a journey through five decades.

Metabolism of steroids and drugs in rodents is sexually differentiated. The reason for this turned out to be the sexually differentiated growth hormone (GH) secretory pattern regulating the expression of a number of hepatic cytochrome P-450 genes. Although not fully resolved, it is clear that several signaling pathways and transcription factors are involved in mediating the effects of GH. It may be argued that such a well-controlled physiological system should have an important biological role and we speculate that the demands of a robust hepatic steroid metabolism during pregnancy has led to the development of this sexually differentiated hypothalamo-pituitary-liver axis.

Animals↗
PubMed2006

Soy-isoflavone-enriched foods and markers of lipid and glucose metabolism in postmenopausal women: interactions with genotype and equol production.

BACKGROUND: The hypocholesterolemic effects of soy foods are well established, and it has been suggested that isoflavones are responsible for this effect. However, beneficial effects of isolated isoflavones on lipid biomarkers of cardiovascular disease risk have not yet been shown. OBJECTIVE: The objective was to investigate the effects of isolated soy isoflavones on metabolic biomarkers of cardiovascular disease risk, including plasma total, HDL, and LDL cholesterol; triacylglycerols; lipoprotein(a); the percentage of small dense LDL; glucose; nonesterified fatty acids; insulin; and the homeostasis model assessment of insulin resistance. Differences with respect to single nucleotide polymorphisms in selected genes [ie, estrogen receptor alpha (XbaI and PvuII), estrogen receptor beta (AluI), and estrogen receptor beta(cx) (Tsp509I), endothelial nitric oxide synthase (Glu298Asp), apolipoprotein E (Apo E2, E3, and E4), cholesteryl ester transfer protein (TaqIB), and leptin receptor (Gln223Arg)] and with respect to equol production were investigated. DESIGN: Healthy postmenopausal women (n = 117) participated in a randomized, double-blind, placebo-controlled, crossover dietary intervention trial. Isoflavone-enriched (genistein-to-daidzein ratio of 2:1; 50 mg/d) or placebo cereal bars were consumed for 8 wk, with a wash-out period of 8 wk before the crossover. RESULTS: Isoflavones did not have a significant beneficial effect on plasma concentrations of lipids, glucose, or insulin. A significant difference between the responses of HDL cholesterol to isoflavones and to placebo was found with estrogen receptor beta(cx) Tsp509I genotype AA, but not GG or GA. CONCLUSIONS: Isoflavone supplementation, when provided in the form and dose used in this study, had no effect on lipid or other metabolic biomarkers of cardiovascular disease risk in postmenopausal women but may increase HDL cholesterol in an estrogen receptor beta gene-polymorphic subgroup.

Aged↗
PubMed2006

Functional characterization of a novel variant of estrogen receptor beta identified in screening of DNA derived from African Americans.

OBJECTIVE: Information on single nucleotide polymorphisms in the estrogen receptor beta (ERbeta) gene is lacking for the African American population. METHODS: In this study, we systematically screened the coding and flanking intron regions of the ERbeta gene in 49 healthy African American individuals. RESULTS: We detected four novel variants, of which one variant (963T-->C) resulted in amino acid change from phenylalanine to leucine at position 289, referred to as ERbetaF289L. This receptor variant was characterized in vitro for transcriptional activity and ligand-binding. These studies revealed that ERbetaF289L had reduced estrogen binding affinity and impaired response to 17beta-estradiol induced transactivation compared to the wild-type ERbeta. CONCLUSION: This novel variant might confer genetic susceptibility to certain endocrine related diseases in African Americans.

Black or African American↗
PubMed2006

Liver X receptor gene polymorphisms and adipose tissue expression levels in obesity.

OBJECTIVE: LXRA and LXRB genes regulate adiposity, energy dissipation, as well as glucose and lipid homeostasis in mice. We investigated the LXR genes in human obesity. METHODS: LXRA and LXRB mRNAs were quantified in abdominal subcutaneous adipose tissue of obese and nonobese women. The LXRA and LXRB genes were screened for polymorphisms and common single nucleotide polymorphisms genotyped in obese and nonobese women. RESULTS: Relative LXRA mRNA expression levels were higher in obese women (P=0.03). One LXRA single nucleotide polymorphism, rs2279238, and one common haplotype, CAAGCC, as well as two LXRB single nucleotide polymorphisms, LB44732G>A and rs2695121, were associated with obesity phenotypes (nominal P values of 0.0075, 0.0014, 0.008 and 0.02, respectively). Furthermore, there was evidence of interaction between LXRA and LXRB alleles in determining body mass index. CONCLUSION: Our results support a role for LXRA in human adipose tissue. The nominal associations of LXRA and LXRB alleles with obesity are interesting and should be further investigated in independent data sets.

Adipose Tissue↗
PubMed2006

Estrogen receptor-beta gene disruption potentiates estrogen-inducible aggression but not sexual behaviour in male mice.

Aggressive behaviour of gonadally intact male mice is increased by estrogen receptor (ER)-beta gene disruption, whereas sexual behaviour remains unchanged. The elevated aggression levels following ER-beta gene disruption is pronounced during repeated aggression tests in young animals and the first aggression test in adults. In the present study, the roles of ER-beta activation in the regulation of aggressive and sexual behaviour were investigated in gonadectomized ER-beta knockout (betaERKO) and wild-type (WT) male mice treated with various doses of estrogen. Overall, estradiol benzoate (EB) treatment induced higher levels of aggression in betaERKO mice than in WT mice. In WT mice, the levels of aggression induced by EB were highest in the lowest-dose (2.5 microg/day) group and gradually decreased in higher-dosage groups. On the other hand, equally high levels of aggressive behaviour were induced by all three doses of EB in betaERKO mice. A marked genotype difference in dose responses is inferred, such that the ER-alpha-mediated facilitatory action of estrogen is more pronounced at lower and physiological doses and the ER-beta-mediated inhibitory action is only unveiled at higher doses of estrogen. In contrast to aggression, the levels of sexual behaviour induced by EB were not different between betaERKO and WT at either dose of EB (2.5 and 12.5 microg/day) examined. These findings support the notion that ER-beta activation may exert an attenuating action on male aggression induced by estrogen through ER-alpha-mediated brain mechanisms, whereas its effect on male sexual behaviour is relatively small.

Aggression↗
PubMed2006

Cholesterol-sensing receptors, liver X receptor alpha and beta, have novel and distinct roles in osteoclast differentiation and activation.

UNLABELLED: The liver X receptor (alpha,beta) is responsible for regulating cholesterol homeostasis in cells. However, our studies using the LXRalpha-/-, LXRbeta-/-, and LXRalpha-/-beta-/- mice show that both LXRalpha and beta are also important for bone turnover, mainly by regulating osteoclast differentiation/activity. INTRODUCTION: The liver X receptors (alpha,beta) are primarily responsible for regulating cholesterol homeostasis within cells and the whole body. However, as recent studies show that the role for this receptor is expanding, we studied whether the LXRs could be implicated in bone homeostasis and development. MATERIALS AND METHODS: pQCT was performed on both male and female LXRalpha-/-, LXRbeta-/-, LXRalpha-/-beta-/-, and WT mice at 4 months and 1 year of age. Four-month-old female mice were additionally analyzed with reference to qPCR, immunohistochemistry, histomorphometry, transmission electron microscopy, and serum bone turnover markers. RESULTS: At the mRNA level, LXRbeta was more highly expressed than LXRalpha in both whole long bones and differentiating osteoblast-like MC3T3-E1 and osteoclast-like RAW 264.7 cells. Four-month-old female LXRalpha-/- mice had a significant increase in BMD because of an increase in all cortical parameters. No difference was seen regarding trabecular BMD. Quantitative histomorphometry showed that these mice had significantly more endosteal osteoclasts in the cortical bone; however, these cells appeared less active than normal cells as suggested by a significant reduction in serum levels of cross-linked carboxyterminal telopeptides of type I collagen (CTX) and a reduction in bone TRACP activity. Conversely, the female LXRbeta-/- mice exhibited no change in BMD, presumably because a significant decline in the number of the trabecular osteoclasts was compensated for by an increase in the expression of the osteoclast markers cathepsin K and TRACP. These mice also had a significant decrease in serum CTX, suggesting decreased bone resorption; however, in addition presented with an increase in the expression of osteoblast associated genes, bone formation markers, and serum leptin levels. CONCLUSIONS: Our findings show that both LXRs influence cellular function within the bone, with LXRalpha having an impact on osteoclast activity, primarily in cortical bone, whereas LXRbeta modulates trabecular bone turnover.

Acid Phosphatase↗
PubMed2005

Estrogen receptor (ER) beta modulates ERalpha-mediated transcriptional activation by altering the recruitment of c-Fos and c-Jun to estrogen-responsive promoters.

In this study, an estrogen receptor (ER) alpha-expressing T47D cell line containing an inducible tet-off FLAG-ERbeta was used to examine the influence of ERbeta on ERalpha activity. Real-time PCR analysis of mRNA levels of two well-studied estrogen-responsive genes, pS2 and progesterone receptor (PR), showed that the expression levels of both genes were reduced in the presence of ERbeta. Chromatin immunoprecipitation assays showed that the 17beta-estradiol (E2)-induced recruitment patterns to the pS2 and PR promoters were similar for both ERalpha and ERbeta. ERbeta expression did not significantly influence the kinetic recruitment profile of ERalpha to the pS2 promoter, but it was evident that ERalpha occupancy at the PR promoter was reduced. The E2-induced recruitment of c-Fos to a 12-O-tetradecanoylphorbol-13-acetate response element site in the PR promoter was significantly reduced in the presence of ERbeta, whereas only a slight reduction in the recruitment of c-Fos to the pS2 promoter was observed. ERbeta expression resulted in a significant reduction in the E2-induced expression of c-Fos mRNA. The recruitment pattern of c-Jun was also altered by ERbeta, although the expression levels of c-Jun were not. Expression of ERbeta caused a further 30-50% decrease of the E2-induced reduction in ERalpha protein after 3 h of E2 treatment, showing that ERbeta influences ERalpha protein levels. The altered recruitment of the activating protein-1 complex, combined with the reduction in ERalpha protein levels, may partly explain the antagonistic effect of ERbeta on ERalpha-mediated transcription.

Cell Line↗
PubMed2005

Transcriptional corepression by SHP: molecular mechanisms and physiological consequences.

Small heterodimer partner (SHP; NR0B2), an exceptional member of the mammalian nuclear receptor family, directly modulates the activities of conventional nuclear receptors by acting as an inducible and tissue-specific corepressor. Recent progress in dissecting underlying molecular mechanisms, identifying target factors and target genes, and uncovering physiological functions points to the regulatory involvement of SHP in diverse metabolic and intracellular pathways that awaits future clarification. In this review, we carry out a comprehensive survey of all published data and discuss our current understanding of molecular mechanisms and physiological consequences governing SHP action.

Animals↗
PubMed2005

Nongenomic effects of estrogen: why all the uncertainty?

It is clear that estradiol has profound, rapid effects on the conformation of the estrogen receptors (ERs), ERalpha and ERbeta, which mediate the transcriptional effects of estradiol. Estrogen can elicit many other rapid changes in cells including changes in ion fluxes across membranes and stimulation of kinases and phosphatases. The proteins which are the targets of these actions are the subject of intense investigation. One of the issues that have not been satisfactorily resolved is whether ERalpha or ERbeta can reside in the plasma membrane and participate in the rapid effects of estrogen. In the present commentary, we take a careful look at some of the published data in an attempt to understand why it is so difficult to obtain a definitive answer to this question.

Animals↗