Unravelling the in vivo
 regulation and metabolic role of the alternative oxidase pathway in C3
 species under photoinhibitory conditions

In addition to the metabolic role of vitamin D, which is well known and clearly defined, there have been many hypotheses regarding its anti-proliferative and pro-apoptotic role. Epidemiology and Significance of Prostate Cancer. Prostate cancer is the second most common malignancy in men. Long period of cancerogenesis, available tumor markers and high incidence make this cancer ideal for preventive measures. Physiological Role of Vitamin D and its Effect on Prostate Cancer Cells. In vitro and in vivo studies have shown the anti-proliferative and pro-apoptopic role of vitamin D. Disorders of vitamin D metabolism are noted in vitamin D gene level, vitamin D receptor, vitamin D responsive elements and androgen receptors. We present the most important effect of those changes on vitamin D metabolism. Conclusion. Available studies on vitamin D level in serum, prostate tissue, observed activity of vitamin D enzymes and genetic changes give us only a slight insight into the basic mechanisms of vitamin D action in the development of prostate cancer; therefore, further investigations are needed.

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Transcript analysis reveals an extended regulon and the importance of protein–protein co-operativity for the Escherichia coli methionine repressor

Biochemical Journal ◽

10.1042/bj20060021 ◽

2006 ◽

Vol 396 (2) ◽

pp. 227-234 ◽

Cited By ~ 31

Author(s):

Ferenc Marincs ◽

Iain W. Manfield ◽

Jonathan A. Stead ◽

Kenneth J. Mcdowall ◽

Peter G. Stockley

Keyword(s):

Escherichia Coli ◽

Gene Replacement ◽

Dna Arrays ◽

Promoter Regions ◽

Mobility Shift ◽

Metabolic Role ◽

Mobility Shift Assay

We have used DNA arrays to investigate the effects of knocking out the methionine repressor gene, metJ, on the Escherichia coli transcriptome. We assayed the effects in the knockout strain of supplying wild-type or mutant MetJ repressors from an expression plasmid, thus establishing a rapid assay for in vivo effects of mutations characterized previously in vitro. Repression is largely restricted to known genes involved in the biosynthesis and uptake of methionine. However, we identified a number of additional genes that are significantly up-regulated in the absence of repressor. Sequence analysis of the 5′ promoter regions of these genes identified plausible matches to met-box sequences for three of these, and subsequent electrophoretic mobility-shift assay analysis showed that for two such loci their repressor affinity is higher than or comparable with the known metB operator, suggesting that they are directly regulated. This can be rationalized for one of the loci, folE, by the metabolic role of its encoded enzyme; however, the links to the other regulated loci are unclear, suggesting both an extension to the known met regulon and additional complexity to the role of the repressor. The plasmid gene replacement system has been used to examine the importance of protein–protein co-operativity in operator saturation using the structurally characterized mutant repressor, Q44K. In vivo, there are detectable reductions in the levels of regulation observed, demonstrating the importance of balancing protein–protein and protein–DNA affinity.

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Augmented expression and secretion of adipose-derived pigment epithelium-derived factor does not alter local angiogenesis or contribute to the development of systemic metabolic derangements

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00046.2014 ◽

2014 ◽

Vol 306 (12) ◽

pp. E1367-E1377 ◽

Cited By ~ 10

Author(s):

Thomas V. Lakeland ◽

Melissa L. Borg ◽

Maria Matzaris ◽

Amany Abdelkader ◽

Roger G. Evans ◽

...

Keyword(s):

Adipose Tissue ◽

Energy Expenditure ◽

Body Mass ◽

Pigment Epithelium ◽

In Vivo Studies ◽

Whole Body ◽

Pigment Epithelium Derived Factor ◽

Metabolic Role

Impaired coupling of adipose tissue expansion and vascularization is proposed to lead to adipocyte hypoxia and inflammation, which in turn contributes to systemic metabolic derangements. Pigment epithelium-derived factor (PEDF) is a powerful antiangiogenic factor that is secreted by adipocytes, elevated in obesity, and implicated in the development of insulin resistance. We explored the angiogenic and metabolic role of adipose-derived PEDF through in vivo studies of mice with overexpression of PEDF in adipocytes (PEDF-aP2). PEDF expression in white adipocytes and PEDF secretion from adipose tissue was increased in transgenic mice, but circulating levels of PEDF were not increased. Overexpression of PEDF did not alter vascularization, the partial pressure of O2, cellular hypoxia, or gene expression of inflammatory markers in adipose tissue. Energy expenditure and metabolic substrate utilization, body mass, and adiposity were not altered in PEDF-aP2 mice. Whole body glycemic control was normal as assessed by glucose and insulin tolerance tests, and adipocyte-specific glucose uptake was unaffected by PEDF overexpression. Adipocyte lipolysis was increased in PEDF-aP2 mice and associated with increased adipose triglyceride lipase and decreased perilipin 1 expression. Experiments conducted in mice rendered obese by high-fat feeding showed no differences between PEDF-aP2 and wild-type mice for body mass, adiposity, whole body energy expenditure, glucose tolerance, or adipose tissue oxygenation. Together, these data indicate that adipocyte-generated PEDF enhances lipolysis but question the role of PEDF as a major antiangiogenic or proinflammatory mediator in adipose tissue in vivo.

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The Role of the Alternative Oxidase in Stabilizing the in Vivo Reduction State of the Ubiquinone Pool and the Activation State of the Alternative Oxidase

PLANT PHYSIOLOGY ◽

10.1104/pp.118.2.599 ◽

1998 ◽

Vol 118 (2) ◽

pp. 599-607 ◽

Cited By ~ 59

Author(s):

Frank F. Millenaar ◽

Joris J. Benschop ◽

Anneke M. Wagner ◽

Hans Lambers

Keyword(s):

Alternative Oxidase

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The Metabolic Effects of Angiopoietin-like protein 8 (ANGPLT8) are Differentially Regulated by Insulin and Glucose in Adipose Tissue and Liver and are Controlled by AMPK Signaling

10.1101/734954 ◽

2019 ◽

Author(s):

Lu Zhang ◽

Chris E. Shannon ◽

Terry M. Bakewell ◽

Muhammad A. Abdul-Ghani ◽

Marcel Fourcaudot ◽

...

Keyword(s):

Adipose Tissue ◽

Transcriptional Control ◽

Metabolic Effects ◽

Luciferase Reporter ◽

Ampk Signaling ◽

Insulin Clamp ◽

Metabolic Role

AbstractObjectiveThe angiopoietin-like protein (ANGPTL) family represents a promising therapeutic target for dyslipidemia, which is a feature of obesity and type 2 diabetes (T2DM). The aim of the present study was to determine the metabolic role of ANGPTL8 and to investigate its nutritional, hormonal and molecular regulation in key metabolic tissues.MethodsThe metabolism of ANGPTL8 knockout mice (ANGPTL8−/−) was examined in mice following chow and high-fat diets (HFD). The regulation of ANGPTL8 expression by insulin and glucose was quantified using a combination of in vivo insulin clamp experiments in mice and in vitro experiments in hepatocytes and adipocytes. The role of AMPK signaling was examined, and the transcriptional control of ANGPTL8 was determined using bioinformatic and luciferase reporter approaches.ResultsThe ANGPTL8−/−mice had improved glucose tolerance and displayed reduced fed and fasted plasma triglycerides. However, there was no reduction in steatosis in ANGPTL8−/−mice after the HFD. Insulin acutely activated ANGPTL8 expression in liver and adipose tissue, which was mediated by C/EBPβ. Using insulin clamp experiments we observed that glucose further enhanced ANGPTL8 expression in the presence of insulin in adipocytes only. The activation of AMPK signaling potently suppressed the effect of insulin on ANGPTL8 expression in hepatocytes.ConclusionThese data show that ANGPTL8 plays an important metabolic role in mice that may extend beyond triglyceride metabolism. The finding that insulin and glucose have distinct roles in regulating ANGPTL8 expression in liver and adipose tissue may provide important clues about the function of ANGPTL8 in these tissues.

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The diversity of sex steroid action: novel functions of hydroxysteroid (17β) dehydrogenases as revealed by genetically modified mouse models

Journal of Endocrinology ◽

10.1530/joe-11-0315 ◽

2011 ◽

Vol 212 (1) ◽

pp. 27-40 ◽

Cited By ~ 54

Author(s):

Taija Saloniemi ◽

Heli Jokela ◽

Leena Strauss ◽

Pirjo Pakarinen ◽

Matti Poutanen

Keyword(s):

Mouse Models ◽

Drug Targets ◽

Genetically Modified ◽

Cholesterol Biosynthesis ◽

Sex Steroid ◽

Target Cells ◽

Metabolic Role

Disturbed action of sex steroid hormones, i.e. androgens and estrogens, is involved in the pathogenesis of various severe diseases in humans. Interestingly, recent studies have provided data further supporting the hypothesis that the circulating hormone concentrations do not explain all physiological and pathological processes observed in hormone-dependent tissues, while the intratissue sex steroid concentrations are determined by the expression of steroid metabolising enzymes in the neighbouring cells (paracrine action) and/or by target cells themselves (intracrine action). This local sex steroid production is also a valuable treatment option for developing novel therapies against hormonal diseases. Hydroxysteroid (17β) dehydrogenases (HSD17Bs) compose a family of 14 enzymes that catalyse the conversion between the low-active 17-keto steroids and the highly active 17β-hydroxy steroids. The enzymes frequently expressed in sex steroid target tissues are, thus, potential drug targets in order to lower the local sex steroid concentrations. The present review summarises the recent data obtained for the role of HSD17B1, HSD17B2, HSD17B7 and HSD17B12 enzymes in various metabolic pathways and their physiological and pathophysiological roles as revealed by the recently generated genetically modified mouse models. Our data, together with that provided by others, show that, in addition to having a role in sex steroid metabolism, several of these HSD17B enzymes possess key roles in other metabolic processes: for example, HD17B7 is essential for cholesterol biosynthesis and HSD17B12 is involved in elongation of fatty acids. Additional studiesin vitroandin vivoare to be carried out in order to fully define the metabolic role of the HSD17B enzymes and to evaluate their value as drug targets.

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Regulation of ANGPTL8 in liver and adipose tissue by nutritional and hormonal signals and its effect on glucose homeostasis in mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00339.2019 ◽

2020 ◽

Vol 318 (5) ◽

pp. E613-E624

Author(s):

Lu Zhang ◽

Chris E. Shannon ◽

Terry M. Bakewell ◽

Muhammad A. Abdul-Ghani ◽

Marcel Fourcaudot ◽

...

Keyword(s):

Adipose Tissue ◽

Transcriptional Control ◽

Luciferase Reporter ◽

Ampk Signaling ◽

Insulin Clamp ◽

Metabolic Role ◽

Promising Therapeutic Target

The angiopoietin-like protein (ANGPTL) family represents a promising therapeutic target for dyslipidemia, which is a feature of obesity and type 2 diabetes (T2DM). The aim of the present study was to determine the metabolic role of ANGPTL8 and to investigate its nutritional, hormonal, and molecular regulation in key metabolic tissues. The regulation of Angptl8 gene expression by insulin and glucose was quantified using a combination of in vivo insulin clamp experiments in mice and in vitro experiments in primary and cultured hepatocytes and adipocytes. The role of AMPK signaling was examined, and the transcriptional control of Angptl8 was determined using bioinformatic and luciferase reporter approaches. The metabolism of Angptl8 knockout mice (ANGPTL8−/−) was examined following chow and high-fat diets (HFD). Insulin acutely increased Angptl8 expression in liver and adipose tissue, which involved the CCAAT/enhancer-binding protein (C/EBPβ) transcription factor. In insulin clamp experiments, glucose further enhanced Angptl8 expression in the presence of insulin in adipose tissue. The activation of AMPK signaling antagonized the effect of insulin on Angptl8 expression in hepatocytes and adipocytes. The ANGPTL8−/− mice had improved glucose tolerance and displayed reduced fed and fasted plasma triglycerides. However, there was no change in body weight or steatosis in ANGPTL8−/− mice after the HFD. These data show that ANGPTL8 plays important metabolic roles in mice that extend beyond triglyceride metabolism. The finding that insulin, glucose, and AMPK signaling regulate Angptl8 expression may provide important clues about the distinct function of ANGPTL8 in these tissues.

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Metabolic Changes in Human CD36 Deficiency Displayed by Glucose Loading

Thrombosis and Haemostasis ◽

10.1055/s-0037-1616523 ◽

2001 ◽

Vol 86 (10) ◽

pp. 995-999 ◽

Cited By ~ 17

Author(s):

Hidekatsu Yanai ◽

Hironobu Fujiwara ◽

Mie Morimoto ◽

Yukihiro Takahashi ◽

Shu-Ping Hui ◽

...

Keyword(s):

Metabolic Changes ◽

Type I ◽

Type Ii ◽

Loading Test ◽

Glucose Loading ◽

Cd36 Deficiency ◽

Metabolic Role

SummaryPrevious in vitro studies have shown that CD36 participates in cellular fatty acid (FA) uptake. In vivo evidence for a physiologic role of CD36 in this process is poor and mostly obtained in animals. To examine the metabolic role of human CD36, we performed a glucose loading test for normals (n = 16) and subjects with CD36 deficiency, both Type I (n = 5) and Type II (n = 16). After 30 min, FA levels had fallen by 60.1% in normals but by only 31.7% in Type II deficiency (P <0.01 vs. normals) and 16.5% in Type I deficiency which remained significantly higher than the other two groups out to 2 h. Further, changes in triglyceride and glucose metabolism were observed in the both types of CD36 deficiency. Impaired fast FA clearance by muscle and consequently increased hepatic FA uptake seem to underlie these changes. We conclude that human CD36 deficiency causes systemic metabolic changes.

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Integration of constraint-based modelling with faecal metabolomics reveals large deleterious effects of Fusobacteria species on community butyrate production

10.1101/2020.09.09.290494 ◽

2020 ◽

Author(s):

Johannes Hertel ◽

Almut Heinken ◽

Filippo Martinelli ◽

Ines Thiele

Keyword(s):

In Silico ◽

Association Studies ◽

Healthy Controls ◽

Theoretical Concepts ◽

Metabolic Functions ◽

Metabolic Role ◽

Model Predictions ◽

Butyrate Production

SummaryIntegrating constraint-based community modelling with population statistics, we introduce new theoretical concepts for interrogating the metabolic functions of the microbiome, applying them to a public metagenomic dataset consisting of 365 colorectal cancer cases (CRC) and 251 healthy controls. We found that 1) glutarate production capability was significantly enriched in CRC microbiomes and mechanistically linked to lysine fermentation in Fusobacteria species, 2) acetate and butyrate production potentials were lowered in CRC, 3) Fusobacteria presence had large negative ecological effects on community butyrate production in CRC and healthy controls. Validating the model predictions against faecal metabolomics, our in silico frameworks correctly predicted in vivo species metabolite correlations with high accuracy. In conclusion, highlighting the value of combining statistical association studies with in silico modelling, this study delivers insights on the metabolic role of Fusobacteria in the gut, while providing a proof of concept for the validity of constraint-based community modelling.

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