Role of A Kinase Anchor Proteins in the Tissue-Specific Regulation of Lipoprotein Lipase

Lipoprotein lipase (LPL) has been implicated in the delivery of chylomicron-located α-tocopherol (α-TocH) to peripheral tissues. To investigate the role of LPL in the cellular uptake of α-TocH in peripheral tissue in vivo, three lines of transgenic mice [mouse creatine kinase- (MCK) L, MCK-M and MCK-H] expressing various amounts of human LPL were compared with regard to α-TocH levels in plasma, skeletal muscle, cardiac muscle, adipose tissue and brain. Depending on the copy number of the transgene, LPL activity was increased 3- to 27-fold in skeletal muscle and 1.3- to 3.7-fold in cardiac muscle. The intracellular levels of α-TocH in skeletal muscle were significantly increased in MCK-M and MCK-H animals and correlated highly with the tissue-specific LPL activity (r = 0.998). The highest levels were observed in MCK-H (21.4 nmol/g) followed by MCK-M (13.3 nmol/g) and MCK-L (8.2 nmol/g) animals when compared with control mice (7.3 nmol/g). Excellent correlation was also observed between intracellular α-TocH and non-esterified fatty acid (NEFA) levels (r = 0.998). Although LPL activities in cardiac muscle were also increased in the transgenic mouse lines, α-TocH concentrations in the heart remained unchanged. Similarly, α-TocH levels in plasma, adipose tissue and brain were unaffected by the tissue specific overexpression of LPL in muscle. The transgenic model presented in this report provides evidence that the uptake of α-TocH in muscle is directly dependent on the level of LPL expression in vivo. Increased intracellular α-TocH concentrations with increased triglyceride lipolysis and NEFA uptake might protect the myocyte from oxidative damage during increased β-oxidation.

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Absence of 11-keto reduction of cortisone and 11-ketotestosterone in the model organism zebrafish

Journal of Endocrinology ◽

10.1530/joe-16-0495 ◽

2017 ◽

Vol 232 (2) ◽

pp. 323-335 ◽

Cited By ~ 10

Author(s):

Maria Tsachaki ◽

Arne Meyer ◽

Benjamin Weger ◽

Denise V Kratschmar ◽

Janina Tokarz ◽

...

Keyword(s):

Stress Responses ◽

Teleost Fish ◽

Model Organism ◽

Synthetic Analogue ◽

Recombinant Enzymes ◽

Tissue Specific ◽

Zebrafish Larvae ◽

Specific Regulation ◽

Glucocorticoid Action

Zebrafish are widely used as model organism. Their suitability for endocrine studies, drug screening and toxicity assessements depends on the extent of conservation of specific genes and biochemical pathways between zebrafish and human. Glucocorticoids consist of inactive 11-keto (cortisone and 11-dehydrocorticosterone) and active 11β-hydroxyl forms (cortisol and corticosterone). In mammals, two 11β-hydroxysteroid dehydrogenases (11β-HSD1 and 11β-HSD2) interconvert active and inactive glucocorticoids, allowing tissue-specific regulation of glucocorticoid action. Furthermore, 11β-HSDs are involved in the metabolism of 11-oxy androgens. As zebrafish and other teleost fish lack a direct homologue of 11β-HSD1, we investigated whether they can reduce 11-ketosteroids. We compared glucocorticoid and androgen metabolism between human and zebrafish using recombinant enzymes, microsomal preparations and zebrafish larvae. Our results provide strong evidence for the absence of 11-ketosteroid reduction in zebrafish. Neither human 11β-HSD3 nor the two zebrafish 11β-HSD3 homologues, previously hypothesized to reduce 11-ketosteroids, converted cortisone and 11-ketotestosterone (11KT) to their 11β-hydroxyl forms. Furthermore, zebrafish microsomes were unable to reduce 11-ketosteroids, and exposure of larvae to cortisone or the synthetic analogue prednisone did not affect glucocorticoid-dependent gene expression. Additionally, a dual-role of 11β-HSD2 by inactivating glucocorticoids and generating the main fish androgen 11KT was supported. Thus, due to the lack of 11-ketosteroid reduction, zebrafish and other teleost fish exhibit a limited tissue-specific regulation of glucocorticoid action, and their androgen production pathway is characterized by sustained 11KT production. These findings are of particular significance when using zebrafish as a model to study endocrine functions, stress responses and effects of pharmaceuticals.

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Tissue-specific regulation of lipoprotein lipase in humans: effects of fasting

European Journal of Clinical Investigation ◽

10.1111/j.1365-2362.2005.01470.x ◽

2005 ◽

Vol 35 (3) ◽

pp. 194-200 ◽

Cited By ~ 31

Author(s):

T. Ruge ◽

M. Svensson ◽

J. W. Eriksson ◽

G. Olivecrona

Keyword(s):

Lipoprotein Lipase ◽

Tissue Specific ◽

Specific Regulation

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Tissue-specific regulation of lipoprotein lipase by isoproterenol in normal-weight humans

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1996.271.5.r1280 ◽

1996 ◽

Vol 271 (5) ◽

pp. R1280-R1286 ◽

Cited By ~ 2

Author(s):

R. H. Eckel ◽

D. R. Jensen ◽

I. R. Schlaepfer ◽

T. J. Yost

Keyword(s):

Skeletal Muscle ◽

Fatty Acids ◽

Adipose Tissue ◽

Lipoprotein Lipase ◽

Plasma Norepinephrine ◽

Vastus Lateralis Muscle ◽

Specific Response ◽

Tissue Specific ◽

Percent Change ◽

Specific Regulation

Lipoprotein lipase (LPL) is a hydrolytic enzyme, involved in lipoprotein metabolism and nutrient partitioning, that is subject to tissue-specific regulation. Evidence for divergent regulation of the lipase by insulin has been demonstrated, but alterations in the tissue-specific response of LPL to catecholamines has not been studied in humans. The regulation of LPL in gluteal adipose tissue and vastus lateralis muscle by isoproterenol (epinephrine isopropyl homologue) in humans was examined over 2 h in subjects infused with 0 (saline) or 8 or 24 ng.kg-1.min-1 isoproterenol. The infusion of normal saline into control subjects failed to alter adipose tissue or skeletal muscle LPL activity. However, in the saline-infused subjects there was a positive correlation between the percent change in plasma norepinephrine concentrations and the percent change in muscle LPL activity (r = 0.826, P < 0.05). Isoproterenol infusion did not change LPL in either adipose tissue or muscle compared with saline-infused controls, but plasma insulin levels in addition to plasma glucose, free fatty acids, and glycerol were increased. To prevent the isoproterenol-induced hyperinsulinemia, a pancreatic clamp technique was utilized. An increase in muscle LPL was demonstrated (P = 0.037) with no change in adipose tissue LPL. The change in muscle LPL activity after the 2-h infusion correlated with the change in muscle mRNA (P = 0.021). Overall, these studies indicate that in humans the response of LPL to catecholamines is tissue specific with no effect in adipose tissue but a stimulation in skeletal muscle. Endogenous regulation of LPL in muscle by catecholamines could be important in muscle fuel metabolism and could relate to effects of adenosine 3',5'-cyclic monophosphate and/or fatty acids at the level of the LPL gene.

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Tissue-specific regulation of the Na, K-ATPase by the cytosolic NaAF: some thoughts on brain function

F1000Research ◽

10.12688/f1000research.2-241.v1 ◽

2013 ◽

Vol 2 ◽

pp. 241 ◽

Cited By ~ 1

Author(s):

Tushar Ray

Keyword(s):

Intracellular Signaling ◽

Local Environment ◽

Ph Homeostasis ◽

Tissue Specific ◽

Dual Channel ◽

Atpase System ◽

Specific Regulation ◽

Histone Kinase ◽

And Function

The dual topology P-2 ATPase, which consists of a α²β² tetramer, explains numerous functions of the cation transporting ATPase system. The ubiquitous cytosolic protein regulator (NaAF) of 170 k Da mass regulates P-2 ATPase function in a low Ca (µM) neighborhood where Ca acts as the terminal regulator in the intracellular signaling cascade. The Na, K- ATPase also seems to function as an H, K-ATPase or a Ca-ATPase in altered states based on the local environment (low pH or high Ca) in a tissue specific manner. These altered effects are analogous to that of the 80 k Da cytosolic HAF in regulating the gastric H, K-ATPase system of the parietal cells. However there are some important differences. The HAF stimulates the Na, K-ATPase but the NaAF cannot stimulate H, K-ATPase. Also, HAF is as effective as NaAF in stimulating the kidney Na, K-ATPase but about 60% as effective in stimulating brain Na, K-ATPase. These observations reveal that the Na, K- ATPase systems from kidney and brain, consisting of different kinds of αβ–isoforms, interact differently with the HAF molecule; thus substantiating that P-2 ATPase system plays different roles in different tissues in response to an universal NaAF. Another rare feature of the HAF is that it has histone kinase activity, suggesting that the HAF and NaAF may be capable of sending a direct signal to the nucleus for gene expression.In this paper, the central role of the NaAF-regulated Na, K-ATPase system in the activity and function of brain tissue is discussed. It is noted that the altered function of the nerve terminus located Na, K-ATPase system works as a Ca-pump (after depolarization) and as a Na-pump (in repolarization) in alternate sequence. The possible role of Ca-sensing receptor (CaR) in the voltage gated channeling of Ca has been raised and the possibility of a dual channel Na/H antiporter (NhaA) in pH homeostasis is discussed.

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Ctcf Haploinsufficiency Mediates Intron Retention in A Tissue-specific Manner

10.1101/851923 ◽

2019 ◽

Author(s):

Adel B Alharbi ◽

Ulf Schmitz ◽

Amy D Marshall ◽

Darya Vanichkina ◽

Rajini Nagarajah ◽

...

Keyword(s):

Gene Expression ◽

Intron Retention ◽

Regulation Of Gene Expression ◽

Splicing Factors ◽

Tissue Specific ◽

Genome Wide ◽

Liver And Kidney ◽

Specific Regulation ◽

Dose Dependent

AbstractCTCF is a master regulator of gene transcription and chromatin organization with occupancy at thousands of DNA target sites. CTCF is essential for embryonic development and somatic cell viability and has been characterized as a haploinsufficient tumor suppressor. Increasing evidence demonstrates CTCF as a key player in several alternative splicing (AS) regulatory mechanisms, including transcription elongation, regulation of splicing factors, and epigenetic regulation. However, the genome-wide impact of Ctcf dosage on AS has not been investigated. We examined the effect of Ctcf haploinsufficiency on gene expression and AS in multiple tissues from Ctcf hemizygous (Ctcf+/-) mice. Distinct tissue-specific differences in gene expression and AS were observed in Ctcf+/- mice compared to wildtype mice. We observed a surprisingly large number of increased intron retention (IR) events in Ctcf+/- liver and kidney, specifically in genes associated with cytoskeletal organization, splicing and metabolism. This study provides further evidence for Ctcf dose-dependent and tissue-specific regulation of gene expression and AS. Our data provide a strong foundation for elucidating the mechanistic role of CTCF in AS regulation and its biological consequences.

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