DYRK1A overexpression decreases plasma lecithin:cholesterol acyltransferase activity and apolipoprotein A-I levels

Tlili, Asma; Noll, Christophe; Middendorp, Sandrine; Duchon, Arnaud; Jouan, Marie; Benabou, Eva; Hérault, Yann; Paul, Jean–Louis; Delabar, Jean–Maurice; Janel, Nathalie

doi:10.1016/j.ymgme.2013.07.014

Cited by 4 publications

(9 citation statements)

References 32 publications

(33 reference statements)

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Section: Discussionmentioning

confidence: 99%

“…Furthermore, truncated DYRK1A contributes to inflammatory cytokine production by astrocytes via activation of the STAT3 pathway. In mBACtgDyrk1A mice, Tlili et al [26] showed that overexpression of DYRK1A increases the hepatic expression of STAT3 and decreases Tyr-705 phosphorylation but does not influence Ser727 phosphorylation. We further hypothesize that local overexpression of DYRK1A in the early stages of spermatogenesis disrupts the GDNF/retinoic acid balance (Figure 4), which in turn would determine the fate of SSCs (i.e., self-renewal vs. differentiation and entry into spermatogenesis) [20].…”

Section: Discussionmentioning

confidence: 99%

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DYRK1A Overexpression in Mice Downregulates the Gonadotropic Axis and Disturbs Early Stages of Spermatogenesis

Dard

Moreau

Parizot

et al. 2021

Genes

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Down syndrome (DS) is the most common chromosomal disorder. It is responsible for intellectual disability (ID) and several medical conditions. Although men with DS are thought to be infertile, some spontaneous paternities have been reported. The few studies of the mechanism of infertility in men with DS are now dated. Recent research in zebrafish has indicated that overexpression of DYRK1A (the protein primarily responsible for ID in DS) impairs gonadogenesis at the embryonic stage. To better ascertain DYRK1A’s role in infertility in DS, we investigated the effect of DYRK1A overexpression in a transgenic mouse model. We found that overexpression of DYRK1A impairs fertility in transgenic male mice. Interestingly, the mechanism in mice differs slightly from that observed in zebrafish but, with disruption of the early stages of spermatogenesis, is similar to that seen in humans. Unexpectedly, we observed hypogonadotropic hypogonadism in the transgenic mice.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

DYRK1A Overexpression in Mice Downregulates the Gonadotropic Axis and Disturbs Early Stages of Spermatogenesis

Dard

Moreau

Parizot

et al. 2021

Genes

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“…Similarly, Delabar et al (2014) have described increased CBS activity in the liver of Dyrk1A-overexpressing mice. This group also showed that forced expression of Dyrk1A (using an adenoviral construct) in the liver of CBS+/− mice induced increased CBS activity both in the liver (Tlili et al, 2013;Latour et al, 2015) and the brain (Baloula et al, 2018). The pathways involved in this regulation have been explored: decreased homocysteine levels, resulting from Dyrk1A overexpression, induced increased phosphorylation of the serine threonine kinase Akt (on Serine 473) (Guedj et al, 2012;Abekhoukh et al, 2013), which is then activated to promote cell survival by inhibiting apoptosis.…”

Section: Dyrk1a Positively Regulates Cbs Activitymentioning

confidence: 99%

New insights into the regulation of Cystathionine beta synthase (CBS), an enzyme involved in intellectual deficiency in Down syndrome

et al. 2023

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Down syndrome (DS), the most frequent chromosomic aberration, results from the presence of an extra copy of chromosome 21. The identification of genes which overexpression contributes to intellectual disability (ID) in DS is important to understand the pathophysiological mechanisms involved and develop new pharmacological therapies. In particular, gene dosage of Dual specificity tyrosine phosphorylation Regulated Kinase 1A (DYRK1A) and of Cystathionine beta synthase (CBS) are crucial for cognitive function. As these two enzymes have lately been the main targets for therapeutic research on ID, we sought to decipher the genetic relationship between them. We also used a combination of genetic and drug screenings using a cellular model overexpressing CYS4, the homolog of CBS in Saccharomyces cerevisiae, to get further insights into the molecular mechanisms involved in the regulation of CBS activity. We showed that overexpression of YAK1, the homolog of DYRK1A in yeast, increased CYS4 activity whereas GSK3β was identified as a genetic suppressor of CBS. In addition, analysis of the signaling pathways targeted by the drugs identified through the yeast-based pharmacological screening, and confirmed using human HepG2 cells, emphasized the importance of Akt/GSK3β and NF-κB pathways into the regulation of CBS activity and expression. Taken together, these data provide further understanding into the regulation of CBS and in particular into the genetic relationship between DYRK1A and CBS through the Akt/GSK3β and NF-κB pathways, which should help develop more effective therapies to reduce cognitive deficits in people with DS.

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“…Lipidomics analysis showed that not only triglycerides (TG) content but also ceramide content were increased in HHcy mice which have decreased liver DYRK1A protein expression (36, 62). We previously demonstrated altered lipoprotein metabolism in mice overexpressing DYRK1A (63). Note that mice overexpressing DYRK1A have, on the contrary, not only a decreased plasma Hcy level (37) but also a decreased serum TG level (0.369 ± 0.04 vs. 0.519 ± 0.057 mmol/L; p < 0.05 by Student's t -test; n = 8 for each).…”

Section: Homocysteine a Link Between Nafld T2dm And Admentioning

confidence: 99%

Deciphering the Link Between Hyperhomocysteinemia and Ceramide Metabolism in Alzheimer-Type Neurodegeneration

et al. 2019

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Aging is one of the strongest risk factor for Alzheimer's disease (AD). However, several data suggest that dyslipidemia can either contribute or serve as co-factors in AD appearance. AD could be examined as a metabolic disorder mediated by peripheral insulin resistance. Insulin resistance is associated with dyslipidemia, which results in increased hepatic ceramide generation. Hepatic steatosis induces pro-inflammatory cytokine activation which is mediated by the increased ceramides production. Ceramides levels increased in cells due to perturbation in sphingolipid metabolism and upregulated expression of enzymes involved in ceramide synthesis. Cytotoxic ceramides and related molecules generated in liver promote insulin resistance, traffic through the circulation due to injury or cell death caused by local liver inflammation, and because of their hydrophobic nature, they can cross the blood-brain barrier and thereby exert neurotoxic responses as reducing insulin signaling and increasing pro-inflammatory cytokines. These abnormalities propagate a cascade of neurodegeneration associated with oxidative stress and ceramide generation, which potentiate brain insulin resistance, apoptosis, myelin degeneration, and neuro-inflammation. Therefore, excess of toxic lipids generated in liver can cause neurodegeneration. Elevated homocysteine level is also a risk factor for AD pathology and is narrowly associated with metabolic diseases and non-alcoholic fatty liver disease. The existence of a homocysteine/ceramides signaling pathway suggests that homocysteine toxicity could be partly mediated by intracellular ceramide accumulation due to stimulation of ceramide synthase. In this article, we briefly examined the role of homocysteine and ceramide metabolism linking metabolic diseases and non-alcoholic fatty liver disease to AD. We therefore analyzed the expression of mainly enzymes implicated in ceramide and sphingolipid metabolism and demonstrated deregulation of de novo ceramide biosynthesis and S1P metabolism in liver and brain of hyperhomocysteinemic mice.

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DYRK1A overexpression decreases plasma lecithin:cholesterol acyltransferase activity and apolipoprotein A-I levels

Cited by 4 publications

References 32 publications

DYRK1A Overexpression in Mice Downregulates the Gonadotropic Axis and Disturbs Early Stages of Spermatogenesis

DYRK1A Overexpression in Mice Downregulates the Gonadotropic Axis and Disturbs Early Stages of Spermatogenesis

New insights into the regulation of Cystathionine beta synthase (CBS), an enzyme involved in intellectual deficiency in Down syndrome

Deciphering the Link Between Hyperhomocysteinemia and Ceramide Metabolism in Alzheimer-Type Neurodegeneration

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