Cholesterogenic genes expression in brain and liver of ganglioside-deficient mice

Mlinac, Kristina; Tacer, Klementina Fon; Heffer-Lauc, Marija; Rozman, Damjana; Bognar, Svjetlana Kalanj

doi:10.1007/s11010-012-1375-y

Cited by 3 publications

(5 citation statements)

References 40 publications

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“…Furthermore, a disarranged ganglioside environment of Neuroplastin with aging [60] and altered lipid raft functionality during neurodegeneration [61] were reported. In addition, gangliosides are reported to influence cholesterol homeostasis [62], which could be a contributing factor in PMCA regulation [63]. It appears that reshaping the ganglioside milieu of neuronal membranes causes a domino effect, leading to functional changes in ion regulation, and probably other cellular systems as well.…”

Section: Discussionmentioning

confidence: 99%

Plasma Membrane Calcium ATPase-Neuroplastin Complexes Are Selectively Stabilized in GM1-Containing Lipid Rafts

Ilić

Lin

Malci

et al. 2021

IJMS

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The recent identification of plasma membrane (Ca2+)-ATPase (PMCA)-Neuroplastin (Np) complexes has renewed attention on cell regulation of cytosolic calcium extrusion, which is of particular relevance in neurons. Here, we tested the hypothesis that PMCA-Neuroplastin complexes exist in specific ganglioside-containing rafts, which could affect calcium homeostasis. We analyzed the abundance of all four PMCA paralogs (PMCA1-4) and Neuroplastin isoforms (Np65 and Np55) in lipid rafts and bulk membrane fractions from GM2/GD2 synthase-deficient mouse brains. In these fractions, we found altered distribution of Np65/Np55 and selected PMCA isoforms, namely PMCA1 and 2. Cell surface staining and confocal microscopy identified GM1 as the main complex ganglioside co-localizing with Neuroplastin in cultured hippocampal neurons. Furthermore, blocking GM1 with a specific antibody resulted in delayed calcium restoration of electrically evoked calcium transients in the soma of hippocampal neurons. The content and composition of all ganglioside species were unchanged in Neuroplastin-deficient mouse brains. Therefore, we conclude that altered composition or disorganization of ganglioside-containing rafts results in changed regulation of calcium signals in neurons. We propose that GM1 could be a key sphingolipid for ensuring proper location of the PMCA-Neuroplastin complexes into rafts in order to participate in the regulation of neuronal calcium homeostasis.

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Section: Discussionmentioning

confidence: 99%

Plasma Membrane Calcium ATPase-Neuroplastin Complexes Are Selectively Stabilized in GM1-Containing Lipid Rafts

Ilić

Lin

Malci

et al. 2021

IJMS

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“…Ganglioside synthesis involves stepwise action of various glycosyl and sialyltransferases [ 30 , 33 , 34 ]. Blockage of ganglioside biosynthetic pathways at a particular step in synthesis results in a change in the ganglioside profile, which can cause deficiency and/or accumulation of certain gangliosides depending on the blocked site in synthesis [ 35 ]. Therefore, changes in ganglioside composition, ganglioside modifications, and the presence or absence of certain ganglioside species can lead to alterations in cellular metabolism.…”

Section: Introductionmentioning

confidence: 99%

“…This deficiency leads to accumulation of a-series gangliosides (GM1, GM2, GM3, GD1a) and a deficiency of b- and c-series gangliosides (GD3, GD1b, GT1b, GT1c, GT2, GT3) [ 36 ]. Loss of certain gangliosides markedly alters ganglioside composition, even though the total concentration of gangliosides in the KO mice remains the same as in wild-type mice (WT) [ 35 ].…”

Section: Introductionmentioning

confidence: 99%

A Lack of GD3 Synthase Leads to Impaired Renal Expression of Connexins and Pannexin1 in St8sia1 Knockout Mice

Meter

Racetin

Vukojević

et al. 2022

IJMS

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The aim of this study was to determine the effects of altered ganglioside composition on the expression of Cx37, Cx40, Cx43, Cx45, and Panx1 in different kidney regions of St8sia1 gene knockout mice (St8sia1 KO) lacking the GD3 synthase enzyme. Experiments were performed in twelve male 6-month-old mice: four wild-type (C57BL/6-type, WT) and eight St8sia1 KO mice. After euthanasia, kidney tissue was harvested, embedded in paraffin wax, and processed for immunohistochemistry. The expression of connexins and Panx1 was determined in different regions of the kidney: cortex (CTX.), outer stripe of outer medulla (O.S.), inner stripe of outer medulla (IN.S.), and inner medulla (IN.MED.). We determined significantly lower expression of Cx37, Cx40, Cx45, and Panx1 in different parts of the kidneys of St8sia1 KO mice compared with WT. The most consistent decrease was found in the O.S. where all markers (Cx 37, 40, 45 and Panx1) were disrupted in St8si1 KO mice. In the CTX. region, we observed decrease in the expression of Cx37, Cx45, and Panx1, while reduced expression of Cx37 and Panx1 was more specific to IN.S. The results of the present study suggest that deficiency of GD3 synthase in St8sia1 KO mice leads to disruption of renal Cx expression, which is probably related to alteration of ganglioside composition.

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“…There is some evidence that GM3 inhibits apolipoprotein B secretion in liver cells 17 and might regulate hepatic cholesterol metabolism. 18 In light of these observations, the aim of this study was to examine the role of HEXA in hepatic lipid metabolism.…”

Section: Introductionmentioning

confidence: 99%

“…While gangliosides are present in the liver 16 , little is known about the impact of gangliosides or their regulatory proteins in hepatic lipid metabolism in vivo. There is some evidence that GM3 inhibits apolipoprotein B secretion in liver cells 17 and might regulate hepatic cholesterol metabolism 18 . In light of these observations, the aim of this study was to examine the role of HEXA in hepatic lipid metabolism.…”

Section: Introductionmentioning

confidence: 99%

Hexosaminidase A (HEXA) regulates hepatic sphingolipid and lipoprotein metabolism in mice

et al. 2021

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Hexosaminidase A (HexA), a heterodimer consisting of HEXA and HEXB, converts the ganglioside sphingolipid GM2 to GM3 by removing a terminal N-acetyl-dgalactosamine. HexA enzyme deficiency in humans leads to GM2 accumulation in cells, particularly in neurons, and is associated with neurodegeneration. While HexA and sphingolipid metabolism have been extensively investigated in the context of neuronal lipid metabolism, little is known about the metabolic impact of HexA and ganglioside degradation in other tissues. Here, we focussed on the role of HexA in the liver, which is a major regulator of systemic lipid metabolism. We find that hepatic Hexa expression is induced by lipid availability and increased in the presence of hepatic steatosis, which is associated with increased hepatic GM3 content. To assess the impact of HEXA on hepatic lipid metabolism, we used an adeno-associated virus to overexpress HEXA in the livers of high-fat diet fed mice. HEXA overexpression was associated with increased hepatic GM3 content and increased expression of enzymes involved in the degradation of glycated sphingolipids, ultimately driving sphingomyelin accumulation in the liver. In addition, HEXA overexpression led to substantial proteome remodeling in cell surface lipid rafts, which was associated with increased VLDL processing and secretion, hypertriglyceridemia and ectopic lipid accumulation in peripheral tissues. This study established an important role of HEXA in modulating hepatic sphingolipid and lipoprotein metabolism.

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Cholesterogenic genes expression in brain and liver of ganglioside-deficient mice

Cited by 3 publications

References 40 publications

Plasma Membrane Calcium ATPase-Neuroplastin Complexes Are Selectively Stabilized in GM1-Containing Lipid Rafts

Plasma Membrane Calcium ATPase-Neuroplastin Complexes Are Selectively Stabilized in GM1-Containing Lipid Rafts

A Lack of GD3 Synthase Leads to Impaired Renal Expression of Connexins and Pannexin1 in St8sia1 Knockout Mice

Hexosaminidase A (HEXA) regulates hepatic sphingolipid and lipoprotein metabolism in mice

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