Uptake and Cellular Localization of Exogenous Lipids byGiardia lamblia,a Primitive Eukaryote

Stevens, Tamara; Gibson, George R.; Adam, Rodney D.; Maier, Julie; Allison-Ennis, Melissa; Das, Siddhartha

doi:10.1006/expr.1997.4162

Cited by 39 publications

(35 citation statements)

References 35 publications

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“…To investigate the nature of the fi rst N-terminal hydrophobic sequence, HA tags were introduced at the N-terminal end either of the full-length GlGCS or of a variant lacking the fi rst hydrophobic stretch (aa [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. Both reporters showed an equivalent signal and distribution, indicating that, like the mammalian homolog, the parasite protein is not proteolytically processed to remove the fi rst hydrophobic sequence (data not shown).…”

Section: Discussionmentioning

confidence: 99%

“…Lipid neosynthesis is limited in G. lamblia , and the parasite is thought to rely on lipids taken up from the environment, namely, the host intestinal content. Indeed, in vitro analyses showed negligible incorporation of lipid precursors, such as acetate and glycerol ( 11 ), while robust incorporation of exogenous radiolabeled fatty acids (12)(13)(14), phospholipids ( 14 ), ceramide, and gangliosides ( 15,16 ) could be demonstrated. In addition, uptake of fl uorescent sphingolipid analogs, including ceramide and sphingomyelin, has been reported ( 12,14,15 ).…”

Section: Gene Expression Analysismentioning

confidence: 99%

“…Indeed, in vitro analyses showed negligible incorporation of lipid precursors, such as acetate and glycerol ( 11 ), while robust incorporation of exogenous radiolabeled fatty acids (12)(13)(14), phospholipids ( 14 ), ceramide, and gangliosides ( 15,16 ) could be demonstrated. In addition, uptake of fl uorescent sphingolipid analogs, including ceramide and sphingomyelin, has been reported ( 12,14,15 ). Importantly, acyl chain desaturation ( 17 ), deacylation/reacylation, and head group exchange ( 18 ) have been shown to occur in G. lamblia , indicating that the parasite can remodel the incorporated exogenous lipids to fulfi ll its own needs.…”

Section: Gene Expression Analysismentioning

confidence: 99%

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Glucosylceramide synthesis inhibition affects cell cycle progression, membrane trafficking, and stage differentiation in Giardia lamblia

Štefanić

Spycher

Morf

et al. 2010

Journal of Lipid Research

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Ceramide, a central molecule in the sphingolipid biosynthesis, plays a critical role as second messenger in cellular signaling that regulates antiproliferative processes, including apoptosis, cell differentiation, and cell cycle arrest in different cell types. Levels of ceramide, a highly bioactive molecule, must be tightly controlled by diverse, coordinated mechanisms, including ceramide degradation, phosphorylation, or sphingolipid metabolism. Glucosylceramide synthase (GCS), also defi ned as ceramide glucosyltransferase (CGT), metabolizes ceramide to glucosylceramide (GlcCer), a glycosylated form of ceramide that does not have antiproliferative activity. GCS plays a crucial role in cell survival after apoptotic stimuli, Abstract Synthesis of glucosylceramide via glucosylceramide synthase (GCS) is a crucial event in higher eukaryotes, both for the production of complex glycosphingolipids and for regulating cellular levels of ceramide, a potent antiproliferative second messenger. In this study, we explored the dependence of the early branching eukaryote Giardia lamblia on GCS activity. Biochemical analyses revealed that the parasite has a GCS located in endoplasmic reticulum (ER) membranes that is active in proliferating and encysting trophozoites. Pharmacological inhibition of GCS induced aberrant cell division, characterized by arrest of cytokinesis, incomplete cleavage furrow formation, and consequent block of replication. Importantly, we showed that increased ceramide levels were responsible for the cytokinesis arrest. In addition, GCS inhibition resulted in prominent ultrastructural abnormalities, including accumulation of cytosolic vesicles, enlarged lysosomes, and clathrin disorganization. Moreover, anterograde traffi cking of the encystations-specifi c protein CWP1 was severely compromised and resulted in inhibition of stage differentiation. Our results reveal novel aspects of lipid metabolism in G. lamblia and specifically highlight the vital role of GCS in regulating cell cycle progression, membrane traffi cking events, and stage differentiation in this parasite. In addition, we identifi ed ceramide as a potent bioactive molecule, underscoring the universal conservation of ceramide signaling in eukaryotes. -Štefanić,

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Section: Discussionmentioning

confidence: 99%

Section: Gene Expression Analysismentioning

confidence: 99%

Section: Gene Expression Analysismentioning

confidence: 99%

See 1 more Smart Citation

Glucosylceramide synthesis inhibition affects cell cycle progression, membrane trafficking, and stage differentiation in Giardia lamblia

Štefanić

Spycher

Morf

et al. 2010

Journal of Lipid Research

View full text Add to dashboard Cite

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“…Fatty acid desaturase activity, including desaturation of oleate to linoleate and linolenate, has been documented (75). Arachidonic acid is incorporated into neutral lipids, phospholipids, and a wide variety of cellular lipids (108), while palmitic acid, myristic acid, and oleic acid are transesterified primarily into phospholipids (28), including cellular phospholipids, (e.g., phosphatidylglycerol, phosphatidylcholine, phosphatidylethanolamine, and phosphatidylinositol) (149,154,228,313). Interesterification also occurs with incorporation of conjugated fatty acids into phosphatidylglycerol (108).…”

Section: Lipid Metabolismmentioning

confidence: 99%

Biology ofGiardia lamblia

2001

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Giardia lamblia is a common cause of diarrhea in humans and other mammals throughout the world. It can be distinguished from other Giardia species by light or electron microscopy. The two major genotypes of G. lamblia that infect humans are so different genetically and biologically that they may warrant separate species or subspecies designations. Trophozoites have nuclei and a well-developed cytoskeleton but lack mitochondria, peroxisomes, and the components of oxidative phosphorylation. They have an endomembrane system with at least some characteristics of the Golgi complex and encoplasmic reticulum, which becomes more extensive in encysting organisms. The primitive nature of the organelles and metabolism, as well as small-subunit rRNA phylogeny, has led to the proposal that Giardia spp. are among the most primitive eukaryotes. G. lamblia probably has a ploidy of 4 and a genome size of approximately 10 to 12 Mb divided among five chromosomes. Most genes have short 5′ and 3′ untranslated regions and promoter regions that are near the initiation codon. Trophozoites exhibit antigenic variation of an extensive repertoire of cysteine-rich variant-specific surface proteins. Expression is allele specific, and changes in expression from one vsp gene to another have not been associated with sequence alterations or gene rearrangements. The Giardia genome project promises to greatly increase our understanding of this interesting and enigmatic organism

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“…NO is critical for synapses [100][101][102][103] (b) Increasing cholesterol availability to the developing brain, cholesterol as a glial synaptogenic factor and indirect trigger for myelination in the brain [34,104,28,105,27] Infection (a) ApoE4 by downregulating LDL receptors may starve enteric pathogens from cholesterol and block proliferation. The LDL-receptor pathway is also highly conserved across the animal kingdom [106][107][108][109][110] (b) ApoE is secreted in a polarized manner by enterocytes, increased by 25-OHcholesterol and decreased by LPS through an LXR α /RXR independent signaling pathway [47].…”

Section: Boxmentioning

confidence: 99%

Role of apolipoprotein E4 in protecting children against early childhood diarrhea outcomes and implications for later development

et al. 2007

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SummaryOur group and others have reported a series of studies showing that heavy burdens of diarrheal diseases in the formative first two years of life in children in urban shantytowns have profound consequences of impaired physical and cognitive development lasting into later childhood and schooling. Based on these previous studies showing that apolipoprotein E4 (APOE4) is relatively common in favela children, we review recent data suggesting a protective role for the APOE4 allele in the cognitive and physical development of children with heavy burdens of diarrhea in early childhood. Despite being a marker for cognitive decline with Alzheimer's and cardiovascular diseases later in life, APOE4 appears to be important for cognitive development under the stress of heavy diarrhea. The reviewed findings provide a potential explanation for the survival advantage in evolution of the thrifty APOE4 allele and raise questions about its implications for human development under life-style changes and environmental challenges.

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Uptake and Cellular Localization of Exogenous Lipids byGiardia lamblia,a Primitive Eukaryote

Cited by 39 publications

References 35 publications

Glucosylceramide synthesis inhibition affects cell cycle progression, membrane trafficking, and stage differentiation in Giardia lamblia

Glucosylceramide synthesis inhibition affects cell cycle progression, membrane trafficking, and stage differentiation in Giardia lamblia

Biology ofGiardia lamblia

Role of apolipoprotein E4 in protecting children against early childhood diarrhea outcomes and implications for later development

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