Characterization of a novel CI-976-sensitive lysophospholipid acyltransferase that is associated with the Golgi complex

Chambers, Kimberly; Brown, William J.

doi:10.1016/j.bbrc.2003.12.016

Cited by 22 publications

(21 citation statements)

References 25 publications

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“…Additionally, the amphipathic nature of LPC results in its rapid nonspecific internalization through plasma membranes (47,48), raising the possibility that some of its effects may be mediated intracellularly. For example, internalized LPC can induce macrophage apoptosis by inhibiting the ratelimiting enzyme of the de novo phosphatidylcholine biosynthetic pathway, CTP:phosphocholine cytidylyltransferase (47), and its reacylation by cytosolic acyltransferases promotes monocyte inflammatory responses to lipopolysaccharide (49)(50)(51). Our data nevertheless suggest that specific modulation of G2A activity in macrophages could provide a therapeutic approach to attenuate atherosclerotic lesion destabilization.…”

Section: Discussionmentioning

confidence: 76%

Loss of G2A promotes macrophage accumulation in atherosclerotic lesions of low density lipoprotein receptor-deficient mice

Parks

Gambill

Lusis

et al. 2005

Journal of Lipid Research

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Lysophosphatidylcholine (LPC) is considered a major proatherogenic component of oxidized low density lipoprotein based on its proinflammatory actions in vitro. LPC stimulates macrophage and T-cell chemotaxis via the G protein-coupled receptor G2A and may thus promote inflammatory cell infiltration during atherosclerotic lesion development. However, G2A also mediates proapoptotic effects of LPC and may therefore promote the death of inflammatory cells within developing lesions. To determine how these effects of LPC modify atherogenesis, we examined atherosclerotic lesion development in G2A-sufficient and G2A-deficient low density lipoprotein receptor knockout mice. Although LPC species capable of activating G2A-dependent responses were increased during lesion development, G2A-deficient mice developed lesions similar in size to those in their G2A-sufficient counterparts. Loss of G2A during atherosclerotic lesion development did not reduce macrophage and T-cell infiltration but instead resulted in increased lesional macrophage content associated with reduced numbers of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeled cells and decreased collagen deposition. These data indicate that the ability of LPC to stimulate macrophage and T-cell chemotaxis via G2A is not manifested in vivo and that G2A-mediated proapoptotic rather than chemotactic action is most penetrant during atherogenesis and may modify the stability of atherosclerotic lesions by promoting macrophage death.

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Section: Discussionmentioning

confidence: 76%

Loss of G2A promotes macrophage accumulation in atherosclerotic lesions of low density lipoprotein receptor-deficient mice

Parks

Gambill

Lusis

et al. 2005

Journal of Lipid Research

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“…6A). CI-976, a small, hydrophobic, membrane-permeant compound which inhibits COP II vesicle budding from the ER (Chambers and Brown, 2004; Chambers et al, 2005), reduced cell viability by more than 50% relative to control cells ( p <0.0001), while CytoD, a fungal metabolite that inhibits actin polymerization in the cell cytoskeleton (Ramm et al, 1994), reduced viability by 25% ( p <0.0006; Fig. 6B).…”

Section: Resultsmentioning

confidence: 99%

Iron loaded ferritin secretion and inhibition by CI-976 in Aedes aegypti larval cells

Geiser¹,

Shen²,

Mayo³

et al. 2009

Comparative Biochemistry and Physiology Part B: Biochemistry an

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Ferritin is a multimer of 24 subunits of heavy and light chains. In mammals, iron taken into cells is stored in ferritin or incorporated into iron-containing proteins. Very little ferritin is found circulating in mammalian serum; most is retained in the cytoplasm. Female mosquitoes, such as Aedes aegypti (yellow fever mosquito, Diptera), require a blood meal for oogenesis. Mosquitoes receive a potentially toxic level of iron in the blood meal which must be processed and stored. We demonstrate by 59Fe pulse-chase experiments that cultured A. aegypti larval CCL-125 cells take up iron from culture media and store it in ferritin found mainly in the membrane fraction and secrete iron-loaded ferritin. We observe that in these larval cells ferritin co-localizes with ceramide-containing membranes in the absence of iron. With iron treatment, ferritin is found associated with ceramide-containing membranes as well as in cytoplasmic non-ceramide vesicles. Treatment of CCL-125 cells with iron and CI-976, an inhibitor of lysophospholipid acyl transferases, disrupts ferritin secretion with a concomitant decrease in cell viability. Interfering with ferritin secretion may limit the ability of mosquitoes to adjust to the high iron load of the blood meal and decrease iron delivery to the ovaries reducing egg numbers.

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“…Since BFA and CI-976 have similar effects on the Golgi complex, CtBP/BARS may be a possible target of CI-976. However, CtBP/BARS is an LPA-specific LPAAT, whereas CI-976 was found to be selective for a Golgiassociated LPCAT (Chambers and Brown, 2004;Drecktrah et al, 2003). In addition, CtBP/BARS is capable of inducing fission of membrane tubules when its LPAAT activity is compromised (Carcedo et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…These studies led to the identification of a novel inhibitory activity for a previously characterized antagonist of acyl-CoA cholesterol acyltransferase (ACAT), CI-976 (Harte et al, 1995). We found that CI-976 was a potent inhibitor of a Golgi-associated LPAT activity that displayed a preference for lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE) (Chambers and Brown, 2004;Drecktrah et al, 2003). Remarkably, CI-976 caused a dramatic stimulation of Golgi tubule formation and redistribution of resident enzymes back to the ER.…”

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confidence: 99%

A unique lysophospholipid acyltransferase (LPAT) antagonist, CI-976, affects secretory and endocytic membrane trafficking pathways

Chambers

Judson

Brown

2005

Journal of Cell Science

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Previous studies have shown that inhibition of a Golgi-complex-associated lysophospholipid acyltransferase (LPAT) activity by the drug CI-976 stimulates Golgi tubule formation and subsequent redistribution of resident Golgi proteins to the endoplasmic reticulum (ER). Here, we show that CI-976 stimulates tubule formation from all subcompartments of the Golgi complex, and often these tubules formed independently, i.e. individual tubules usually did not contain markers from different subcompartments. Whereas the cis, medial and trans Golgi membranes redistributed to the ER, the trans Golgi network (TGN) collapsed back to a compact juxtanuclear position similar to that seen with brefeldin A (BFA) treatment. Also similar to BFA, CI-976 induced the formation of endosome tubules, but unlike BFA, these tubules did not fuse with TGN tubules. Finally, CI-976 produced an apparently irreversible block in the endocytic recycling pathway of transferrin (Tf) and Tf receptors (TfRs) but had no direct effect on Tf uptake from the cell surface. Tf and TfRs accumulated in centrally located, Rab11-positive vesicles indicating that CI-976 inhibits export of cargo from the central endocytic recycling compartment. These results, together with previous studies, demonstrate that CI-976 inhibits multiple membrane trafficking steps, including ones found in the endocytic and secretory pathways, and imply a wider role for lysophospholipid acyltransferases in membrane trafficking.

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Characterization of a novel CI-976-sensitive lysophospholipid acyltransferase that is associated with the Golgi complex

Cited by 22 publications

References 25 publications

Loss of G2A promotes macrophage accumulation in atherosclerotic lesions of low density lipoprotein receptor-deficient mice

Loss of G2A promotes macrophage accumulation in atherosclerotic lesions of low density lipoprotein receptor-deficient mice

Iron loaded ferritin secretion and inhibition by CI-976 in Aedes aegypti larval cells

A unique lysophospholipid acyltransferase (LPAT) antagonist, CI-976, affects secretory and endocytic membrane trafficking pathways

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