The ratio of phosphatidylcholine to phosphatidylethanolamine influences membrane integrity and steatohepatitis

Li, Zhaoyu; Agellon, Luis B.; Allen, Theresa M.; Umeda, Masato; Jewell, Laurence D.; Mason, Andrew L.; Vance, Dennis E.

doi:10.1016/j.cmet.2006.03.007

Cited by 618 publications

(585 citation statements)

References 47 publications

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“…PE is also redistributed and exposed to the extracellular environment that signals cell death when the membrane asymmetry is compromised [32]. Li et al described that the decrease in the ratio of PC to PE was associated with a reduction in membrane integrity (Caballero et al2010; [25]). However, a more recent study attributed the loss of membrane integrity to PC deficiency alone [31].…”

Section: Discussionmentioning

confidence: 99%

“…It was identified through the two ions found in this group with m/z 750.4191 and 806.4842. In cells, PS is located exclusively in the intracellular environment (Caballero et al), which plays an important role because many intracellular proteins, such as protein kinases, require PS for proper activation and/or location [7,25,31]. Moreover, PS has also been described as a marker of apoptosis [4,15,16].…”

Section: Discussionmentioning

confidence: 99%

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The follicular microenviroment as a predictor of pregnancy: MALDI-TOF MS lipid profile in cumulus cells

Montani

Cordeiro

Regiani

et al. 2012

J Assist Reprod Genet

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Purpose This research proposed to study the changes in lipid composition in cumulus cells (CCs) from women who achieved pregnancy compared with women who did not, after in vitro fertilization treatment. This approach has the potential to provide novel information on the lipid metabolism of the CCs and as an additional method to predict pregnancy. Method Fifty-four samples from couples with tubal and male factor infertility and where the female partner was age 35 or younger were divided in two groups according to their level of hCG 14 days after embryo transfer as follows: (1) 23 samples in pregnant group and (2) 31 samples in non-pregnant group. Lipid extraction was performed by the Bligh-Dyer protocol, and lipid profiles were obtained by MALDI-TOF MS. Mass spectra data were processed with MassLynx, and statistical analysis was performed using MarkerLynx extended statistic. OPLS-DA model was built. Results S-plot Analysis revealed three ions as potential markers in the pregnant group, and five ions in the nonpregnant group. These ions were identified in the human metabolome database (HMDB) as phosphatidylcholine in the pregnant group and as phosphatidylethanolamine, phosphatidylserine and phosphatidylinositol species in the non-pregnant group. These lipids might be involved in cell proliferation and differentiation, apoptosis and GAP junction regulation. Conclusion We conclude that MALDI-TOF MS can be used as an informative and fast analytical strategy to obtain and study the lipid profile of cumulus cells and can potentially be used as a supporting tool to predict pregnancy based on the metabolic state of the CCs.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The follicular microenviroment as a predictor of pregnancy: MALDI-TOF MS lipid profile in cumulus cells

Montani

Cordeiro

Regiani

et al. 2012

J Assist Reprod Genet

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“…Li et al (16) later suggested that a reduction in the PC/PE ratio affects hepatocyte membrane integrity and plays a role in the progression of steatosis to steatohepatitis in humans. Mechanistic Amino acid one-letter code sizes are proportional to amino acid volumes.…”

Section: Resultsmentioning

confidence: 99%

Mutations disrupting the Kennedy phosphatidylcholine pathway in humans with congenital lipodystrophy and fatty liver disease

Payne

Lim

Girousse

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

131

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Significance The characterization of rare monogenic human disorders can and has yielded unique biological insights. Our phenotypic description and functional characterization of human loss-of-function mutations in PCYT1A is both clinically important for patients and their families afflicted with this rare but serious metabolic disease and biologically helpful in advancing understanding of the physiological consequences of impaired PCYT1A activity in humans.

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“…This study presents the first structural analysis of a eukaryotic cytidylyltransferase, providing a view into the workings of the active site of the enzyme that controls the rate of phosphatidylcholine synthesis and helps maintain a balanced membrane phospholipid composition (38,48,49). The CCT236 structure, which provides a complete catalytic domain as well as an intimately associated N-terminal extension, expands the repertoire of folds within the nucleotidyltransferase family and reveals unique features that have evolved to bind and position the phosphocholine group.…”

Section: Discussionmentioning

confidence: 99%

Crystal Structure of a Mammalian CTP: Phosphocholine Cytidylyltransferase Catalytic Domain Reveals Novel Active Site Residues within a Highly Conserved Nucleotidyltransferase Fold

Lee

Johnson

Ding

et al. 2009

Journal of Biological Chemistry

104

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CTP:phosphocholine cytidylyltransferase (CCT) is the key regulatory enzyme in the synthesis of phosphatidylcholine, the most abundant phospholipid in eukaryotic cell membranes. The CCT-catalyzed transfer of a cytidylyl group from CTP to phosphocholine to form CDP-choline is regulated by a membrane lipid-dependent mechanism imparted by its C-terminal membrane binding domain. We present the first analysis of a crystal structure of a eukaryotic CCT. A deletion construct of rat CCT␣ spanning residues 1-236 (CCT236) lacks the regulatory domain and as a result displays constitutive activity. The 2.2-Å structure reveals a CCT236 homodimer in complex with the reaction product, CDP-choline. Each chain is composed of a complete catalytic domain with an intimately associated N-terminal extension, which together with the catalytic domain contributes to the dimer interface. Although the CCT236 structure reveals elements involved in binding cytidine that are conserved with other members of the cytidylyltransferase superfamily, it also features nonconserved active site residues, His-168 and Tyr-173, that make key interactions with the ␤-phosphate of CDP-choline. Mutagenesis and kinetic analyses confirmed their role in phosphocholine binding and catalysis. These results demonstrate structural and mechanistic differences in a broadly conserved protein fold across the cytidylyltransferase family. Comparison of the CCT236 structure with those of other nucleotidyltransferases provides evidence for substrate-induced active site loop movements and a disorder-to-order transition of a loop element in the catalytic mechanism.A key rate-limiting step in the synthesis of phosphatidylcholine in animal cells is the formation of the headgroup donor, CDP-choline, by transfer of a cytidylyl group from CTP to phosphocholine. This reaction is catalyzed by CTP:phosphocholine cytidylyltransferase (CCT 4 ; EC 2.7.7.15), an enzyme subject to many layers of regulation (1-4). The ubiquitous and best studied isoform of mammalian CCT (CCT␣, 367 residues) has been described as having four domains (Fig. 1A). An N-terminal domain (ϳ75 residues) housing its nuclear localization signal (NLS) sequence is followed by an ϳ150-residue catalytic domain, an ϳ60-residue membrane binding domain (domain M), and an unstructured phosphorylated tail (ϳ50 residues) (2, 4). CCT functions as a homodimer (5).CCT activation requires transformation of the enzyme from a soluble form to a membrane lipid-bound form. When the full-length soluble CCT interacts with anionic membrane surfaces, domain M transforms from a mixture of structural elements into an amphipathic ␣-helix (6 -8). Domain M appears to act as an autoinhibitory device, whose interaction with phosphatidylcholine-deficient membranes releases an inhibitory constraint at the active site to enhance k cat by 2 orders of magnitude (9). The primary evidence for this model is the constitutive activity of a construct lacking domain M, CCT236 (9).To elucidate the mechanism whereby membrane binding activates this important re...

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The ratio of phosphatidylcholine to phosphatidylethanolamine influences membrane integrity and steatohepatitis

Cited by 618 publications

References 47 publications

The follicular microenviroment as a predictor of pregnancy: MALDI-TOF MS lipid profile in cumulus cells

The follicular microenviroment as a predictor of pregnancy: MALDI-TOF MS lipid profile in cumulus cells

Mutations disrupting the Kennedy phosphatidylcholine pathway in humans with congenital lipodystrophy and fatty liver disease

Crystal Structure of a Mammalian CTP: Phosphocholine Cytidylyltransferase Catalytic Domain Reveals Novel Active Site Residues within a Highly Conserved Nucleotidyltransferase Fold

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