Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 24, Pages 8901-8906Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1408523111
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Funding
- Wellcome Trust [WT098498, WT095515, WT098051, WT091551, WT091310]
- Medical Research Council Metabolic Diseases Unit
- United Kingdom National Institute for Health Research Cambridge Biomedical Research Centre
- European Union/European Federation of Pharmaceutical Industries and Associations Innovative Medicines Initiative (European Medical Information Framework) [115372]
- National Institute of General Medical Sciences [R01 GM09719]
- Medical Research Council [G0701532, G0600717B, G0600717, MC_UU_12012/5/B] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0513-10109] Funding Source: researchfish
- MRC [G0701532, G0600717] Funding Source: UKRI
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Phosphatidylcholine (PC) is the major glycerophospholipid in eukaryotic cells and is an essential component in all cellular membranes. The biochemistry of de novo PC synthesis by the Kennedy pathway is well established, but less is known about the physiological functions of PC. We identified two unrelated patients with defects in the Kennedy pathway due to biallellic loss-of-function mutations in phosphate cytidylyltransferase 1 alpha (PCYT1A), the rate-limiting enzyme in this pathway. The mutations lead to a marked reduction in PCYT1A expression and PC synthesis. The phenotypic consequences include some features, such as severe fatty liver and low HDL cholesterol levels, that are predicted by the results of previously reported liver-specific deletion of murine Pcyt1a. Both patients also had lipodystrophy, severe insulin resistance, and diabetes, providing evidence for an additional and essential role for PCYT1A-generated PC in the normal function of white adipose tissue and insulin action.
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