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Proc Natl Acad Sci U S A. 2014 Jun 17;111(24):8901-6. doi: 10.1073/pnas.1408523111. Epub 2014 Jun 2.

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

Author information

  • 1Metabolic Disease Group, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SA, United Kingdom;
  • 2University of Cambridge, Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Cambridge CB2 0QQ, United Kingdom;
  • 3Diabetes Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892;
  • 4Department of Cell Biology, School of Medicine, Yale University, New Haven, CT 06520;
  • 5Wolfson Brain Imaging Centre, University of Cambridge, Cambridge CB2 0QQ, United Kingdom;
  • 6Moorfields Eye Hospital National Health Service Trust, London EC1V 2PD, United Kingdom; and.
  • 7Centre for Endocrinology, Diabetes and Research, Royal Surrey County Hospital, Guildford GU2 7XX, United Kingdom.
  • 8University of Cambridge, Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Cambridge CB2 0QQ, United Kingdom; so104@medschl.cam.ac.uk ib1@sanger.ac.uk dbs23@medschl.cam.ac.uk.
  • 9Metabolic Disease Group, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SA, United Kingdom;University of Cambridge, Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Cambridge CB2 0QQ, United Kingdom; so104@medschl.cam.ac.uk ib1@sanger.ac.uk dbs23@medschl.cam.ac.uk.

Abstract

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.

PMID:
24889630
[PubMed - indexed for MEDLINE]
PMCID:
PMC4066527
Free PMC Article
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