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

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.

authors

Payne F,Lim K,Girousse A,Brown RJ,Kory N,Robbins A,Xue Y,Sleigh A,Cochran E,Adams C,Dev Borman A,Russel-Jones D,Gorden P,Semple RK,Saudek V,O'Rahilly S,Walther TC,Barroso I,Savage DB

doi

10.1073/pnas.1408523111

subject

Has Abstract

pub_date

2014-06-17 00:00:00

pages

8901-6

issue

24

eissn

0027-8424

issn

1091-6490

pii

1408523111

journal_volume

111

pub_type

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