Name: Loss of phospholipase PLAAT3 causes a mixed lipodystrophic and neurological syndrome due to impaired PPAR? signaling
Keywords: Loss of phospholipase plaat3 causes a mixed lipodystrophic and neurological syndrome due to impaired ppar? signaling

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Loss of phospholipase PLAAT3 causes a mixed lipodystrophic and neurological syndrome due to impaired PPAR? signaling

ABSTRACT: PLAAT3 is a phospholipid modifying enzyme predominantly expressed in neural and white adipose tissue (WAT). It is a potential drug target for metabolic syndrome as Plaat3 deficiency in mice protects against diet-induced obesity. We identified seven patients from four unrelated consanguineous families, with homozygous loss-of-function variants in PLAAT3, presenting a severe lipodystrophy syndrome (LS) associated with metabolic complications, as well as neurological features including demyelinating neuropathy and intellectual disability. Multi-omics analysis of mouse Plaat3-/- and patient-derived WAT showed enrichment of arachidonic acid-containing membrane phospholipids and a strong decrease in the signaling of PPAR?, the master regulator of adipocyte differentiation. The present dataset describes the proteomics shotgun analysis of WAT samples from Plaat3-/- and Plaat3-/+ mice. We found that proteins involved in fatty acid metabolic and lipid biosynthetic processes were less abundant in Plaat3-/- WAT, whereas proteins involved in autophagy and catabolism were more abundant. In line with transcriptomics data obtained from mice and human WAT, PPAR? and its coactivators were identified as strong transcriptional regulators within the set of downregulated proteins. Along with validation experiments in PLAAT3-deficient human adipose stem cells, these findings establish PLAAT3 deficiency as a novel hereditary LS with neurological manifestations, caused by a PPAR?-dependent defect in WAT differentiation and function.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Sara Dufour

LAB HEAD: Bart Dermaut

PROVIDER: PXD038815 | Pride | 2023-08-29

REPOSITORIES: Pride

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