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Loss of phospholipase PLAAT3 causes lipodystrophy due to impaired PPAR훾 signaling

ABSTRACT: Loss of phospholipase PLAAT3 causes lipodystrophy due to impaired PPAR훾 signaling

PROVIDER: PRJNA976263 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24740052_1.fastq.gz	Fastqsanger.gz
	SRR24740052_2.fastq.gz	Fastqsanger.gz
	SRR24740053_1.fastq.gz	Fastqsanger.gz
	SRR24740053_2.fastq.gz	Fastqsanger.gz
	SRR24740054_1.fastq.gz	Fastqsanger.gz

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Loss of phospholipase PLAAT3 causes lipodystrophy due to impaired PPAR signaling

Project description:PLAAT3 is a phospholipid modifying enzyme predominantly expressed in neural and white adipose tissue (WAT). We identified loss-of-function variants in human PLAAT3 as the cause of a severe lipodystrophy syndrome associated with neurological with features. To identify the underlying molecular pathways associated with PLAAT3 deficiency, we performed RNA sequencing and differential gene expression analysis on WAT specimens from Plaat3 knockout mice.

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

Project description: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 PPAR𝛾, 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, PPAR𝛾 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 PPAR𝛾-dependent defect in WAT differentiation and function.

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