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FLASH GENE

Symbol

PNPLA2

contributors: mct/npt/pgu - updated : 23-06-2015

HGNC name	patatin-like phospholipase domain containing 2
HGNC id	30802

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	NLSDM neutral lipid storage disease without ichthyosis but with mild myopathy
Location	11p15.5      Physical location : 818.900 - 825.569
Synonym name	adipose triglyceride lipase
	desnutrin
	transport-secretion protein 2.2
	pigment epithelium-derived factor receptor
	triglyceride hydrolase
Synonym symbol(s)	TTS-2.2, ATGL, iPLA2zeta, TTS2, PEDF-R, FP17548, DKFZp667M109
EC.number	3.1.1.3

DNA

TYPE	functioning gene
STRUCTURE	6.67 kb     10 Exon(s)

MAPPING

cloned

Y

linked

N

status

provisional

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_020376 10 - 2443 NP_065109 55.2 504 - 2008 19029121

EXPRESSION

Type	ubiquitous

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular heart       highly Homo sapiens Endocrine neuroendocrine pituitary     highly Hearing/Equilibrium ear       highly Reproductive male system testis

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Connective adipose brown     Homo sapiens Connective adipose white     Homo sapiens Muscular striatum skeletal     Homo sapiens

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	N-terminal patatin domain with a glycine-rich region, lipase domain that interacts with two C-terminal domains of GBF1, HDS (Homology downstream of Sec7) 1 and HDS2
	a GXSXG serine hydrolase motif that is part of the catalytic dyad essential for lipase activit
	an aspartate active site motif
	a esterase of the alpha/beta hydrolase fold domain
	four transmembrane domains interrupted by two extracellular loops and three intracellular regions along its polypeptide sequence
	C-terminal region interacts with N-terminal domains of GBF1, including the catalytic Sec7 domain, but not with full-length GBF1 or its entire N-terminus , C-terminus domain whose hydrophobic portion is required for binding to lipid droplets (LDs)

HOMOLOGY

interspecies

homolog to murine Atgl

Homologene

FAMILY

patatin-like phospholipase family

CATEGORY

regulatory

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm,cytosolic
text	associated with lipid droplets of adipocytes

basic FUNCTION	having a catalytic activity and nutrient reservoir activity and responsible for the initial step in triglycerides catabolism and having a possible contribution to the pathophysiology of obesity
	important component of the lipolytic process and the mobilization of lipid stores
	adipocyte protein that may function as a lipase and play a role in the adaptive response to a low energy state, such as fasting, by providing fatty acids to other tissues for oxidation
	participating in triacylglycerol hydrolysis and the acyl-CoA independent transacylation of acylglycerols, thereby facilitating energy mobilization and storage in adipocytes
	playing an essential role in the metabolism of lipid droplets in the muscle
	adipose triglyceride lipase involved in the degradation of intracellular triglycerides
	lipid hydrolase with diverse substrate specificities such as triacylglycerol hydrolases, phospholipases, and a retinylester hydrolase
	adipocyte-specific protein with lipid hydrolase activity
	its activity is required for proper energy supply of the skeletal muscle during exercise
	acts in retinal differentiation, survival and maintenance by interacting with high affinity receptors on the surface of target cells
	crucial role for CIDEC-PNPLA2 interactions in regulating lipolysis, triglyceride accumulation, and insulin signaling in human adipocytes

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

lipid/lipoprotein

signaling

a component

component of the retina that is a phospholipase-linked membrane protein with high affinity for SERPINF1

INTERACTION

DNA

RNA

small molecule

protein	interacting with FOXO1 (FOXO1 may play an important role in the regulation of lipolysis in adipocytes by controlling the expression of PNPLA2)
	C-terminal 64 AAs of PLIN5 are critical for the differential binding of PNPLA2 to PLIN5 and PLIN1
	interacting with SIRT1 (SIRT1 controls PNPLA2 transcription primarily by deacetylating FOXO1)
	GBF1 and PNPLA2 interact directly and in cells, through multiple contact sites on each protein (interaction that may be involved in the membrane trafficking pathway mediated by GBF1, Arf1 and COPI, contributing to the localization of ATGL to lipid droplets)
	regulates both basal and stimulated lipolysis by interacting with adipose triglyceride lipase PNPLA2
	PDCD1 promotes fatty acid beta-oxidation (FAO) of endogenous lipids by increasing expression of CPT1A, and inducing lipolysis as indicated by elevation of the lipase PNPLA2, the lipolysis marker glycerol and release of fatty acids

cell & other

REGULATION

induced by

by fasting and glucocorticoids

Phosphorylated by

phosphorylated/activated by AMPK to increase lipolysis and brings fatty acid oxidation and UCP1 induction for thermogenesis

ASSOCIATED DISORDERS

corresponding disease(s)

NLSDM

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional     --over   decreases intracellular triglyceride levels constitutional       gain of function by fasting in adipose tissue constitutional     --over   is sufficient to alter myocardial energy metabolism and improve cardiac function constitutional     --other   altered PNPLA2 and LIPE expression in skeletal muscle could promote diacylglycerol accumulation and disrupt insulin signaling and action constitutional     --over   LIPE or PNPLA2 overexpression resulted in increased triglyceride-specific hydrolase capacity, but only PNPLA2 overexpression increased whole cell lipolysis

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed cancer     pharmacological inhibition of lipases LIPE and PNPLA2) may represent a powerful strategy to avoid the devastating condition of cachexia in response to cancer or other chronic diseases

ANIMAL & CELL MODELS

	Atgl-/- mice were protected from tumor-associated skeletal muscle loss
	Mice deficient for adipose triglyceride lipase (ATGL-ko) exhibit defective lipolysis and accumulate TG in adipose tissue and muscle