Disease relevance of PNPLA3

• Two ADPN polymorphisms showed association with obesity [1].
• Despite reasonable lipid profiles and remarkably elevated ADPN levels, our pediatric RTR with stable graft function displayed a risk for arteriosclerosis because of increased cIMT and mild hyperhomocysteinemia [2].

High impact information on PNPLA3

• Carriers of the obesity-associated variants showed a lesser increase in the levels of adipose tissue ADPN mRNA and an increased basal lipolysis [1].
• Visceral ADPN mRNA expression was correlated to measures of insulin sensitivity (fasting insulin and homeostasis model assessment) [1].
• Our results suggest that obese subjects that are insulin resistant and/or carriers of the obesity-associated ADPN alleles fail to upregulate the gene and that upregulation of adiponutrin may be an appropriate response to orchestrate energy excess [1].
• Obese subjects had increased levels of subcutaneous and visceral abdominal adipose tissue ADPN mRNA [1].
• Adiponutrin is one of three recently identified adipocyte lipases [1].

Biological context of PNPLA3

• This is consistent with a function for Desnutrin/ATGL, GS2, and GS2-Like in lipolysis, but not for Adiponutrin [3].
• Using bioinformatics, we identified three additional Adiponutrin family members (GS2, GS2-Like, and PNPLA1) [3].
• All four proteins show lipase activity in vitro, which is dependent on the presence of the active site serine for Adiponutrin, Desnutrin/ATGL, and GS2 [3].
• We also studied genetic variation in ADPN and its relation to obesity, lipolysis, and mRNA expression [1].
• The presence of quinolones does not prevent dimerization since incubation of the enzyme-DNA complex with both ADPNP and quinolones gives rise to a complex whose proteolytic pattern retains the characteristic signature of dimerization but has lost the quinolone-induced protection [4].

Anatomical context of PNPLA3

• Consistent with previously reported data, Desnutrin/ATGL is upregulated by fasting in adipose tissue, whereas Adiponutrin is downregulated [3].
• Adiponutrin and a related protein, adipocyte triglyceride lipase (ATGL; also known as Desnutrin), were recently described as adipocyte-specific proteins with lipid hydrolase activity [3].

Associations of PNPLA3 with chemical compounds

• Expression, regulation, and triglyceride hydrolase activity of Adiponutrin family members [3].
• Serum lipid/lipoprotein fractions, homocysteine and ADPN levels as well as intima-media thickness of the cIMT were determined in both groups [2].
• There were inverse correlations between log time post-transplantation and log ADPN as well as HDL cholesterol (r = -0.438, p < 0.05 and r = -0.578, p < 0.05, respectively) [2].
• There were no correlation between log ADPN, log homocysteine, log apolipoprotein B, lipoprotein (a), creatinine clearance and cumulative steroid dose [2].
• Limited supercoiling can be achieved in the presence of the non-hydrolysable ATP analogue, 5'-adenylyl beta,gamma-imidodiphosphate (ADPNP) [5].

Other interactions of PNPLA3

• Additionally, Adiponutrin and GS2-Like, but not Desnutrin/ATGL, are strongly induced in the liver of ob/ob mice [3].
• In vitro we find that the 24 kDa protein does not interact with the gyrase A or B proteins or with DNA, and fails to hydrolyse ATP or show significant binding to ATP, ADP or ADPNP [6].
• Compared with other adipocyte proteins such as leptin and adiponectin, adiponutrin mRNA did not show correlation with either adiposity indexes or with leptin or adiponectin mRNAs [7].

Analytical, diagnostic and therapeutic context of PNPLA3

• We have probed the wrapping of DNA around gyrase in the presence and in the absence of ADPNP using direct observation by atomic force microscopy (AFM) [5].
• These results have been corroborated using a DNA relaxation assay involving topoisomerase I. We have re-analysed previous hydroxyl-radical footprinting and crystallography data, and highlight the fact that the gyrase-DNA complex is surprisingly asymmetric in the absence of nucleotide but is symmetric in the presence of ADPNP [5].

References