PNPLA3, the triacylglycerol synthesis/hydrolysis/storage dilemma, and nonalcoholic fatty liver disease

Table 1 Patatin-like phospholipase domain containing 3 protein features and functions

PNPLA3 belongs to the IPLA2/lipase family. The protein encoded by PNPLA3 is a triacylglycerol lipase that mediates triacylglycerol hydrolysis in adipocytes. Multifunctional enzyme that has both triacylglycerol lipase and acylglycerol O-acyltransferase activity (http://genatlas.medecine.univ-paris5.fr/)

Lipid hydrolase with an unusual folding topology that differs from classical lipases[38]

The enzyme is highly regulated by changes in energy balance: nutritional control of PNPLA3 being affected by a feed-forward loop[36]

PNPLA3 mRNA increases during differentiation of rat adipocytes in an insulin-dependent manner[39]

PNPLA3 mRNA expression is upregulated by tri-iodothyronine in adipocytes in vitro, in humans and rats, and in vivo in rat WAT[39]

PNPLA3 mRNA expression is upregulated by tri-iodothyronine in adipocytes in vitro, in humans and rats, and in vivo in rat white adipose tissue[40]

Promoter region of the human adiponutrin/PNPLA3 gene is regulated by glucose and insulin[33]

Fasting significantly downregulates PNPLA3 mRNA expression in liver and adipose tissue[35]

Feeding significantly upregulates PNPLA3 mRNA in liver and fat[34]

Liver PNPLA3 mRNA is expressed in human liver in higher levels compared with adipose tissue[36]

PNPLA3 mRNA is highly expressed in liver of b/ob mice[40] and visceral and subcutaneous adipose issue in obese humans[41]

PNPLA3 mRNA is expressed in hepatocytes but not in Kupffer cells[35,36]

PNPLA3 is expressed in hepatocytes but not in liver endothelial and Kupffer cells; microarray-based gene profiling showed that the expression level of

PNPLA3 in hepatocytes is correlated with that of genes associated with the lipogenic pathway such as ME1, SPOT14, and SCD1[35]

PNPLA3 is regulated in human hepatocytes by glucose via ChREBP[42]

SREBP1c is able to induce PNPLA3 expression in human immortalized hepatocytes and in HepG2 hepatoma cells[37]

PNPLA3: Patatin-like phospholipase domain containing 3; SREBP1c: Sterol regulatory element binding protein 1; ChREBP: Carbohydrate-responsive element-binding protein; ME1: Malic enzyme; SCD1: Stearoyl-CoA desaturase 1.