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World J Gastroenterol. Nov 14, 2012; 18(42): 6018-6026
Published online Nov 14, 2012. doi: 10.3748/wjg.v18.i42.6018
PNPLA3, the triacylglycerol synthesis/hydrolysis/storage dilemma, and nonalcoholic fatty liver disease
Silvia Sookoian, Carlos J Pirola
Silvia Sookoian, Department of Clinical and Molecular Hepatology, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires, National Council of Scientific and Technological Research (CONICET), Autonomous City of Buenos Aires 1427, Argentina
Carlos J Pirola, Department of Molecular Genetics and Biology of Complex Diseases, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires, National Council of Scientific and Technological Research (CONICET), Autonomous City of Buenos Aires 1427, Argentina
Author contributions: Sookoian S and Pirola CJ were both equally involved in the conception and design, acquisition of data, analysis and interpretation of data; drafting the article and final approval of the version to be published.
Supported by Grants PICT 2008-1521 and PICT 2010 0441, from National Agency for Science and Technology; UBACYT CM04, from Universidad de Buenos Aires; and Sookoian S and Pirola CJ belong to National Council of Scientific and Technical Research.
Correspondence to: Carlos J Pirola, PhD, Department of Molecular Genetics and Biology of Complex Diseases, Institute of Medical Research A Lanari-IDIM, Combatientes de Malvinas 3150, Ciudad Autonoma de Buenos Aires 1427, Argentina. pirola.carlos@lanari.fmed.uba.ar
Telephone: +54-11-45148701 Fax: +54-11-45238947
Received: July 17, 2012
Revised: August 6, 2012
Accepted: August 26, 2012
Published online: November 14, 2012
Processing time: 174 Days and 10.3 Hours
Abstract

Genome-wide and candidate gene association studies have identified several variants that predispose individuals to developing nonalcoholic fatty liver disease (NAFLD). However, the gene that has been consistently involved in the genetic susceptibility of NAFLD in humans is patatin-like phospholipase domain containing 3 (PNPLA3, also known as adiponutrin). A nonsynonymous single nucleotide polymorphism in PNPLA3 (rs738409 C/G, a coding variant that encodes an amino acid substitution  I148M) is significantly associated with fatty liver and histological disease severity, not only in adults but also in children. Nevertheless, how PNPLA3 influences the biology of fatty liver disease is still an open question. A recent article describes new aspects about PNPLA3 gene/protein function and suggests that the  I148M variant promotes hepatic lipid synthesis due to a gain of function. We revise here the published data about the role of the  I148M variant in lipogenesis/lipolysis, and suggest putative areas of future research. For instance we explored in silico whether the rs738409 C or G alleles have the ability to modify miRNA binding sites and miRNA gene regulation, and we found that prediction of PNPLA3 target miRNAs shows two miRNAs potentially interacting in the 3’UTR region (hsa-miR-769-3p and hsa-miR-516a-3p). In addition, interesting unanswered questions remain to be explored. For example, PNPLA3 lies between two CCCTC-binding factor-bound sites that could be tested for insulator activity, and an intronic histone 3 lysine 4 trimethylation peak predicts an enhancer element, corroborated by the DNase I hypersensitivity site peak. Finally, an interaction between PNPLA3 and glycerol-3-phosphate acyltransferase 2 is suggested by data miming.

Keywords: Adiponutrin; Nonalcoholic fatty liver disease; miRNA; Glycerol-3-phosphate acyltransferase 2; Systems biology; Rs738409; Epigenetics