首页|PNPLA3, the triacylglycerol synthesis/hydrolysis/storage dilemma, and nonalcoholic fatty liver disease
PNPLA3, the triacylglycerol synthesis/hydrolysis/storage dilemma, and nonalcoholic fatty liver disease
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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 glycerol3-phosphate acyltransferase 2 is suggested by data miming.
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
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
National Agency for Science and TechnologyNational Agency for Science and TechnologyUniversidad de Buenos AiresSookoian S and Pirola CJ belong to National Council of Scientific and Technical Research
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