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The I148M substitution in patatin-like phospholipase domain containing 3 (PNPLA3I148M) determines a genetic form of nonalcoholic fatty liver disease. To elucidate the mode of PNPLA3 action in human hepatocytes, we studied effects of WT PNPLA3 (PNPLA3WT) and PNPLA3I148M on HuH7 cell lipidome after [13C]glycerol labeling, cellular turnover of oleic acid labeled with 17 deuterium atoms ([D17]oleic acid) in triacylglycerols (TAGs), and subcellular distribution of the protein variants. PNPLA3I148M induced a net accumulation of unlabeled TAGs, but not newly synthesized total [13C]TAGs. Principal component analysis (PCA) revealed that both PNPLA3WT and PNPLA3I148M induced a relative enrichment of TAGs with saturated FAs or MUFAs, with concurrent enrichment of polyunsaturated phosphatidylcholines. PNPLA3WT associated in PCA with newly synthesized [13C]TAGs, particularly 52:1 and 50:1, while PNPLA3I148M associated with similar preexisting TAGs. PNPLA3WT overexpression resulted in increased [D17]oleic acid labeling of TAGs during 24 h, and after longer incubations their turnover was accelerated, effects not detected with PNPLA3I148M. PNPLA3I148M localized more extensively to lipid droplets (LDs) than PNPLA3WT, suggesting that the substitution alters distribution of PNPLA3 between LDs and endoplasmic reticulum/cytosol. This study reveals a function of PNPLA3 in FA-selective TAG remodeling, resulting in increased TAG saturation. A defect in TAG remodeling activity likely contributes to the TAG accumulation observed in cells expressing PNPLA3I148M. The I148M substitution in patatin-like phospholipase domain containing 3 (PNPLA3I148M) determines a genetic form of nonalcoholic fatty liver disease. To elucidate the mode of PNPLA3 action in human hepatocytes, we studied effects of WT PNPLA3 (PNPLA3WT) and PNPLA3I148M on HuH7 cell lipidome after [13C]glycerol labeling, cellular turnover of oleic acid labeled with 17 deuterium atoms ([D17]oleic acid) in triacylglycerols (TAGs), and subcellular distribution of the protein variants. PNPLA3I148M induced a net accumulation of unlabeled TAGs, but not newly synthesized total [13C]TAGs. Principal component analysis (PCA) revealed that both PNPLA3WT and PNPLA3I148M induced a relative enrichment of TAGs with saturated FAs or MUFAs, with concurrent enrichment of polyunsaturated phosphatidylcholines. PNPLA3WT associated in PCA with newly synthesized [13C]TAGs, particularly 52:1 and 50:1, while PNPLA3I148M associated with similar preexisting TAGs. PNPLA3WT overexpression resulted in increased [D17]oleic acid labeling of TAGs during 24 h, and after longer incubations their turnover was accelerated, effects not detected with PNPLA3I148M. PNPLA3I148M localized more extensively to lipid droplets (LDs) than PNPLA3WT, suggesting that the substitution alters distribution of PNPLA3 between LDs and endoplasmic reticulum/cytosol. This study reveals a function of PNPLA3 in FA-selective TAG remodeling, resulting in increased TAG saturation. A defect in TAG remodeling activity likely contributes to the TAG accumulation observed in cells expressing PNPLA3I148M. Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem closely associated with all features of the metabolic syndrome (1–3) Romeo et al. (4Romeo S. Kozlitina J. Xing C. Pertsemlidis A. Cox D. Pennacchio L.A. Boerwinkle E. Cohen J.C. Hobbs H.H. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease.Nat. Genet. 2008; 40: 1461-1465Crossref PubMed Scopus (2212) Google Scholar) first described a single-nucleotide polymorphism (rs738409; C>G/I148M) in the patatin-like phospholipase domain containing 3 (PNPLA3, adiponutrin) gene, to be strongly associated with NAFLD. A meta-analysis of 16 studies demonstrated that homozygous carriers of PNPLA3I148M have on the average a 73% higher liver fat content than weight-matched homozygous carriers of the major allele (5Sookoian S. Pirola C.J. Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease.Hepatology. 2011; 53: 1883-1894Crossref PubMed Scopus (668) Google Scholar). However, NAFLD associated with PNPLA3I148M is distinct from obesity-associated common NAFLD, as it is not characterized by features of the metabolic syndrome such as hyperinsulinemia or dyslipidemia (1Cohen J.C. Horton J.D. Hobbs H.H. Human fatty liver disease: old questions and new insights.Science. 2011; 332: 1519-1523Crossref PubMed Scopus (1566) Google Scholar, 5Sookoian S. Pirola C.J. Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease.Hepatology. 2011; 53: 1883-1894Crossref PubMed Scopus (668) Google Scholar). In vitro assays using recombinant PNPLA3 have suggested that the WT PNPLA3 (PNPLA3WT) hydrolyzes emulsified triacylglycerol (TAG) and that the I148M substitution in PNPLA3 (PNPLA3I148M) abolishes this activity (6He S. McPhaul C. Li J.Z. Garuti R. Kinch L. Grishin N.V. Cohen J.C. Hobbs H.H. A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis.J. Biol. Chem. 2010; 285: 6706-6715Abstract Full Text Full Text PDF PubMed Scopus (466) Google Scholar, 7Jenkins C.M. Mancuso D.J. Yan W. Sims H.F. Gibson B. Gross R.W. Identification, cloning, expression, and purification of three novel human calcium-independent phospholipase A2 family members possessing triacylglycerol lipase and acylglycerol transacylase activities.J. Biol. Chem. 2004; 279: 48968-48975Abstract Full Text Full Text PDF PubMed Scopus (676) Google Scholar, 8Lake A.C. Sun Y. Li J.L. Kim J.E. Johnson J.W. Li D. Revett T. Shih H.H. Liu W. Paulsen J.E. et al.Expression, regulation, and triglyceride hydrolase activity of Adiponutrin family members.J. Lipid Res. 2005; 46: 2477-2487Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar). Moreover, the protein was shown to display a transacylase activity (7Jenkins C.M. Mancuso D.J. Yan W. Sims H.F. Gibson B. Gross R.W. Identification, cloning, expression, and purification of three novel human calcium-independent phospholipase A2 family members possessing triacylglycerol lipase and acylglycerol transacylase activities.J. Biol. Chem. 2004; 279: 48968-48975Abstract Full Text Full Text PDF PubMed Scopus (676) Google Scholar), and to prefer oleic acid (18:1n-9) as the fatty acyl moiety (9Huang Y. Cohen J.C. Hobbs H.H. Expression and characterization of a PNPLA3 protein isoform (I148M) associated with nonalcoholic fatty liver disease.J. Biol. Chem. 2011; 286: 37085-37093Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar). Opposing a putative role as a lipase, PNPLA3 is induced by glucose and insulin (10Moldes M. Beauregard G. Faraj M. Peretti N. Ducluzeau P.H. Laville M. Rabasa-Lhoret R. Vidal H. Clement K. Adiponutrin gene is regulated by insulin and glucose in human adipose tissue.Eur. J. Endocrinol. 2006; 155: 461-468Crossref PubMed Scopus (48) Google Scholar, 11Rae-Whitcombe S.M. Kennedy D. Voyles M. Thompson M.P. Regulation of the promoter region of the human adiponutrin/PNPLA3 gene by glucose and insulin.Biochem. Biophys. Res. Commun. 2010; 402: 767-772Crossref PubMed Scopus (32) Google Scholar, 12Soronen J. Laurila P.P. Naukkarinen J. Surakka I. Ripatti S. Jauhiainen M. Olkkonen V.M. Yki-Järvinen H. Adipose tissue gene expression analysis reveals changes in inflammatory, mitochondrial respiratory and lipid metabolic pathways in obese insulin-resistant subjects.BMC Med. Genomics. 2012; 5: 9Crossref PubMed Scopus (61) Google Scholar) and is a target gene of the lipogenic transcription factors SREBP-1c and the carbohydrate responsive element binding protein, ChREBP (13Huang Y. He S. Li J.Z. Seo Y.K. Osborne T.F. Cohen J.C. Hobbs H.H. A feed-forward loop amplifies nutritional regulation of PNPLA3.Proc. Natl. Acad. Sci. USA. 2010; 107: 7892-7897Crossref PubMed Scopus (276) Google Scholar, 14Dubuquoy C. Robichon C. Lasnier F. Langlois C. Dugail I. Foufelle F. Girard J. Burnol A.F. Postic C. Moldes M. Distinct regulation of adiponutrin/PNPLA3 gene expression by the transcription factors ChREBP and SREBP1c in mouse and human hepatocytes.J. Hepatol. 2011; 55: 145-153Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar, 15Perttilä J. Huaman-Samanez C. Caron S. Tanhuanpää K. Staels B. Yki-Järvinen H. Olkkonen V.M. PNPLA3 is regulated by glucose in human hepatocytes, and its I148M mutant slows down triglyceride hydrolysis.Am. J. Physiol. Endocrinol. Metab. 2012; 302: E1063-E1069Crossref PubMed Scopus (70) Google Scholar, 16Qiao A. Liang J. Ke Y. Li C. Cui Y. Shen L. Zhang H. Cui A. Liu X. Liu C. et al.Mouse patatin-like phospholipase domain-containing 3 influences systemic lipid and glucose homeostasis.Hepatology. 2011; 54: 509-521Crossref PubMed Scopus (62) Google Scholar). Kumari et al. (17Kumari M. Schoiswohl G. Chitraju C. Paar M. Cornaciu I. Rangrez A.Y. Wongsiriroj N. Nagy H.M. Ivanova P.T. Scott S.A. et al.Adiponutrin functions as a nutritionally regulated lysophosphatidic acid acyltransferase.Cell Metab. 2012; 15: 691-702Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar) suggested that the protein acts as lipogenic lysophosphatidic acid (LPA) acyltransferase, converting to acid and that the I148M substitution this acts as a both and TAGs, this the fat accumulation in the PNPLA3I148M allele PNPLA3 have metabolic L. Li J.Z. Schoiswohl G. K. Kumari M. Gross R.W. et in not to fatty liver disease or metabolic Lipid Res. 2011; Full Text Full Text PDF PubMed Scopus Google Scholar, W. B. Li L. L. phospholipase domain-containing in is not associated with fatty liver disease.Hepatology. 2010; PubMed Scopus Google Scholar), et al. N. T. J.L. F. R. I. M. et of patatin-like phospholipase domain-containing 3 on and insulin in PubMed Scopus Google Scholar) that PNPLA3 in liver to In with the study by et al. C. M. M. M. M. J. A. et phospholipase domain-containing 3 (PNPLA3) I148M in and in Hepatol. 2012; Full Text Full Text PDF PubMed Scopus (204) Google Scholar) in human a of in I148M carriers of liver suggesting that PNPLA3I148M a mutant that TAG accumulation of by the of TAG Li et al. J.Z. Y. R. Ivanova P.T. T. J. Cohen J.C. Hobbs H.H. overexpression of PNPLA3I148M in mouse liver 2012; PubMed Scopus Google Scholar) WT human PNPLA3 or the I148M variant in liver or adipose Expression of but not the WT protein, in the liver the fatty liver The metabolic studies suggested that the in TAGs associated with the I148M allele from changes in TAG PNPLA3WT and PNPLA3I148M on lipid droplets (LDs) (6He S. McPhaul C. Li J.Z. Garuti R. Kinch L. Grishin N.V. Cohen J.C. Hobbs H.H. A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis.J. Biol. Chem. 2010; 285: 6706-6715Abstract Full Text Full Text PDF PubMed Scopus (466) Google Scholar, F. J. functions in lipid PubMed Scopus Google Scholar). the by PNPLA3I148M NAFLD is In the we the by PNPLA3 and its I148M variant the lipid content and of human cells in PNPLA3WT or PNPLA3I148M in the HuH7 cell the cells labeling of TAGs with and turnover with oleic acid (18:1n-9) labeled with 17 deuterium atoms TAGs, and by of the between PNPLA3WT and PNPLA3I148M was by their subcellular in the or of HuH7 cells H. K. K. T. J. of human cells with functions in Res. Google Scholar) in containing and The PNPLA3 to was by from human adipose tissue and the of and The I148M substitution to the allele was in the PNPLA3 with the and protein of analysis of preexisting and newly synthesized HuH7 cells on with PNPLA3WT, or using after was to a labeling containing of [13C]glycerol 24 h, with and of of was total cell protein analysis using the The cell from labeling TAG and in both in the and shown in the first analysis of TAG the cells on and as described and with and or 24 in this the cells with and of analysis of TAG HuH7 cells in 24 as and labeled or with using as a The and the unlabeled and labeled TAG detected by as to et al. J. M. A the and purification of total from Biol. Chem. Full Text PDF PubMed Google Scholar) and in was with containing and lipid The and by both and mode in the of R. J. of in from with and using PubMed Scopus Google Scholar). The unlabeled and by the of cell with or labeling, and was by the in A. M. analysis of lipidome Chem. 2006; PubMed Scopus Google Scholar). In of total was by as in et al. R. A. S. P.H. A. R. acid in of as of or 2005; Scopus Google Scholar). In to the the acyl detected by in TAGs mode the and mode the FAs of using a with The TAG and the turnover studied using the by the mode of the unlabeled and analysis of and by cellular using a A of total lipid and J. Physiol. PubMed Scopus Google Scholar). of was to cell and was as of was and the was to and the was by The the in the mode the of The the of by using and using as The by analysis and the by lipid by using the and the A. M. analysis of lipidome Chem. 2006; PubMed Scopus Google Scholar). To the subcellular distribution of HuH7 cells with PNPLA3WT or by using to with cells with oleic as described M. Y. E. of by triglyceride Genet. PubMed Scopus Google Scholar). cells after with to the and with a The of cells PNPLA3 distribution was by of cells from a of the cellular lipid the between PNPLA3WT, and PNPLA3I148M by using by of of lipid component analysis (PCA) was The PCA between the and the lipid the variation in the PCA was using and the relative of the and using the first In of the the by of M. a in of and In and B. Scholar). To the of TAG remodeling, of by the of a on the by using the function in the of R. The in the of cells PNPLA3 was in or endoplasmic by PNPLA3WT or PNPLA3I148M in the cell PNPLA3 protein of by analysis 24 of the cells to 24 metabolic labeling of with and the cellular by the [13C]glycerol labeling of the cells expressing PNPLA3I148M a net of unlabeled TAGs with while expression of PNPLA3WT such the unlabeled TAGs that in the cells the labeling, the the newly synthesized of the of similar in and cells expressing form of PNPLA3 suggesting that PNPLA3 not TAG with (6He S. McPhaul C. Li J.Z. Garuti R. Kinch L. Grishin N.V. Cohen J.C. Hobbs H.H. A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis.J. Biol. Chem. 2010; 285: 6706-6715Abstract Full Text Full Text PDF PubMed Scopus (466) Google Scholar, 15Perttilä J. Huaman-Samanez C. Caron S. Tanhuanpää K. Staels B. Yki-Järvinen H. Olkkonen V.M. PNPLA3 is regulated by glucose in human hepatocytes, and its I148M mutant slows down triglyceride hydrolysis.Am. J. Physiol. Endocrinol. Metab. 2012; 302: E1063-E1069Crossref PubMed Scopus (70) Google Scholar), the cells or 24 in a with and the PNPLA3I148M a in TAG not PNPLA3I148M expression in net TAG accumulation in the of of TAGs, but with a in their To in the of PNPLA3 on the we studied the lipid of the cells the from the described in in to the TAG of both PNPLA3WT and PNPLA3I148M cells to from of the The component of the TAG variation between the and the of expressing form of PNPLA3 characterized by increased relative of TAGs with saturated and The WT and I148M cells with to component of the a component by the of [13C]glycerol in TAG PNPLA3WT cell TAGs on more newly synthesized and and in and of their unlabeled than the I148M cells on This is with a more remodeling of TAGs in cells expressing the PNPLA3WT as with the PNPLA3I148M The between the cells and on the PCA studied by the that the TAG of the three cell from not the PCA by that the of cells was from of the and the PNPLA3WT the I148M cells with containing or PNPLA3WT cells localized in the PCA between the PNPLA3I148M and and not in from the The total cellular content was by of the of cellular the major of hepatocytes, a in both and acid and while the total cellular content not between the and cells the of cells with of the PNPLA3 from the and the PNPLA3WT induced a more in the than PNPLA3I148M This in the of TAGs with and MUFAs, net of from TAGs to by the The was in of the not In h, the of the cells was The relative of and and increased as with the or cells by the of Kumari et al. (17Kumari M. Schoiswohl G. Chitraju C. Paar M. Cornaciu I. Rangrez A.Y. Wongsiriroj N. Nagy H.M. Ivanova P.T. Scott S.A. et al.Adiponutrin functions as a nutritionally regulated lysophosphatidic acid acyltransferase.Cell Metab. 2012; 15: 691-702Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar) suggesting that PNPLA3 we the and in the HuH7 The of cells or the total cellular of not from the To the that PNPLA3 the remodeling of TAGs, we labeling of HuH7 cells in containing with the of PNPLA3 (9Huang Y. Cohen J.C. Hobbs H.H. Expression and characterization of a PNPLA3 protein isoform (I148M) associated with nonalcoholic fatty liver disease.J. Biol. Chem. 2011; 286: 37085-37093Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar), or h, by lipid and analysis of the TAGs. the 24 analysis of the relative of unlabeled TAGs revealed a of TAGs in cells expressing PNPLA3WT, not observed with PNPLA3I148M this the relative of in cells more as with or the all three of cells the the that PNPLA3WT both TAGs and its from a remodeling activity in PNPLA3I148M. To the subcellular distribution and the putative of PNPLA3 on we the WT or I148M in HuH7 by with the In cells PNPLA3 associated with but of the cells in a more likely and PNPLA3I148M associated more with a distribution in of the cells of the cells 24 with to TAG resulted in of the of both PNPLA3WT and PNPLA3I148M suggesting that the lipid content metabolic of the LDs PNPLA3 with analysis of the cells that both the and the and similar The of PNPLA3 function and the TAG accumulation in carriers of the I148M allele the of PNPLA3 suggested to as a TAG lipase (6He S. McPhaul C. Li J.Z. Garuti R. Kinch L. Grishin N.V. Cohen J.C. Hobbs H.H. A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis.J. Biol. Chem. 2010; 285: 6706-6715Abstract Full Text Full Text PDF PubMed Scopus (466) Google Scholar, C. M. M. M. M. J. A. et phospholipase domain-containing 3 (PNPLA3) I148M in and in Hepatol. 2012; Full Text Full Text PDF PubMed Scopus (204) Google Scholar) or as a lipogenic (17Kumari M. Schoiswohl G. Chitraju C. Paar M. Cornaciu I. Rangrez A.Y. Wongsiriroj N. Nagy H.M. Ivanova P.T. Scott S.A. et al.Adiponutrin functions as a nutritionally regulated lysophosphatidic acid acyltransferase.Cell Metab. 2012; 15: 691-702Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar), the study a human a more mode of PNPLA3 action in TAG remodeling, activity that is in the I148M The this PNPLA3WT overexpression net of cellular PNPLA3I148M net accumulation of TAGs and slows down TAG cellular lipid (6He S. McPhaul C. Li J.Z. Garuti R. Kinch L. Grishin N.V. Cohen J.C. Hobbs H.H. A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis.J. Biol. Chem. 2010; 285: 6706-6715Abstract Full Text Full Text PDF PubMed Scopus (466) Google Scholar, 15Perttilä J. Huaman-Samanez C. Caron S. Tanhuanpää K. Staels B. Yki-Järvinen H. Olkkonen V.M. PNPLA3 is regulated by glucose in human hepatocytes, and its I148M mutant slows down triglyceride hydrolysis.Am. J. Physiol. Endocrinol. Metab. 2012; 302: E1063-E1069Crossref PubMed Scopus (70) Google PNPLA3WT and PNPLA3I148M cellular enrichment of and TAGs, and enrichment of with [13C]glycerol labeling, PNPLA3WT is associated with cellular enrichment of newly synthesized or acyl and or PNPLA3I148M with the unlabeled labeling in PNPLA3WT, but not the of this TAGs during 24 and its turnover during longer labeling PNPLA3WT not the total cellular TAG it a distinct on the and of its fatty acyl (9Huang Y. Cohen J.C. Hobbs H.H. Expression and characterization of a PNPLA3 protein isoform (I148M) associated with nonalcoholic fatty liver disease.J. Biol. Chem. 2011; 286: 37085-37093Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar), TAGs, activity in PNPLA3I148M. The that the in observed in TAGs, and not in and that the total cellular content was not that PNPLA3 not lipid the of (17Kumari M. Schoiswohl G. Chitraju C. Paar M. Cornaciu I. Rangrez A.Y. Wongsiriroj N. Nagy H.M. Ivanova P.T. Scott S.A. et al.Adiponutrin functions as a nutritionally regulated lysophosphatidic acid acyltransferase.Cell Metab. 2012; 15: 691-702Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar). However, not changes of In with the cell we of PNPLA3WT or PNPLA3I148M on as by labeling J. Huaman-Samanez C. Caron S. Tanhuanpää K. Staels B. Yki-Järvinen H. Olkkonen V.M. PNPLA3 is regulated by glucose in human hepatocytes, and its I148M mutant slows down triglyceride hydrolysis.Am. J. Physiol. Endocrinol. Metab. 2012; 302: E1063-E1069Crossref PubMed Scopus (70) Google Scholar). remodeling is a in hepatocytes, and in to that the acyl of triacylglycerol and of fatty acid the of triacylglycerol by hepatocytes.J. Lipid Res. Full Text Full Text PDF PubMed Google Scholar, A. Y. Y. M. S. T. K. T. and that the fatty acid of and the of lipid in cells and Lipid Res. 53: PubMed Scopus Google Scholar). cell overexpression of PNPLA3 reveals that PNPLA3 the to the and This of TAG by of the FAs by and to the to form G. D. J. of acid by A2 and Biophys. PubMed Scopus Google Scholar) or to to TAGs. PNPLA3 or between transacylase activity (7Jenkins C.M. Mancuso D.J. Yan W. Sims H.F. Gibson B. Gross R.W. Identification, cloning, expression, and purification of three novel human calcium-independent phospholipase A2 family members possessing triacylglycerol lipase and acylglycerol transacylase activities.J. Biol. Chem. 2004; 279: 48968-48975Abstract Full Text Full Text PDF PubMed Scopus (676) Google Scholar). PNPLA3 shown to display both TAG lipase and transacylase in vitro (6He S. McPhaul C. Li J.Z. Garuti R. Kinch L. Grishin N.V. Cohen J.C. Hobbs H.H. A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis.J. Biol. Chem. 2010; 285: 6706-6715Abstract Full Text Full Text PDF PubMed Scopus (466) Google Scholar, 7Jenkins C.M. Mancuso D.J. Yan W. Sims H.F. Gibson B. Gross R.W. Identification, cloning, expression, and purification of three novel human calcium-independent phospholipase A2 family members possessing triacylglycerol lipase and acylglycerol transacylase activities.J. Biol. Chem. 2004; 279: 48968-48975Abstract Full Text Full Text PDF PubMed Scopus (676) Google Scholar, 8Lake A.C. Sun Y. Li J.L. Kim J.E. Johnson J.W. Li D. Revett T. Shih H.H. Liu W. Paulsen J.E. et al.Expression, regulation, and triglyceride hydrolase activity of Adiponutrin family members.J. Lipid Res. 2005; 46: 2477-2487Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar). The with TAG remodeling of The observed enrichment of cellular TAGs with and that the remodeling activity However, PNPLA3 fatty activity in suggesting that PNPLA3 not TAGs (9Huang Y. Cohen J.C. Hobbs H.H. Expression and characterization of a PNPLA3 protein isoform (I148M) associated with nonalcoholic fatty liver disease.J. Biol. Chem. 2011; 286: 37085-37093Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar). the activity PNPLA3 (7Jenkins C.M. Mancuso D.J. Yan W. Sims H.F. Gibson B. Gross R.W. Identification, cloning, expression, and purification of three novel human calcium-independent phospholipase A2 family members possessing triacylglycerol lipase and acylglycerol transacylase activities.J. Biol. Chem. 2004; 279: 48968-48975Abstract Full Text Full Text PDF PubMed Scopus (676) Google Scholar) target The that PNPLA3I148M associated in [13C]glycerol labeling with the preexisting unlabeled 52:1 and TAGs and the WT protein with the newly synthesized the of TAG by as as the of by PNPLA3I148M on labeling of TAGs and turnover of the suggested that a of the PNPLA3I148M is a defect in TAG of and in a of FAs or of triacylglycerol and of fatty acid the of triacylglycerol by hepatocytes.J. Lipid Res. Full Text Full Text PDF PubMed Google Scholar), such a defect in net TAG In accumulation of LDs in TAG the of TAG is T. of fatty from adipose tissue Lipid Res. PubMed Scopus Google Scholar). TAG remodeling in cells expressing PNPLA3I148M LDs with a TAG to This is with the effects of human PNPLA3I148M in the liver of J.Z. Y. R. Ivanova P.T. T. J. Cohen J.C. Hobbs H.H. overexpression of PNPLA3I148M in mouse liver 2012; PubMed Scopus Google Scholar) and the human C. M. M. M. M. J. A. et phospholipase domain-containing 3 (PNPLA3) I148M in and in Hepatol. 2012; Full Text Full Text PDF PubMed Scopus (204) Google Scholar). PNPLA3 was shown to to LDs in both (6He S. McPhaul C. Li J.Z. Garuti R. Kinch L. Grishin N.V. Cohen J.C. Hobbs H.H. A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis.J. Biol. Chem. 2010; 285: 6706-6715Abstract Full Text Full Text PDF PubMed Scopus (466) Google Scholar) and cells F. J. functions in lipid PubMed Scopus Google Scholar). in cells that PNPLA3I148M more extensively with than Moreover, of the cells the of both PNPLA3WT and PNPLA3I148M with the the of PNPLA3I148M on (6He S. McPhaul C. Li J.Z. Garuti R. Kinch L. Grishin N.V. Cohen J.C. Hobbs H.H. A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis.J. Biol. Chem. 2010; 285: 6706-6715Abstract Full Text Full Text PDF PubMed Scopus (466) Google Scholar, J.Z. Y. R. Ivanova P.T. T. J. Cohen J.C. Hobbs H.H. overexpression of PNPLA3I148M in mouse liver 2012; PubMed Scopus Google Scholar, F. J. functions in lipid PubMed Scopus Google Scholar), its increased with LDs is a novel is that the in and in the of TAG to PNPLA3 with the and that this is more with PNPLA3I148M net TAG the the more of PNPLA3I148M its function in TAG the of lipase or activity on the F. J. functions in lipid PubMed Scopus Google Scholar). PNPLA3 transcription to a of lipogenic induced by glucose and insulin (10Moldes M. Beauregard G. Faraj M. Peretti N. Ducluzeau P.H. Laville M. Rabasa-Lhoret R. Vidal H. Clement K. Adiponutrin gene is regulated by insulin and glucose in human adipose tissue.Eur. J. Endocrinol. 2006; 155: 461-468Crossref PubMed Scopus (48) Google Scholar, 11Rae-Whitcombe S.M. Kennedy D. Voyles M. Thompson M.P. Regulation of the promoter region of the human adiponutrin/PNPLA3 gene by glucose and insulin.Biochem. Biophys. Res. Commun. 2010; 402: 767-772Crossref PubMed Scopus (32) Google Scholar, 12Soronen J. Laurila P.P. Naukkarinen J. Surakka I. Ripatti S. Jauhiainen M. Olkkonen V.M. Yki-Järvinen H. Adipose tissue gene expression analysis reveals changes in inflammatory, mitochondrial respiratory and lipid metabolic pathways in obese insulin-resistant subjects.BMC Med. Genomics. 2012; 5: 9Crossref PubMed Scopus (61) Google Scholar), with the that its function is not PNPLA3 acts to of TAG remodeling, be the role of this it of increased of PNPLA3 to the metabolic of the LDs and of FAs between the of and a that PNPLA3 TAG remodeling in a FA-selective The with a in PNPLA3I148M a defect in TAG remodeling, resulting in TAG The to and with labeled with 17 deuterium atoms endoplasmic protein lipid lysophosphatidic acid nonalcoholic fatty liver disease acid component component analysis patatin-like phospholipase domain containing 3 saturated of triacylglycerol
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