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Mini-Review

PNPLA3-I148M: a problem of plenty in non-alcoholic fatty liver disease

Pages 201-208 | Received 10 Oct 2018, Accepted 31 Mar 2019, Published online: 07 May 2019

References

  • Younossi ZM, Stepanova M, Afendy M, et al. Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008. Clin Gastroenterol Hepatol. 2011 Jun;9(6):524–530 e1; quiz e60. PubMed PMID: 21440669.
  • Younossi ZM, Koenig AB, Abdelatif D, et al. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016 Jul;64(1):73–84. PubMed PMID: 26707365.
  • Hamaguchi M, Kojima T, Takeda N, et al. The metabolic syndrome as a predictor of nonalcoholic fatty liver disease. Ann Intern Med. 2005 Nov 15;143(10):722–728. PubMed PMID: 16287793.
  • Romeo S, Kozlitina J, Xing C, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2008 Dec;40(12):1461–1465. PubMed PMID: 18820647; PubMed Central PMCID: PMCPMC2597056.
  • Cohen JC, Horton JD, Hobbs HH. Human fatty liver disease: old questions and new insights. Science. 2011 Jun 24;332(6037):1519–1523. . PubMed PMID: 21700865; PubMed Central PMCID: PMCPMC3229276.
  • Parikh ND, Marrero WJ, Wang J, et al. Projected increase in obesity and non-alcoholic-steatohepatitis-related liver transplantation waitlist additions in the United States. Hepatology. 2017 Aug 17. DOI:10.1002/hep.29473. PubMed PMID: 28833326.
  • Petersen KF, Dufour S, Feng J, et al. Increased prevalence of insulin resistance and nonalcoholic fatty liver disease in Asian-Indian men. Proc Natl Acad Sci U S A. 2006 Nov 28;103(48):18273–18277. PubMed PMID: 17114290; PubMed Central PMCID: PMCPMC1693873.
  • Browning JD, Szczepaniak LS, Dobbins R, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology. 2004 Dec;40(6):1387–1395. PubMed PMID: 15565570.
  • Tian C, Stokowski RP, Kershenobich D, et al. Variant in PNPLA3 is associated with alcoholic liver disease. Nat Genet. 2010 Jan;42(1):21–23. PubMed PMID: 19946271.
  • Trepo E, Romeo S, Zucman-Rossi J, et al. PNPLA3 gene in liver diseases. J Hepatol. 2016 Aug;65(2):399–412. PubMed PMID: 27038645.
  • Baulande S, Lasnier F, Lucas M, et al. Adiponutrin, a transmembrane protein corresponding to a novel dietary- and obesity-linked mRNA specifically expressed in the adipose lineage. J Biol Chem. 2001 Sep 7;276(36):33336–33344. PubMed PMID: 11431482.
  • Kershaw EE, Hamm JK, Verhagen LA, et al. Adipose triglyceride lipase: function, regulation by insulin, and comparison with adiponutrin. Diabetes. 2006 Jan;55(1):148–157. PubMed PMID: 16380488; PubMed Central PMCID: PMCPMC2819178.
  • Villena JA, Roy S, Sarkadi-Nagy E, et al. Desnutrin, an adipocyte gene encoding a novel patatin domain-containing protein, is induced by fasting and glucocorticoids: ectopic expression of desnutrin increases triglyceride hydrolysis. J Biol Chem. 2004 Nov 5;279(45):47066–47075. PubMed PMID: 15337759.
  • Wilson PA, Gardner SD, Lambie NM, et al. Characterization of the human patatin-like phospholipase family. J Lipid Res. 2006 Sep;47(9):1940–1949. PubMed PMID: 16799181.
  • Liu YM, Moldes M, Bastard JP, et al. Adiponutrin: A new gene regulated by energy balance in human adipose tissue. J Clin Endocrinol Metab. 2004 Jun;89(6):2684–2689. PubMed PMID: 15181042.
  • Moldes M, Beauregard G, Faraj M, et al. Adiponutrin gene is regulated by insulin and glucose in human adipose tissue. Eur J Endocrinol. 2006 Sep;155(3):461–468. PubMed PMID: 16914601.
  • Kotronen A, Johansson LE, Johansson LM, et al. A common variant in PNPLA3, which encodes adiponutrin, is associated with liver fat content in humans. Diabetologia. 2009 Jun;52(6):1056–1060. PubMed PMID: 19224197.
  • Kienesberger PC, Oberer M, Lass A, et al. Mammalian patatin domain containing proteins: a family with diverse lipolytic activities involved in multiple biological functions. J Lipid Res. 2009 Apr;50 Suppl:S63–S68. PubMed PMID: 19029121; PubMed Central PMCID: PMCPMC2674697.
  • Rydel TJ, Williams JM, Krieger E, et al. The crystal structure, mutagenesis, and activity studies reveal that patatin is a lipid acyl hydrolase with a Ser-Asp catalytic dyad. Biochemistry. 2003 Jun 10;42(22):6696–6708. PubMed PMID: 12779324.
  • Strickland JA, Orr GL, Walsh TA. Inhibition of Diabrotica larval growth by patatin, the lipid acyl hydrolase from potato tubers. Plant Physiol. 1995 Oct;109(2):667–674. PubMed PMID: 12228621; PubMed Central PMCID: PMCPMC157634.
  • Banfalvi Z, Kostyal Z, Barta E. Solanum brevidens possesses a non-sucrose-inducible patatin gene. Mol Gen Genet. 1994 Nov 15;245(4):517–522. PubMed PMID: 7808402.
  • Gunn PJ, Green CJ, Pramfalk C, et al. In vitro cellular models of human hepatic fatty acid metabolism: differences between Huh7 and HepG2 cell lines in human and fetal bovine culturing serum. Physiol Rep. 2017 Dec;5(24). DOI:10.14814/phy2.13532. PubMed PMID: 29263118; PubMed Central PMCID: PMCPMC5742701.
  • Huang Y, He S, Li JZ, et al. A feed-forward loop amplifies nutritional regulation of PNPLA3. Proc Natl Acad Sci U S A. 2010 Apr 27;107(17):7892–7897. PubMed PMID: 20385813; PubMed Central PMCID: PMCPMC2867902.
  • Pirazzi C, Valenti L, Motta BM, et al. PNPLA3 has retinyl-palmitate lipase activity in human hepatic stellate cells. Hum Mol Genet. 2014 Aug 1;23(15):4077–4085. PubMed PMID: 24670599; PubMed Central PMCID: PMCPMC4082369.
  • Pingitore P, Dongiovanni P, Motta BM, et al. PNPLA3 overexpression results in reduction of proteins predisposing to fibrosis. Hum Mol Genet. 2016 Dec 1;25(23):5212–5222. PubMed PMID: 27742777; PubMed Central PMCID: PMCPMC5886043.
  • Bruschi FV, Claudel T, Tardelli M, et al. The PNPLA3 I148M variant modulates the fibrogenic phenotype of human hepatic stellate cells. Hepatology. 2017 Jun;65(6):1875–1890. PubMed PMID: 28073161.
  • Lake AC, Sun Y, Li JL, et al. Expression, regulation, and triglyceride hydrolase activity of Adiponutrin family members. J Lipid Res. 2005 Nov;46(11):2477–2487. PubMed PMID: 16150821.
  • Kantartzis K, Peter A, Machicao F, et al. Dissociation between fatty liver and insulin resistance in humans carrying a variant of the patatin-like phospholipase 3 gene. Diabetes. 2009 Nov;58(11):2616–2623. PubMed PMID: 19651814; PubMed Central PMCID: PMCPMC2768178.
  • Jelenik T, Kaul K, Sequaris G, et al. Mechanisms of insulin resistance in primary and secondary nonalcoholic fatty liver. Diabetes. 2017 Aug;66(8):2241–2253. PubMed PMID: 28490610; PubMed Central PMCID: PMCPMC5521856.
  • Franko A, Merkel D, Kovarova M, et al. Dissociation of fatty liver and insulin resistance in I148M PNPLA3 carriers: differences in diacylglycerol (DAG) FA18:1 lipid species as a possible explanation. Nutrients. 2018 Sep 17;10(9):1314. PubMed PMID: 30227635; PubMed Central PMCID: PMCPMC6164484.
  • Li JZ, Huang Y, Karaman R, et al. Chronic overexpression of PNPLA3I148M in mouse liver causes hepatic steatosis. J Clin Invest. 2012 Nov;122(11):4130–4144. PubMed PMID: 23023705; PubMed Central PMCID: PMCPMC3484461.
  • Dutta AK. Adiponutrin (PNPLA3) in liver fibrogenesis: is unaltered HepG2 cell line a better model system compared to murine models?. Med Hypotheses. 2015 Dec;85(6):736–739. . PubMed PMID: 26519102.
  • Smagris E, BasuRay S, Li J, et al. Pnpla3I148M knockin mice accumulate PNPLA3 on lipid droplets and develop hepatic steatosis. Hepatology. 2015 Jan;61(1):108–118. PubMed PMID: 24917523; PubMed Central PMCID: PMCPMC4262735.
  • Hoekstra M, Li Z, Kruijt JK, et al. The expression level of non-alcoholic fatty liver disease-related gene PNPLA3 in hepatocytes is highly influenced by hepatic lipid status. J Hepatol. 2010 Feb;52(2):244–251. PubMed PMID: 20015565.
  • He S, McPhaul C, Li JZ, et al. A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis. J Biol Chem. 2010 Feb 26;285(9):6706–6715. PubMed PMID: 20034933; PubMed Central PMCID: PMC2825465.
  • Chamoun Z, Vacca F, Parton RG, et al. PNPLA3/adiponutrin functions in lipid droplet formation. Biol Cell. 2013 May;105(5):219–233. PubMed PMID: 23398201.
  • Ruhanen H, Perttila J, Holtta-Vuori M, et al. PNPLA3 mediates hepatocyte triacylglycerol remodeling. J Lipid Res. 2014 Apr;55(4):739–746. PubMed PMID: 24511104; PubMed Central PMCID: PMCPMC3966707.
  • BasuRay S, Smagris E, Cohen JC, et al. The PNPLA3 variant associated with fatty liver disease (I148M) accumulates on lipid droplets by evading ubiquitylation. Hepatology. 2017 Oct;66(4):1111–1124. PubMed PMID: 28520213; PubMed Central PMCID: PMCPMC5605398.
  • Dubuquoy C, Robichon C, Lasnier F, et al. Distinct regulation of adiponutrin/PNPLA3 gene expression by the transcription factors ChREBP and SREBP1c in mouse and human hepatocytes. J Hepatol. 2011 Jul;55(1):145–153. PubMed PMID: 21145868.
  • Perttila J, Huaman-Samanez C, Caron S, et al. PNPLA3 is regulated by glucose in human hepatocytes, and its I148M mutant slows down triglyceride hydrolysis. Am J Physiol Endocrinol Metab. 2012 May 15;302(9):E1063–9. PubMed PMID: 22338072.
  • Lee JH, Lee GY, Jang H, et al. Ring finger protein20 regulates hepatic lipid metabolism through protein kinase A-dependent sterol regulatory element binding protein1c degradation. Hepatology. 2014 Sep;60(3):844–857. PubMed PMID: 24425205; PubMed Central PMCID: PMCPMC4258077.
  • Jenkins CM, Mancuso DJ, Yan W, et al. 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 Nov 19;279(47):48968–48975. PubMed PMID: 15364929.
  • Huang Y, Cohen JC, Hobbs HH. Expression and characterization of a PNPLA3 protein isoform (I148M) associated with nonalcoholic fatty liver disease. J Biol Chem. 2011 Oct 28;286(43):37085–37093. . PubMed PMID: 21878620; PubMed Central PMCID: PMCPMC3199456.
  • Kumari M, Schoiswohl G, Chitraju C, et al. Adiponutrin functions as a nutritionally regulated lysophosphatidic acid acyltransferase. Cell Metab. 2012 May 2;15(5):691–702. PubMed PMID: 22560221; PubMed Central PMCID: PMCPMC3361708.
  • McMahon D, Dinh A, Kurz D, et al. Comparative gene identification 58/alpha/beta hydrolase domain 5 lacks lysophosphatidic acid acyltransferase activity. J Lipid Res. 2014 Aug;55(8):1750–1761. PubMed PMID: 24879803; PubMed Central PMCID: PMCPMC4109769.
  • Pingitore P, Pirazzi C, Mancina RM, et al. Recombinant PNPLA3 protein shows triglyceride hydrolase activity and its I148M mutation results in loss of function. Biochim Biophys Acta. 2014 Apr 4;1841(4):574–580. PubMed PMID: 24369119.
  • Mondul A, Mancina RM, Merlo A, et al. PNPLA3 I148M variant influences circulating retinol in adults with nonalcoholic fatty liver disease or obesity. J Nutr. 2015 Aug;145(8):1687–1691. PubMed PMID: 26136587; PubMed Central PMCID: PMCPMC4516767.
  • Luukkonen PK, Zhou Y, Sadevirta S, et al. Hepatic ceramides dissociate steatosis and insulin resistance in patients with non-alcoholic fatty liver disease. J Hepatol. 2016 May;64(5):1167–1175. PubMed PMID: 26780287.
  • Peter A, Kovarova M, Nadalin S, et al. PNPLA3 variant I148M is associated with altered hepatic lipid composition in humans. Diabetologia. 2014 Oct;57(10):2103–2107. PubMed PMID: 24972532.
  • Mitsche MA, Hobbs HH, Cohen JC. Patatin-like phospholipase domain-containing protein 3 promotes transfer of essential fatty acids from triglycerides to phospholipids in hepatic lipid droplets. J Biol Chem. 2018 May 4;293(18):6958–6968. . PubMed PMID: 29555681; PubMed Central PMCID: PMCPMC5936833.
  • Gijon MA, Riekhof WR, Zarini S, et al. Lysophospholipid acyltransferases and arachidonate recycling in human neutrophils. J Biol Chem. 2008 Oct 31;283(44):30235–30245. PubMed PMID: 18772128; PubMed Central PMCID: PMCPMC2573059.
  • Buch S, Stickel F, Trepo E, et al. A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis. Nat Genet. 2015 Dec;47(12):1443–1448. PubMed PMID: 26482880.
  • Basantani MK, Sitnick MT, Cai L, et al. Pnpla3/Adiponutrin deficiency in mice does not contribute to fatty liver disease or metabolic syndrome. J Lipid Res. 2011 Feb;52(2):318–329. PubMed PMID: 21068004; PubMed Central PMCID: PMCPMC3023552.
  • Chen W, Chang B, Li L, et al. Patatin-like phospholipase domain-containing 3/adiponutrin deficiency in mice is not associated with fatty liver disease. Hepatology. 2010 Sep;52(3):1134–1142. PubMed PMID: 20648554; PubMed Central PMCID: PMCPMC2932863.
  • Zimmermann R, Strauss JG, Haemmerle G, et al. Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase. Science. 2004 Nov 19;306(5700):1383–1386. PubMed PMID: 15550674.
  • Nian Z, Sun Z, Yu L, et al. Fat-specific protein 27 undergoes ubiquitin-dependent degradation regulated by triacylglycerol synthesis and lipid droplet formation. J Biol Chem. 2010 Mar 26;285(13):9604–9615. PubMed PMID: 20089860; PubMed Central PMCID: PMCPMC2843210.
  • Takahashi Y, Shinoda A, Kamada H, et al. Perilipin2 plays a positive role in adipocytes during lipolysis by escaping proteasomal degradation. Sci Rep. 2016 Feb 15;6:20975. PubMed PMID: 26876687; PubMed Central PMCID: PMCPMC4753471.
  • Wu Y-T, Tan H-L, Shui G, et al. Dual role of 3-methyladenine in modulation of autophagy via different temporal patterns of inhibition on class I and III phosphoinositide 3-kinase. J Biol Chem. 2010 Apr 2;285(14):10850–10861. PubMed PMID: 20123989; PubMed Central PMCID: PMCPMC2856291.
  • Kaushik S, Cuervo AM. Degradation of lipid droplet-associated proteins by chaperone-mediated autophagy facilitates lipolysis. Nat Cell Biol. 2015 Jun;17(6):759–770. . PubMed PMID: 25961502; PubMed Central PMCID: PMCPMC4449813.
  • Valenti L, Dongiovanni P. Mutant PNPLA3 I148M protein as pharmacological target for liver disease. Hepatology. 2017 Oct;66(4):1026–1028. . PubMed PMID: 28586091.
  • Ghosh M, Niyogi S, Bhattacharyya M, et al. Ubiquitin ligase COP1 controls hepatic fat metabolism by targeting ATGL for degradation. Diabetes. 2016 Dec;65(12):3561–3572. PubMed PMID: 27658392.
  • Wang YJ, Bian Y, Luo J, et al. Cholesterol and fatty acids regulate cysteine ubiquitylation of ACAT2 through competitive oxidation. Nat Cell Biol. 2017 Jul;19(7):808–819. PubMed PMID: 28604676; PubMed Central PMCID: PMCPMC5518634.
  • Negoita F, Blomdahl J, Wasserstrom S, et al. PNPLA3 variant M148 causes resistance to starvation-mediated lipid droplet autophagy in human hepatocytes. J Cell Biochem. 2019 Jan;120(1):343–356. PubMed PMID: 30171718.
  • BasuRayS, Wang Y, Smagris E, Cohen JC,Hobbs HH. Accumulation of PNPLA3 on lipid droplets is the basis of associated hepatic steatosis. PNAS. 2019 Apr 24. doi:10.1073/pnas.1901974116. PMID: 31019090
  • Martinez-Lopez N, Garcia-Macia M, Sahu S, et al. Autophagy in the CNS and periphery coordinate lipophagy and lipolysis in the brown adipose tissue and liver. Cell Metab. 2016 Jan 12;23(1):113–127. PubMed PMID: 26698918; PubMed Central PMCID: PMCPMC4715637.
  • Mazhar K. The future of nonalcoholic fatty liver disease treatment. Med Clin North Am. 2019 Jan;103(1):57–69. . PubMed PMID: 30466676.
  • Kumashiro N, Yoshimura T, Cantley JL, et al. Role of patatin-like phospholipase domain-containing 3 on lipid-induced hepatic steatosis and insulin resistance in rats. Hepatology. 2013 May;57(5):1763–1772. PubMed PMID: 23175050; PubMed Central PMCID: PMCPMC3597437.
  • Linden D, Ahnmark A, Pingitore P, et al. Pnpla3 silencing with antisense oligonucleotides ameliorates nonalcoholic steatohepatitis and fibrosis in Pnpla3 I148M knock-in mice. Mol Metab. 2019 Feb 5. DOI:10.1016/j.molmet.2019.01.013. PubMed PMID: 30772256.
  • Goldstein JL, DeBose-Boyd RA, Brown MS. Protein sensors for membrane sterols. Cell. 2006 Jan 13;124(1):35–46. . PubMed PMID: 16413480.
  • Chen G, Liang G, Ou J, et al. Central role for liver X receptor in insulin-mediated activation of Srebp-1c transcription and stimulation of fatty acid synthesis in liver. Proc Natl Acad Sci U S A. 2004 Aug 3;101(31):11245–11250. PubMed PMID: 15266058; PubMed Central PMCID: PMCPMC509189.
  • Hua X, Nohturfft A, Goldstein JL, et al. Sterol resistance in CHO cells traced to point mutation in SREBP cleavage-activating protein. Cell. 1996 Nov 1;87(3):415–426. PubMed PMID: 8898195.
  • Wu JW, Yang H, Mitchell GA. Potential mechanism underlying the PNPLA3(I) (148) (M) -Hepatic steatosis connection. Hepatology. 2016 Feb;63(2):676–677. . PubMed PMID: 26096616.
  • Smagris E, BasuRay S, Gromada J, et al. Reply. Hepatology. 2016 Feb;63(2):677. PubMed PMID: 26099489.
  • Guo F, Ma Y, Kadegowda AK, et al. Deficiency of liver comparative gene identification-58 causes steatohepatitis and fibrosis in mice. J Lipid Res. 2013 Aug;54(8):2109–2120. PubMed PMID: 23733885; PubMed Central PMCID: PMCPMC3708361.
  • Lass A, Zimmermann R, Haemmerle G, et al. Adipose triglyceride lipase-mediated lipolysis of cellular fat stores is activated by CGI-58 and defective in Chanarin-Dorfman Syndrome. Cell Metab. 2006 May;3(5):309–319. PubMed PMID: 16679289.
  • Wang Y, Kory N, Cohen JC, et al. PNPLA3, CGI-58, and inhibition of hepatic triglyceride hydrolysis in mice. Hepatology. 2019 Feb 25. DOI:10.1002/hep.30583. PubMed PMID: 30802989.