The PNPLA3 variant associated with fatty liver disease (I148M) accumulates on lipid droplets by evading ubiquitylation

Hepatology

Volumn 66, Issue 4, 2017, Pages 1111-1124

  BasuRay, Soumik ^a   Smagris, Eriks ^a   Cohen, Jonathan C ^a   Hobbs, Helen H ^a,b  

^a UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

^b UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BORTEZOMIB; FAT DROPLET; PATATIN LIKE PHOSPHOLIPASE DOMAIN CONTAINING PROTEIN 3; PROTEIN; RNA; SUCROSE; TRIACYLGLYCEROL; UNCLASSIFIED DRUG; 3-METHYLADENINE; ADENINE; CALCIUM INDEPENDENT PHOSPHOLIPASE A2; PNPLA3 PROTEIN, MOUSE; PROTEASOME; SUGAR INTAKE;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CONTROLLED STUDY; FATTY LIVER; FEMALE; GENETIC ASSOCIATION; GENETIC VARIABILITY; LIPID LIVER LEVEL; LIPID STORAGE; MACROAUTOPHAGY; MOUSE; NONHUMAN; PRIORITY JOURNAL; TRANSGENIC MOUSE; UBIQUITINATION; WILD TYPE; ANALOGS AND DERIVATIVES; ANIMAL; CALORIC RESTRICTION; GENETIC PREDISPOSITION; GENETICS; LIPID METABOLISM; METABOLISM; OXIDATION REDUCTION REACTION; SECRETION (PROCESS); SUGAR INTAKE;

ADENINE; ANIMALS; CALORIC RESTRICTION; DIETARY SUCROSE; FATTY LIVER; GENETIC PREDISPOSITION TO DISEASE; LIPID DROPLETS; LIPID METABOLISM; MICE, TRANSGENIC; OXIDATION-REDUCTION; PHOSPHOLIPASES A2, CALCIUM-INDEPENDENT; PROTEASOME ENDOPEPTIDASE COMPLEX; TRIGLYCERIDES; UBIQUITINATION;

EID: 85025067357     PISSN: 02709139     EISSN: 15273350     Source Type: Journal    
DOI: 10.1002/hep.29273     Document Type: Article

References (38)

1. Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008;40:1461-1465.
2. Cohen JC, Horton JD, Hobbs HH. Human fatty liver disease: old questions and new insights. Science 2011;332:1519-1523.
3. Sookoian S, Castano GO, Burgueno AL, Gianotti TF, Rosselli MS, Pirola CJ. A nonsynonymous gene variant in the adiponutrin gene is associated with nonalcoholic fatty liver disease severity. J Lipid Res 2009;50:2111-2116.
4. Valenti L, Dongiovanni P, Ginanni Corradini S, Burza MA, Romeo S. PNPLA3 I148M variant and hepatocellular carcinoma: a common genetic variant for a rare disease. Dig Liver Dis 2013;45:619-624.
5. 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;286:37085-37093.
6. Basantani MK, Sitnick MT, Cai L, Brenner DS, Gardner NP, Li JZ, et al. Pnpla3/Adiponutrin deficiency in mice does not contribute to fatty liver disease or metabolic syndrome. J Lipid Res 2011;52:318-329.
7. Chen W, Chang B, Li L, Chan L. Patatin-like phospholipase domain-containing 3/adiponutrin deficiency in mice is not associated with fatty liver disease. Hepatology 2010;52:1134-1142.
8. Li JZ, Huang Y, Karaman R, Ivanova PT, Brown HA, Roddy T, et al. Chronic overexpression of PNPLA3I148M in mouse liver causes hepatic steatosis. J Clin Invest 2012;122:4130-4144.
9. Kumari M, Schoiswohl G, Chitraju C, Paar M, Cornaciu I, Rangrez AY, et al. Adiponutrin functions as a nutritionally regulated lysophosphatidic acid acyltransferase. Cell Metab 2012;15:691-702.
10. Smagris E, BasuRay S, Li J, Huang Y, Lai KM, Gromada J, et al. Pnpla3I148M knockin mice accumulate PNPLA3 on lipid droplets and develop hepatic steatosis. Hepatology 2015;61:108-118.
11. Ferbitz L, Maier T, Patzelt H, Bukau B, Deuerling E, Ban N. Trigger factor in complex with the ribosome forms a molecular cradle for nascent proteins. Nature 2004;431:590-596.
12. Folch J, Lees M, Sloane Stanley GH. A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem 1957;226:497-509.
13. Moon YA, Hammer RE, Horton JD. Deletion of ELOVL5 leads to fatty liver through activation of SREBP-1c in mice. J Lipid Res 2009;50:412-423.
14. Guan HP, Goldstein JL, Brown MS, Liang G. Accelerated fatty acid oxidation in muscle averts fasting-induced hepatic steatosis in SJL/J mice. J Biol Chem 2009;284:24644-24652.
15. Shimano H, Horton JD, Hammer RE, Shimomura I, Brown MS, Goldstein JL. Overproduction of cholesterol and fatty acids causes massive liver enlargement in transgenic mice expressing truncated SREBP-1a. J Clin Invest 1996;98:1575-1584.
16. Millar JS, Cromley DA, McCoy MG, Rader DJ, Billheimer JT. Determining hepatic triglyceride production in mice: comparison of poloxamer 407 with Triton WR-1339. J Lipid Res 2005;46:2023-2028.
17. Nasrin N, Wu X, Fortier E, Feng Y, Bare OC, Chen S, et al. SIRT4 regulates fatty acid oxidation and mitochondrial gene expression in liver and muscle cells. J Biol Chem 2010;285:31995-32002.
18. Engelking LJ, Kuriyama H, Hammer RE, Horton JD, Brown MS, Goldstein JL, et al. Overexpression of Insig-1 in the livers of transgenic mice inhibits SREBP processing and reduces insulin-stimulated lipogenesis. J Clin Invest 2004;113:1168-1175.
19. De Palma C, Morisi F, Cheli S, Pambianco S, Cappello V, Vezzoli M, et al. Autophagy as a new therapeutic target in Duchenne muscular dystrophy. Cell Death Dis 2012;3:e418.
20. Carmignac V, Svensson M, Korner Z, Elowsson L, Matsumura C, Gawlik KI, et al. Autophagy is increased in laminin alpha2 chain-deficient muscle and its inhibition improves muscle morphology in a mouse model of MDC1A. Hum Mol Genet 2011;20:4891-4902.
21. Smagris E, Gilyard S, BasuRay S, Cohen JC, Hobbs HH. Inactivation of Tm6sf2, a gene defective in fatty liver disease, impairs lipidation but not secretion of very low density lipoproteins. J Biol Chem 2016;291:10659-10676.
22. Huang Y, He S, Li JZ, Seo YK, Osborne TF, Cohen JC, et al. A feed-forward loop amplifies nutritional regulation of PNPLA3. Proc Natl Acad Sci U S A 2010;107:7892-7897.
23. Zimmerman R, Strauss JG, Haemmerle G, Schoiswohl G, Birner-Gruenberger R, Riederer M, et al. Fat mobolization in adipose tissue is promoted by adipose triglyceride lipase. Science 2004;306:1383-1386.
24. Kaushik S, Cuervo AM. Degradation of lipid droplet-associated proteins by chaperone-mediated autophagy facilitates lipolysis. Nat Cell Biol 2015;17:759-770.
25. Marvyn PM, Bradley RM, Button EB, Mardian EB, Duncan RE. Fasting upregulates adipose triglyceride lipase and hormone-sensitive lipase levels and phosphorylation in mouse kidney. Biochem Cell Biol 2015;93:262-267.
26. He S, McPhaul C, Li JZ, Garuti R, Kinch L, Grishin NV, et al. A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis. J Biol Chem 2010;285:6706-6715.
27. Xu G, Sztalryd C, Lu X, Tansey JT, Gan J, Dorward H, et al. Post-translational regulation of adipose differentiation-related protein by the ubiquitin/proteasome pathway. J Biol Chem 2005;280:42841-42847.
28. Seglen PO, Gordon PB. 3-Methyladenine: specific inhibitor of autophagic/lysosomal protein degradation in isolated rat hepatocytes. Proc Natl Acad Sci U S A 1982;79:1889-1892.
29. Blommaart EF, Krause U, Schellens JP, Vreeling-Sindelarova H, Meijer AJ. The phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 inhibit autophagy in isolated rat hepatocytes. Eur J Biochem 1997;243:240-246.
30. Schonfeld G, Patterson BW, Yablonskiy DA, Tanoli TS, Averna M, Elias N, et al. Fatty liver in familial hypobetalipoproteinemia: triglyceride assembly into VLDL particles is affected by the extent of hepatic steatosis. J Lipid Res 2003;44:470-478.
31. Wetterau JR, Aggerbeck LP, Bouma ME, Eisenberg C, Munck A, Hermier M, et al. Absence of microsomal triglyceride transfer protein in individuals with abetalipoproteinemia. Science 1992;258:999-1001.
32. Pirazzi C, Adiels M, Burza MA, Mancina RM, Levin M, Stahlman M, et al. Patatin-like phospholipase domain-containing 3 (PNPLA3) I148M (rs738409) affects hepatic VLDL secretion in humans and in vitro. J Hepatol 2012;57:1276-1282.
33. Chamoun Z, Vacca F, Parton RG, Gruenberg J. PNPLA3/adiponutrin functions in lipid droplet formation. Biol Cell 2013;105:219-233.
34. Ruhanen H, Perttila J, Holtta-Vuori M, Zhou Y, Yki-Jarvinen H, Ikonen E, et al. PNPLA3 mediates hepatocyte triacylglycerol remodeling. J Lipid Res 2014;55:739-746.
35. Nian Z, Sun Z, Yu L, Toh SY, Sang J, Li P. Fat-specific protein 27 undergoes ubiquitin-dependent degradation regulated by triacylglycerol synthesis and lipid droplet formation. J Biol Chem 2010;285:9604-9615.
36. Takahashi Y, Shinoda A, Kamada H, Shimizu M, Inoue J, Sato R. Perilipin2 plays a positive role in adipocytes during lipolysis by escaping proteasomal degradation. Sci Rep 2016;6:20975.
37. Schreiber A, Peter M. Substrate recognition in selective autophagy and the ubiquitin-proteasome system. Biochim Biophys Acta 2014;1843:163-181.
38. Klionsky DJ, Abeliovich H, Agostinis P, Agrawal DK, Aliev G, Askew DS, et al. Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy 2008;4:151-175.