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A feed-forward loop amplifies nutritional regulation of PNPLA3
Open accessAbstract
The upsurge in prevalence of obesity has spawned an epidemic of nonalcoholic fatty liver disease (NAFLD). Previously, we identified a sequence variant (I148M) in patatin-like phospholipase domain-containing protein 3 (PNPLA3) that confers susceptibility to both hepatic triglyceride (TG) deposition and liver injury. To glean insights into the biological role of PNPLA3, we examined the molecular mechanisms by which nutrient status controls hepatic expression of PNPLA3. PNPLA3 mRNA levels, which were low in fasting animals, increased approximately 90-fold with carbohydrate feeding. The increase was mimicked by treatment with a liver X receptor (LXR) agonist and required the transcription factor SREBP-1c. The site of SREBP-1c binding was mapped to intron 1 of Pnpla3 using chromatin immunoprecipitation and electrophoretic mobility shift assays. SREBP-1c also promotes fatty acid synthesis by activating several genes encoding enzymes in the biosynthetic pathway. Addition of fatty acids (C16:0, C18:1, and C18:2) to the medium of cultured hepatocytes (HuH-7) increased PNPLA3 protein mass without altering mRNA levels. The posttranslational increase in PNPLA3 levels persisted after blocking TG synthesis with triascin C. Oleate (400 muM) treatment prolonged the half-life of PNPLA3 from 2.4 to 6.7 h. These findings are consistent with nutritional control of PNPLA3 being effected by a feed-forward loop; SREBP-1c promotes accumulation of PNPLA3 directly by activating Pnpla3 transcription and indirectly by inhibiting PNPLA3 degradation through the stimulation of fatty acid synthesis.
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“In mice, Pnpla3 is predominantly expressed in adipose tissue, where its expression level is 50–100 times higher than in the liver [50,51,52].”
From The HepG2 Cell Line as a Model for Studying Metabolic Dysfunction-Associated Steatotic Liver Disease (2026) · cites this paper as [51]
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Pirazzi, C., Valenti, L. V. C., Motta, B. M., Pingitore, P., Hedfalk, K., Mancina, R. M., Burza, M. A., Indiveri, C., Ferro, Y., Montalcini, T., et al. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddu121 · Cited by 363
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Adiponutrin Functions as a Nutritionally Regulated Lysophosphatidic Acid Acyltransferase
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InfluentialHuang, Y., Cohen, J. C., & Hobbs, H. H. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.290114 · Cited by 312
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“SREBP-1c is the only known transcriptional activator of PNPLA3 expression (Huang et al., 2010).”
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“…animal models with inhibition of VLDL secretion, the TM6SF2 gene variant carriers present liver steatosis with no disorders of glucose metabolism (Jacobs et al., 2010), which may be related to the deficiency of polyunsaturated phosphatidylcholines and excess polyunsaturated FFA in the liver of…”
BackgroundZeng, X., Varady, K. A., Wang, X., Targher, G., Byrne, C. D., Tayyem, R., Latella, G., Bergheim, I., Valenzuela, R., George, J., et al. (2024) · Metabolism · doi:10.1016/j.metabol.2024.156028 · Cited by 138
Genetic Pathways in Nonalcoholic Fatty Liver Disease: Insights From Systems Biology
Sookoian, S. C., Pirola, C. J., Valenti, L. V. C., & Davidson, N. O. (2020) · Hepatology · doi:10.1002/hep.31229 · Cited by 130
“(26-30) Pathophysiological studies established that during obesity and insulin resistance PNPLA3 protein expression is induced in hepatocytes, hepatic stellate cells, and adipocytes and is localized on LDs, where it represents the dominant surface protein.(31,32) PNPLA3 has intrinsic lipase activity on triglycerides,…”
BackgroundHepatic transcriptional responses to fasting and feeding
Bideyan, L., Nagari, R., & Tontonoz, P. (2021) · Genes & Development · doi:10.1101/gad.348340.121 · Cited by 126
“…regulates the expression of genes encoding proteins linked to triglyceride synthesis, including patatin-like phospholipase domain containing 3 (PNPLA3), mitochondrial glycerol-3-phosphate acyltransferase (GPAM), malic enzyme (ME), and glucose-6-phosphate dehydrogenase (G6PD) (Huang et al. 2010).”
BackgroundNutrition and Genetics in NAFLD: The Perfect Binomium
Meroni, M., Longo, M., Rustichelli, A., & Dongiovanni, P. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21082986 · Cited by 125
“Moreover, PNPLA3 protein degradation can be inhibited by the presence of fatty acids [51,52].”
BackgroundEffects of PNPLA3 on Liver Fat and Metabolic Profile in Hispanic Children and Adolescents
Goran, M. I., Walker, R. W., Lê, K., Mahurkar‐Joshi, S., Vikman, S., Davis, J. N., Spruijt‐Metz, D., Weigensberg, M. J., & Allayee, H. (2010) · Diabetes · doi:10.2337/db10-0554 · Cited by 121
Dynamic interactions of ABHD5 with PNPLA3 regulate triacylglycerol metabolism in brown adipocytes
Yang, A., Mottillo, E. P., Mladenovic-Lucas, L., Li, Z., & Granneman, J. G. (2019) · Nature Metabolism · doi:10.1038/s42255-019-0066-3 · Cited by 119
Falleti, E., Fabris, C., Cmet, S., Cussigh, A., Bitetto, D., Fontanini, E., Fornasiere, E., Bignulin, S., Fumolo, E., Bignulin, E., et al. (2011) · Liver International · doi:10.1111/j.1478-3231.2011.02534.x · Cited by 121
Burza, M. A., Pirazzi, C., Maglio, C., Sjöholm, K., Mancina, R. M., Svensson, P., Jacobson, P., Adiels, M., Baroni, M. G., Borén, J., et al. (2012) · Digestive and Liver Disease · doi:10.1016/j.dld.2012.05.006 · Cited by 119
Genetics of nonalcoholic fatty liver disease
Dongiovanni, P., & Valenti, L. V. C. (2015) · Metabolism · doi:10.1016/j.metabol.2015.08.018 · Cited by 118
“[33] Huang Y, He S, Li JZ, Seo YK, Osborne TF, Cohen JC, et al.”
BackgroundSIRT1 Mediates the Effect of GLP-1 Receptor Agonist Exenatide on Ameliorating Hepatic Steatosis
Xu, F., Li, Z., Zheng, X., Liu, H., Liang, H., Xu, H., Chen, Z., Zeng, K., & Weng, J. (2014) · Diabetes · doi:10.2337/db14-0263 · Cited by 114
“PNPLA3, a target gene of SREBP-1c, also plays a role in lipogenesis in mouse liver (23).”
Tang, C. S.-M., Zhang, H., Cheung, C. Y. Y., Xu, M., Ho, J. C.-Y., Zhou, W., Cherny, S. S., Zhang, Y., Holmen, O. L., Au, K., et al. (2015) · Nature Communications · doi:10.1038/ncomms10206 · Cited by 111
PNPLA3 mediates hepatocyte triacylglycerol remodeling
Ruhanen, H., Perttilä, J., Hölttä‐Vuori, M., Zhou, Y., Yki‐Järvinen, H., Ikonen, E., Käkelä, R., & Olkkonen, V. M. (2014) · Journal of Lipid Research · doi:10.1194/jlr.m046607 · Cited by 114
The role of PNPLA3 in health and disease
Pingitore, P., & Romeo, S. (2018) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2018.06.018 · Cited by 115
Toward Genetic Prediction of Nonalcoholic Fatty Liver Disease Trajectories: PNPLA3 and Beyond
Krawczyk, M. J., Liebe, R., & Lammert, F. (2020) · Gastroenterology · doi:10.1053/j.gastro.2020.01.053 · Cited by 114
Metabolic dysfunction–associated fatty liver disease and the risk of 24 specific cancers
Liu, Z., Lin, C., Suo, C., Zhao, R., Li, J., Zhang, T., & Chen, X. (2021) · Metabolism · doi:10.1016/j.metabol.2021.154955 · Cited by 117
Self-citationMitsche, M. A., Hobbs, H. H., & Cohen, J. C. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.002333 · Cited by 108
Self-citationSantoro, N., Savoye, M., Kim, G., Marotto, K., Shaw, M. M., Pierpont, B., & Caprio, S. (2012) · PLoS ONE · doi:10.1371/journal.pone.0037827 · Cited by 108
“In fact, while knock out mice for the pnpla3 do not show any increased fat accumulation into the liver with respect to the wild types [25,26], the administration through viral vectors of the mutated PNPLA3 confers to wild type mice a higher susceptibility to fatty liver [24].”
BackgroundHepatic steatosis in Wilson disease – Role of copper and PNPLA3 mutations
Stättermayer, A. F., Traussnigg, S., Dienes, H., Aigner, E. S., Stauber, R. E., Lackner, K., Hofer, H., Stift, J., Wrba, F., Stadlmayr, A., et al. (2015) · Journal of Hepatology · doi:10.1016/j.jhep.2015.01.034 · Cited by 107
Baselli, G., Dongiovanni, P., Rametta, R., Meroni, M., Pelusi, S., Maggioni, M., Badiali, S., Pingitore, P., Maurotti, S., Montalcini, T., et al. (2020) · Gut · doi:10.1136/gutjnl-2019-319226 · Cited by 106
Palma, R., Pronio, A., Romeo, M., Scognamiglio, F., Ventriglia, L., Ormando, V. M., Lamazza, A., Pontone, S., Federico, A., & Dallio, M. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm11133649 · Cited by 113
“Its expression was regulated by sterol regulatory element-binding protein 1 (SREBP1c)/liver X receptor (LXR) and by carbohydrate response element-binding protein (ChREBP), and activated by post-prandial or pathological hyperinsulinemia [73].”
BackgroundJohnson, S. M., Bao, H., McMahon, C. E., Chen, Y., Burr, S. D., Anderson, A. M., Madeyski-Bengtson, K., Lindén, D., Han, X., & Liu, J. (2024) · Nature Communications · doi:10.1038/s41467-024-49224-x · Cited by 100
“In the liver, carbohydrate feeding triggers increased PNPLA3 expression through the LXR/SREBP-1c pathway 60 , suggesting PNPLA3 functions under lipogenic rather than lipolytic conditions.”
Rong, S., Xia, M., Vale, G., Wang, S., Kim, C.-W., Li, S., McDonald, J. G., Radhakrishnan, A., & Horton, J. D. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2024.01.011 · Cited by 102
“65 A single-nucleotide polymorphism that results in a single amino acid change in PNPLA3 (I148M) is strongly associated with increased liver TG, fibrosis, cirrhosis, and hepatocellular carcinoma.”
TTC39B deficiency stabilizes LXR reducing both atherosclerosis and steatohepatitis
Hsieh, J., Koseki, M., Molusky, M. M., Yakushiji, E., Ichi, I., Westerterp, M., Iqbal, J., Chan, R., Abramowicz, S., Tascau, L., et al. (2016) · Nature · doi:10.1038/nature18628 · Cited by 98
“…carboxylase α (Acc α ), Glycerol-3-phosphate acyltransferase (Gpat1, Gpam), and Glucose-6-phosphate dehydrogenase (G6pd), as well as Patatin-like phospholipase domain-containing protein 3 (Pnpla3, Adiponutrin), which is an SREBP-1 target implicated in human hepatic steatosis 17,18 (Fig 3b).”
PNPLA3/adiponutrin functions in lipid droplet formation
Chamoun, Z., Vacca, F., Parton, R. G., & Grüenberg, J. (2013) · Biology of the Cell · doi:10.1111/boc.201200036 · Cited by 98
“, 2010) and liver in human (Huang et al., 2010) and is tightly controlled by changes in the nutritional status (Baulande et al.”
BackgroundInfluentialLuukkonen, P. K., Porthan, K., Ahlholm, N., Rosqvist, F., Dufour, S., Zhang, X., Lehtimäki, T. E., Seppänen, W., Orho‐Melander, M., Hodson, L., et al. (2023) · Cell Metabolism · doi:10.1016/j.cmet.2023.10.008 · Cited by 97
Palmer, C. N. A., Maglio, C., Pirazzi, C., Burza, M. A., Adiels, M., Burch, L. R., Donnelly, L. A., Colhoun, H. M., Doney, A. S. F., Dillon, J. F., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0039362 · Cited by 94
“PNPLA3 is a membrane bound protein highly expressed in hepatocytes [35].”
BackgroundPNPLA3-Associated Steatohepatitis: Toward a Gene-Based Classification of Fatty Liver Disease
Krawczyk, M. J., Portincasa, P., & Lammert, F. (2013) · Seminars in Liver Disease · doi:10.1055/s-0033-1358525 · Cited by 93
Eicosanoids in Metabolic Syndrome
Hardwick, J. P., Eckman, K., Lee, Y., Abdelmegeed, M. A., Esterle, A. R., Chilian, W. M., Chiang, J. Y. L., & Song, B. (2013) · Advances in pharmacology · doi:10.1016/b978-0-12-404717-4.00005-6 · Cited by 97
“Normally, activation of the IR results in phosphorylation and activation of IRS-1 toward SREBP1c increase in lipogenesis, while IRS-2 activation mediates phosphorylation of FOXO-1 and exclusion from the nucleus where it activates the transcription of genes involved in gluconeogenesis.”
BackgroundInfluentialKrawczyk, M. J., Grünhage, F., Zimmer, V., & Lammert, F. (2010) · Journal of Hepatology · doi:10.1016/j.jhep.2010.10.042 · Cited by 91
Kumashiro, N., Yoshimura, T., Cantley, J. L., Majumdar, S. K., Guebre‐Egziabher, F., Kursawe, R., Vatner, D. F., Fat, I., Kahn, M., Erion, D. M., et al. (2012) · Hepatology · doi:10.1002/hep.26170 · Cited by 89
“Rat pnpla3 is more abundant in adipose tissue than in liver and more abundant in cytosol than in membrane or lipid droplets, which is different from what has been reported in humans.(14,37) However, our findings demonstrating a strong positive correlation between hepatic PNPLA3 expressions and hepatic lipid content an…”
BackgroundResultPerttilä, J., Samanez, C. H., Caron, S., Tanhuanpää, K., Staels, B., Yki‐Järvinen, H., & Olkkonen, V. M. (2012) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00125.2011 · Cited by 87
PNPLA3—A Potential Therapeutic Target for Personalized Treatment of Chronic Liver Disease
Dong, X. C. (2019) · Frontiers in Medicine · doi:10.3389/fmed.2019.00304 · Cited by 88
“In addition to hepatocytes, human PNPLA3 gene is also abundantly expressed in HSCs (121, 139).”
BackgroundInfluentialQiao, A., Liang, J., Ke, Y., Li, C., Cui, Y., Shen, L., Zhang, H., Cui, A., Liu, X., Liu, C., et al. (2011) · Hepatology · doi:10.1002/hep.24402 · Cited by 85
“To this end, primary hepatocytes prepared from wild-type and SREBP-1c-null mouse livers were treated with insulin or the LXR agonist, TO901317.”
BackgroundInfluentialAbsence of adipose triglyceride lipase protects from hepatic endoplasmic reticulum stress in mice
Fuchs, C. D., Claudel, T., Kumari, P., Haemmerle, G., Pollheimer, M. J., Stojaković, T., Scharnagl, H., Halilbasic, E., Gumhold, J., Silbert, D., et al. (2012) · Hepatology · doi:10.1002/hep.25601 · Cited by 86
“PNPLA3 (the closest homolog to ATGL/PNPLA2) has recently been implicated in NAFLD in humans, because a missense mutation [I148M] is associated with increased steatosis and progression to NASH and fibrosis.1,27-29 However, PNPLA3 KO mice do not show altered susceptibility to steatosis,40 which could be the result of sp…”
BackgroundA Nutrigenomic Approach to Non-Alcoholic Fatty Liver Disease
Dongiovanni, P., & Valenti, L. V. C. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18071534 · Cited by 88
Metadata
- Authors
- Huang, Y., He, S., Li, J. Z., Seo, Y.-K., Osborne, T. F., Cohen, J. C., & Hobbs, H. H.
- Affiliations
- Howard Hughes Medical Institute (US)
- The University of Texas Southwestern Medical Center (US)
- University of California, Irvine (US)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2010-04-12
- Volume
- 107
- Issue
- 17
- Pages
- 7892-7897
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2867902
- OpenAlex
- W2096694584
- Cited by
- 386
- References
- 49
- Citations by year
- 2026: 12 · 2025: 21 · 2024: 20 · 2023: 14 · 2022: 17 · 2021: 29 · 2020: 44 · 2019: 18 · 2018: 20 · 2017: 27 · 2016: 20 · 2015: 27 · 2014: 32 · 2013: 17 · 2012: 24
- FWCI
- 19.37
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (HL20948)
- National Heart, Lung, and Blood Institute (HL-20948, R01HL048044, HL48044, HL92550, P01HL020948, RL1HL092550)
- Topics
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- PNPLA3, feed-forward loop, SREBP-1c, liver X receptor, non-alcoholic fatty liver disease, obesity, fatty acid synthesis, post-translational regulation, protein stability, carbohydrate feeding, triglyceride synthesis, oleate
- MeSH terms
- Acyltransferases, Animals, Cell Line, Chromosome Mapping, Dietary Carbohydrates, Fasting, Gene Expression Regulation, Humans, Lipase, Liver, Male, Membrane Proteins, Nutritional Status, Oligonucleotides, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, Electrophoretic Mobility Shift Assay, Chromatin Immunoprecipitation, Intracellular Signaling Peptides and Proteins, Mice, Phospholipases A2, Calcium-Independent
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