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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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“sen to examine the relationship between h-GH-down-regulated genes and known lipogenic genes from previous studies: FADS2 (27), SCD (29), FASN (30), diacylglycerol acryltransferase 2 gene (DGAT2) (31), and the adiponutrin gene [ADPN (32), currently known as PNPLA3 (33)].”
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Kim, K. A., Jang, H., Yang, Y. R., Park, K., Seo, J.-K., Shin, I.-W., Jeon, T.-I., Ahn, S., Suh, P., Osborne, T. F., et al. (2016) · Scientific Reports · doi:10.1038/srep35732 · Cited by 60
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“Thus, we also considered an independent interaction of PNPLA3 genotype with HOMA-IR because PNPLA3 is regulated by insulin through SREBP1 to stimulate triglyceride lipogenesis (33, 34).”
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“Although the clinical and functional impact of Met148 has been extensively studied (4, 6, 8), the focus of these studies have been its role in lipid mobilization and remodeling; it is thus still unknown whether PNPLA3 has a role in the modulation of the global metabolome of the human liver beyond its classical role in…”
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Review article: genetic factors that modify the outcome of viral hepatitis
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“As a result, the SREBP-1c gene is not actively transcribed, nuclear SREBP1c levels are low and Insig-1 mRNA and protein levels are low.”
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“The PNPLA3 gene encodes a 481-amino acid membrane protein located in the endoplasmic reticulum and lipid droplets in hepatocytes and hepatic stellate cells (HSCs)([23]).”
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“nantly expressed in human liver and adipose tissue (16).”
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“C), a pharmacological inhibitor of acyl–coenzyme A synthetase that blocks triglyceride synthesis and disrupts lipid droplet formation (21, 22), reduces viperin enzymatic activity.”
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“e transcription factor SREBP-1c plays key roles by directly activating PNPLA3 transcription and indirectly inhibiting PNPLA3 degradation through the stimulation of fatty acid synthesis [29].”
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“PNPLA3 is known to be expressed in various human tissues, with highest expression levels in the liver [22].”
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“Liver X receptor (LXR) mediates SREBP-1c upregulation, and PNPLA3 mRNA levels increase after LXR agonist treatment [31,32].”
BackgroundRegulation of the promoter region of the human adiponutrin/PNPLA3 gene by glucose and insulin
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“1193 at least in hepatocytes.(28) Moreover, peroxisome proliferator-activated receptor gamma (PPARγ) positively controls LXRα, thus favoring cholesterol efflux from foam cells.”
BackgroundInsights into genetic variants associated with NASH-fibrosis from metabolite profiling
Mann, J. P., Pietzner, M., Wittemans, L. B. L., Rolfe, E. D. L., Kerrison, N. D., Imamura, F., Forouhi, N. G., Fauman, E. B., Allison, M., Griffin, J. L., et al. (2020) · Human Molecular Genetics · doi:10.1093/hmg/ddaa162 · Cited by 39
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The PNPLA3 Ile148Met interacts with overweight and dietary intakes on fasting triglyceride levels
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“In addition to CHOs, PNPLA3 is up-regulated by certain fatty acids that inhibit its degradation (Huang et al. 2010).”
BackgroundInfluentialNew Perspectives on Genetic Prediction for Pediatric Metabolic Associated Fatty Liver Disease
Lin, Y., Wu, C.-C., & Ni, Y. (2020) · Frontiers in Pediatrics · doi:10.3389/fped.2020.603654 · Cited by 38
“PNPLA3 Patatin-like phospholipase domain containing 3 (PNPLA3) gene encodes a transmembrane protein “adiponutrin,” which is expressed predominantly in the liver, retina, skin, and adipose tissue (68, 69).”
BackgroundOmic studies reveal the pathogenic lipid droplet proteins in non-alcoholic fatty liver disease
Zhang, X., Wang, Y., & Liu, P. (2016) · Protein & Cell · doi:10.1007/s13238-016-0327-9 · Cited by 36
“PNPLA3 in humans is predominantly expressed in the liver, with substantially lower expression level in skin and adipose tissue (Huang et al., 2010).”
BackgroundInfluentialTargeting PNPLA3 to Treat MASH and MASH Related Fibrosis and Cirrhosis
Lindén, D., Tesz, G. J., & Loomba, R. S. (2024) · Liver International · doi:10.1111/liv.16186 · Cited by 36
“Importantly, the expression levels of PNPLA3 are highly regulated by fasting and refeeding via the sterol regulatory element binding protein-1c (SREBP-1c) transcription factor which is induced by insulin and liver X receptor (LXR) agonists [45].”
Nutrition Research and the Impact of Computational Systems Biology
Auley, M. T. M. (2013) · Journal of Computer Science & Systems Biology · doi:10.4172/jcsb.1000122 · Cited by 35
“Many of these interactions are non-linear in nature and can involve complex feedback and feed-forward loops [11-13].”
BackgroundOut of the frying pan: dietary saturated fat influences nonalcoholic fatty liver disease
Parks, E. J., Yki‐Järvinen, H., & Hawkins, M. A. (2017) · Journal of Clinical Investigation · doi:10.1172/jci92407 · Cited by 35
Kabbani, M., Michailidis, E., Steensels, S., Fulmer, C. G., Luna, J. M., Pen, J. L., Tardelli, M., Razooky, B. S., Ricardo-Lax, I., Zou, C., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111321 · Cited by 38
Park, J., Cho, B., Kwon, H., Prilutsky, D., Yun, J. M., Choi, H.-C., Hwang, K., Lee, I., Kim, J., & Kong, S. W. (2015) · Liver International · doi:10.1111/liv.12909 · Cited by 35
TINIAKOS, D. G., Anstee, Q. M., & Burt, A. D. (2017) · Elsevier eBooks · doi:10.1016/b978-0-7020-6697-9.00005-4 · Cited by 35
Genetic Risk Factors and Disease Modifiers of Nonalcoholic Steatohepatitis
Kozlitina, J. (2020) · Gastroenterology Clinics of North America · doi:10.1016/j.gtc.2019.09.001 · Cited by 33
The PNPLA3‐I148M variant increases polyunsaturated triglycerides in human adipose tissue
Qadri, S. U., Lallukka-Brück, S. E., Luukkonen, P. K., Zhou, Y., Gastaldelli, A., Orho‐Melander, M., Sammalkorpi, H. E., Juuti, A., Penttilä, A. K., Perttilä, J., et al. (2020) · Liver International · doi:10.1111/liv.14507 · Cited by 34
“P-ALT, U/L 30 (24-39) 36 (26-46) 30 (16-36) 24 (22-61)”
Oxidized metabolites of linoleic acid as biomarkers of liver injury in nonalcoholic steatohepatitis
Santoro, N., Caprio, S., & Feldstein, A. E. (2013) · Clinical Lipidology · doi:10.2217/clp.13.39 · Cited by 33
Marmugi, A., Lukowicz, C., Lasserre, F., Montagner, A., Polizzi, A., Ducheix, S., Goron, A., Gamet‐Payrastre, L., Gerbal‐Chaloin, S., Pascussi, J., et al. (2016) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2016.05.006 · Cited by 32
“As a lipogenic enzyme, Pnpla3 was reported to be transcriptionally regulated by SREBP-1c, LXR and ChREBP in response to insulin and glucose respectively (35, 42, 43).”
BackgroundXia, M., Lin, H., Chen, L., Wu, L., Ma, H., Li, Q., Aleteng, Q., Hu, Y., He, W., Gao, J., et al. (2019) · Diabetologia · doi:10.1007/s00125-018-4805-x · Cited by 32
Bruschi, F. V., Tardelli, M., Herac, M., Claudel, T., & Trauner, M. (2020) · Liver International · doi:10.1111/liv.14402 · Cited by 33
Dallio, M., Romeo, M., Gravina, A. G., Masarone, M., Larussa, T., Abenavoli, L., Persico, M., Loguercio, C., & Federico, A. (2021) · Nutrients · doi:10.3390/nu13051679 · Cited by 32
“The activation of SREBP1c/liver X receptor (LXR) pathway represents a critical moment in MAFLD development since it promotes PNPLA3 expression [150].”
BackgroundResultGenetic-related and carbohydrate-related factors affecting liver fat accumulation
Goran, M. I., Walker, R., & Allayee, H. (2012) · Current Opinion in Clinical Nutrition and Metabolic Care · doi:10.1097/mco.0b013e3283544477 · Cited by 30
Hao, L., Ito, K., Huang, N. K., Sae‐tan, S., Lambert, J. D., & Ross, A. C. (2014) · Metabolism · doi:10.1016/j.metabol.2014.06.016 · Cited by 30
“Our data are consistent with other studies that have shown that PNPLA3 is under the direct control of the transcription factor SREBP1c in response to glucose treatment [22,29].”
InfluentialPNPLA3, a genetic marker of progressive liver disease, still hiding its metabolic function?
Dubuquoy, C., Burnol, A., & Moldes, M. (2012) · Clinics and Research in Hepatology and Gastroenterology · doi:10.1016/j.clinre.2012.06.014 · Cited by 27
Ungerleider, N., Bonomi, L. M., Brown, M., & Schneyer, A. L. (2013) · Endocrinology · doi:10.1210/en.2012-1844 · Cited by 28
Brunt, E. M., Neuschwander‐Tetri, B. A., & Burt, A. D. (2011) · Elsevier eBooks · doi:10.1016/b978-0-7020-3398-8.00006-4 · Cited by 27
White, H. M. (2020) · Journal of Dairy Science · doi:10.3168/jds.2019-18119 · Cited by 27
Kosters, A., Sun, D., Wu, H., Tian, F., Felix, J. C., Li, W., & Karpen, S. J. (2013) · PLoS ONE · doi:10.1371/journal.pone.0071538 · Cited by 26
“Pnpla3 gene expression is directly regulated by Srebp1c [44,45], and indirectly by the LXR/ RXRa heterodimer acting on Srebp1c.”
BackgroundInfluentialHuman genetics of steatotic liver disease: insights into insulin resistance and lipid metabolism
Mancina, R. M., Valenti, L. V. C., & Romeo, S. (2025) · Nature Metabolism · doi:10.1038/s42255-025-01394-8 · Cited by 28
“The link between hyperinsulinaemia and hepatic fat accumulation has been further confirmed by the insulin-mediated upregulation of PNPLA3 expression through SREBP-1c activation 90 .”
Genetics and epigenetics purpose in nonalcoholic fatty liver disease
Botello-Manilla, A. E., Chávez-Tapia, N. C., Uribe, M., & Nuño‐Lámbarri, N. (2020) · Expert Review of Gastroenterology & Hepatology · doi:10.1080/17474124.2020.1780915 · Cited by 28
PNPLA3 genetic variation in alcoholic steatosis and liver disease progression.
Stickel, F., Hampe, J., Trépo, E., Datz, C., & Romeo, S. (2015) · Europe PMC (PubMed Central) · doi:10.3978/j.issn.2304-3881.2014.11.04 · Cited by 26
“Transgenic mice overexpressing the sterol regulatory element binding protein 1a, 1c or 2 (SREPBP-1a, SREBP1c and SREBP2) were used to assess the transcriptional regulation of PNPLA3 (49).”
BackgroundMethodHow Useful Are Monogenic Rodent Models for the Study of Human Non-Alcoholic Fatty Liver Disease?
Mann, J. P., Semple, R. K., & Armstrong, M. J. (2016) · Frontiers in Endocrinology · doi:10.3389/fendo.2016.00145 · Cited by 26
“Expression is suppressed upon fasting (103) and upregulated following a carbohydrate load (104), which is believed to be mediated by steroid regulatory element-binding protein- 1c (SREBP-1c) and carbohydrate-response element-binding protein (ChREBP).”
BackgroundBarbara, M., Scott, A. L., & Alkhouri, N. (2018) · HepatoBiliary Surgery and Nutrition · doi:10.21037/hbsn.2018.08.05 · Cited by 28
Zhang, Y., Cai, W., Song, J., Miao, L., Zhang, B., Xu, Q., Zhang, L., & Yao, H. (2014) · PLoS ONE · doi:10.1371/journal.pone.0108381 · Cited by 25
“After feeding, Steroid Regulatory Element Binding Protein-1c, the master regulator of lipogenesis, induces production of PNPLA3 in the liver; PNPLA3 is also induced during insulin resistance [13].”
BackgroundPNPLA3 rs738409, environmental factors and liver-related mortality in the US population
Gómez, E. V., Gawrieh, S., Vuppalanchi, R., Kettler, C. D., Pike, F., Samala, N. R., & Chalasani, N. (2024) · Journal of Hepatology · doi:10.1016/j.jhep.2024.09.043 · Cited by 24
Mechanisms of Simple Hepatic Steatosis
Matherly, S. C., & Puri, P. (2012) · Clinics in Liver Disease · doi:10.1016/j.cld.2012.05.005 · Cited by 25
PNPLA3 Gene Polymorphism and Liver- and Extrahepatic Cancer–Related Mortality in the United States
Wijarnpreecha, K., Scribani, M., Raymond, P., Harnois, D. M., Keaveny, A. P., Ahmed, A., & Kim, D. (2020) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2020.04.058 · Cited by 24
Enterohepatic Transcription Factor CREB3L3 Protects Atherosclerosis via SREBP Competitive Inhibition
Nakagawa, Y., Wang, Y., Han, S., Okuda, K., Oishi, A., Yagishita, Y., Kumagai, K., Ohno, H., Osaki, Y., Mizunoe, Y., et al. (2020) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2020.11.004 · Cited by 24
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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