Cited by 387Liver Disease Diagnosis and TreatmentLipid metabolism and biosynthesisLipid metabolism and disorders

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A feed-forward loop amplifies nutritional regulation of PNPLA3

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Huang, Yongcheng, He, Shaoqing, Li, John Zhong, Seo, Young-Kyo, Osborne, Timothy F., Cohen, Jonathan C., Hobbs, Helen H.·2010·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.1003585107PMC PMC2867902

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Abstract

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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Background
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Background
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Background
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Background
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Background
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“14 According to consistent pathological skeletal changes in one Homo erectus fossil ancient populations may have been at risk of vitamin A hypervitaminosis.”
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Background
PNPLA3 I148M variant links to adverse metabolic traits in MASLD during fasting and feeding
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“As shown in their study [31], the pathway includes the activation of nuclear receptors, namely, liver X receptor (LXR) and retinoid X receptor (RXR), which, in turn, increases hepatic expression of sterol regulatory element binding protein (SREBP1c).”
Influential
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Background
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Background
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BackgroundInfluential
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Pirola, C. J., & Sookoian, S. C. (2023) · Expert Review of Gastroenterology & Hepatology · doi:10.1080/17474124.2023.2191190 · Cited by 12
Loss of KDM6B epigenetically confers resistance to lipotoxicity in nonalcoholic fatty liver disease–related HCC
Hatano, M., Akiyama, Y., Shimada, S., Yagi, K., Akahoshi, K., Itoh, M., Tanabe, M., Ogawa, Y., & Tanaka, S. (2023) · Hepatology Communications · doi:10.1097/hc9.0000000000000277 · Cited by 12
“The PNPLA3 (I148M) variant has been shown to have a stronger functional competitive effect with ATGL/ PNPLA2 than wild-type PNPLA3, resulting in the development of hepatic steatosis [46,47] .”
Background
The Intersection of Genetic Factors, Aberrant Nutrient Metabolism and Oxidative Stress in the Progression of Cardiometabolic Disease
Butcko, A. J., Putman, A. K., & Mottillo, E. P. (2024) · Antioxidants · doi:10.3390/antiox13010087 · Cited by 12
“Moreover, FAs can increase PNPLA3 protein expression by preventing its degradation and carbohydrates increase the transcriptional regulation of PNPLA3 through activation of SREBP1 [133].”
Background
PNPLA3 in Alcohol‐Related Liver Disease
Galvanin, C., Buch, S., Nahon, P., & Trépo, E. (2024) · Liver International · doi:10.1111/liv.16211 · Cited by 12
“In hepatocytes, PNPLA3 transcription is controlled by insulin through sterol regulatory element-binding protein-1c (SREBP-1c) and carbohydrate response element binding protein (ChREBP) [22].”
Impact of Sexual Dimorphism on Therapy Response in Patients with Metabolic Dysfunction-Associated Steatotic Liver Disease: From Conventional and Nutritional Approaches to Emerging Therapies
Dileo, E., Saba, F., Parasiliti‐Caprino, M., Rosso, C., & Bugianesi, E. (2025) · Nutrients · doi:10.3390/nu17030477 · Cited by 13
Nonalcoholic Fatty Liver Disease (NAFLD) Name Change: Requiem or Reveille?
Singh, S. P., Anirvan, P., Khandelwal, R., & Satapathy, S. K. (2021) · Journal of Clinical and Translational Hepatology · doi:10.14218/jcth.2021.00174 · Cited by 12
Role of Lipid Droplet Proteins in the Development of NAFLD and Hepatic Insulin Resistance
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“Some proteins can interact with transcriptional factors such as SREBP1c and PPAR-alpha/gamma, and some proteins strongly impact a mitochondrial structure.”
Background
Relationship between N,N-dimethylformamide exposure, PNPLA3, GCKR, COL13A1 and TM6SF2 genes, and liver injury
Zhang, X., Jiang, H., Shen, J., Zhang, Y., Gu, Y., Xiao, J., & Lian, Y. (2019) · Ecotoxicology and Environmental Safety · doi:10.1016/j.ecoenv.2018.12.055 · Cited by 12
The I148M PNPLA3 variant mitigates niacin beneficial effects: How the genetic screening in non-alcoholic fatty liver disease patients gains value
Paolini, E., Longo, M., Meroni, M., Tria, G., Cespiati, A., Lombardi, R., Badiali, S., Maggioni, M., Fracanzani, A. L., & Dongiovanni, P. (2023) · Frontiers in Nutrition · doi:10.3389/fnut.2023.1101341 · Cited by 11
“In particular, carbohydrates upregulate mutant PNPLA3 on lipid droplets surfaces, thus hindering their hydrolysis (34).”
Background
PNPLA3-I148M genetic variant rewires lipid metabolism to drive programmed cell death in human hepatocytes
Florentino, R. M., Animasahun, O. H., Haep, N., Nenwani, M., Omoloja, K., Altay, L. N., Achreja, A., Morita, K., Motomura, T., Díaz‐Aragon, R., et al. (2025) · JCI Insight · doi:10.1172/jci.insight.193805 · Cited by 11
“Similarly, GPX4 over-expression was able to combat the cellular stress induced by PUFA exposure in Hep-PNPLA3-I148M cells”
A nutrigenetic precision approach for the management of non-alcoholic fatty liver disease
Pérez-Díaz-del-Campo, N., Dileo, E., Castelnuovo, G., Nicolosi, A., Guariglia, M., Caviglia, G. P., Rosso, C., Armandi, A., & Bugianesi, E. (2023) · Clinical Nutrition · doi:10.1016/j.clnu.2023.09.022 · Cited by 11
“Human and animal studies have strongly demonstrates that the PNPLA3 gene is related to changes in en - ergy balance , being it expression strongly suppressed by fasting and stimulated by refeeding [ 20 ].”
Correlation Between Patatin-Like Phospholipase Domain-Containing Protein 3 Gene Polymorphisms and Liver Cirrhosis in a Chinese Han Population With Chronic Hepatitis B
Tong, J., Guo, J., Hu, J., Hou, S.-H., Zhang, Y., & Li, Q. (2014) · Hepatitis Monthly · doi:10.5812/hepatmon.18943 · Cited by 11
“The PNPLA3 transcription has been found to be regulated by sterol regulatory element binding protein 1c (SREBP-1c) (29).”
Background
Clinical Features of Pediatric Nonalcoholic Fatty Liver Disease
Middleton, J. P., Wiener, R. C., Barnes, B. H., Gurka, M. J., & DeBoer, M. D. (2014) · Clinical Pediatrics · doi:10.1177/0009922813520072 · Cited by 11
“PNPLA3 is associated with fat accumulation and hepatic injury or inflammation.(17,18) Polymorphisms of PNPLA3 differ by race, ethnicity, and may in part, account for racial and ethnic differences in NAFLD, discussed further below.”
Background
Deep Learning Reveals Liver MRI Features Associated With PNPLA3 I148M in Steatotic Liver Disease
Chen, Y., Laevens, B. P. M., Lemainque, T., Müller‐Franzes, G. A., Seibel, T., Dlugosch, C., Clusmann, J., Koop, P., Gong, R., Liu, Y., et al. (2025) · Liver International · doi:10.1111/liv.70164 · Cited by 10
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Hernáez, R. (2011) · Avances en Diabetología · doi:10.1016/j.avdiab.2011.11.004 · Cited by 10
Targeting Hepatic Glycerolipid Synthesis and Turnover to Treat Fatty Liver Disease
Schweitzer, G. G., & Finck, B. N. (2014) · Advances in Hepatology · doi:10.1155/2014/498369 · Cited by 10
Nutritional Genomics in Nonalcoholic Fatty Liver Disease
Vasconcellos, C., Ferreira, O., Lopes, M. F., Ribeiro, A. F., Vasques, J., & Guerreiro, C. S. (2023) · Biomedicines · doi:10.3390/biomedicines11020319 · Cited by 10
Association between rs738408, rs738409 and rs139051polymorphisms in PNPLA3 gene and non-alcoholic fatty liver disease
Najafi, M., Rafiei, A., Ghaemi, A., & Hosseini, V. (2022) · Gene Reports · doi:10.1016/j.genrep.2021.101472 · Cited by 9
The Genetics of Nonalcoholic Fatty Liver Disease: Role of Diet as a Modifying Factor
Kalafati, I. P., Borsa, D., & Dedoussis, G. V. (2014) · Current Nutrition Reports · doi:10.1007/s13668-014-0085-3 · Cited by 9
Insulin treatment improves liver histopathology and decreases expression of inflammatory and fibrogenic genes in a hyperglycemic, dyslipidemic hamster model of NAFLD
Jensen, V. S., Fledelius, C., Zachodnik, C., Damgaard, J., Nygaard, H., Tornqvist, K. S., Kirk, R. K., Viuff, B. M., Wulff, E. M., Lykkesfeldt, J., et al. (2021) · Journal of Translational Medicine · doi:10.1186/s12967-021-02729-1 · Cited by 11
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Luckhoff, H. K. (2015) · World Journal of Hepatology · doi:10.4254/wjh.v7.i9.1192 · Cited by 9
Quantitative digital pathology reveals association of cell-specific PNPLA3 transcription with NAFLD disease activity
Sandhu, B., Matos, M. C. P., Tran, S., Zhong, A. H., Csizmadia, E., Kim, M.-S., Herman, M. A., Nasser, I. A., Lai, M., & Jiang, Z. G. (2019) · JHEP Reports · doi:10.1016/j.jhepr.2019.05.007 · Cited by 9
“9 The current method only allows simultaneous staining of 2 genes, limiting the ability to precisely define cell type.”
Identification of Interactive Genetic Loci Linked to Insulin Resistance in Metabolic Syndrome—An Update
Elfaki, I., Mir, R., Elnageeb, M. E., Hamadi, A., Alharbi, Z. M., Bedaiwi, R. I., Javid, J., Alrasheed, T., Alatawi, D., Alrohaf, B. M., et al. (2025) · Medicina · doi:10.3390/medicina61010083 · Cited by 9
“The PNPLA3 gene encodes an enzyme found fat tissues, retina, skin, and the hepatocytes [137,143].”
Genomic Signatures of MASLD: How Genomics Is Redefining Our Understanding of Metabolic Liver Disease
Saliba‐Gustafsson, P., Härdfeldt, J., Pedrelli, M., & Parini, P. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms262210881 · Cited by 9
“High carbohydrate levels increase PNPLA3 expression in mice [43,44] and human hepatocytes [45,46] through enhanced transcription and reduced protein turnover.”
Adiponutrin (PNPLA3) in liver fibrogenesis: Is unaltered HepG2 cell line a better model system compared to murine models?
Dutta, A. K. (2015) · Medical Hypotheses · doi:10.1016/j.mehy.2015.10.019 · Cited by 8
“The human Adiponutrin is not under the control of carbohydrate-responsive element-binding protein, whereas MRNA expression was induced by liver X receptor agonists and sterol regulatory element-binding transcription factor 1 [27].”
Background
SIRT1 mediates nutritional regulation of SREBP-1c-driven hepatic PNPLA3 transcription via modulation of H3k9 acetylation
Xu, X. L., Deng, X., Chen, Y., Xu, W., Xu, F. L., & Liang, H. (2022) · Genes and Environment · doi:10.1186/s41021-022-00246-1 · Cited by 9
“PNPLA3 shows a biphasic effect of lipid synthesis and lipolysis in vitro [5] PNPLA3 expression is nutritionally regulated, decreasing during fasting and increasing after fasting and re-feeding [6].”
Background
Isoleucine-to-methionine substitution at residue 148 variant of PNPLA3 gene and metabolic outcomes in gestational diabetes
Bo, S., Gambino, R., Menato, G., Canil, S., Ponzo, V., Pinach, S., Durazzo, M., Ghigo, E., Cassader, M., & Musso, G. (2014) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.114.095125 · Cited by 8
Association of PNPLA3 rs738409 polymorphism with liver steatosis but not with cirrhosis in patients with HBV infection: Systematic review with meta‐analysis
Ghalamkari, S., Sharafi, H., & Alavian, S. M. (2017) · The Journal of Gene Medicine · doi:10.1002/jgm.3001 · Cited by 8
“PNPLA3 is regulated with the same mechanism that regulates fat deposition in liver.(31-33) Adiponutrin protein, which is encoded by PNPLA3 gene, is well known for lipase activity during digestion process and adipocyte differentiation.”
Background
Genetic Aspects of Non-Alcoholic Fatty Liver Disease
Bogomolov, P., Kokina, K. Y., Mayorov, A. Y., & Mishina, E. Е. (2019) · Вопросы современной педиатрии · doi:10.15690/vsp.v17i6.1974 · Cited by 8
Associations of Nutrient Intake Changes During Childhood with Adolescent Hepatic Fat: The Exploring Perinatal Outcomes Among CHildren Study
Cohen, C. C., Perng, W., Sauder, K. A., Ringham, B. M., Bellatorre, A., Scherzinger, A. L., Stanislawski, M. A., Lange, L. A., Shankar, K., & Dabelea, D. (2021) · The Journal of Pediatrics · doi:10.1016/j.jpeds.2021.06.027 · Cited by 9
Modifiable lifestyle factors, genetic and acquired risk, and the risk of severe liver disease in the UK Biobank cohort
Liu, Z., Huang, H., Xie, J., Shen, Q., & Xu, C. (2023) · Digestive and Liver Disease · doi:10.1016/j.dld.2023.06.025 · Cited by 8
Variant adiponutrin confers genetic protection against cholestatic itch
Krawczyk, M. J., Milkiewicz, M., Marschall, H., Bartz, C., Grünhage, F., Wunsch, E., Milkiewicz, P., & Lammert, F. (2014) · Scientific Reports · doi:10.1038/srep06374 · Cited by 7
Nonalcoholic fatty liver disease in lean subjects: is it all metabolic-associated fatty liver disease?
Machado, M. V. (2020) · Hepatoma Research · doi:10.20517/2394-5079.2020.90 · Cited by 7
“Carbohydrates upregulate([111,112]), whereas unsaturated fatty acids suppress PNPLA3 expression([113]).”
Background
RORα regulates hepatic lipolysis by inducing transcriptional expression of PNPLA3 in mice
Han, Y., Kim, H., & Lee, M. (2020) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2020.111122 · Cited by 7
“The expression of PNPLA3 is highly dependent on the nutritional status because its expression decreases upon fasting and increases upon feeding (Hoekstra et al., 2010; Huang et al., 2010).”
Enzymes involved in hepatic acylglycerol metabolism in the chicken
Riegler, B., Schliefsteiner, C., Bauer, R., Nimpf, J., & Schneider, W. J. (2011) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2011.02.029 · Cited by 7
Patatin‐like phospholipase domain‐containing protein 3 and Liver Disease: Opportunities to Unravel Mechanisms Underlying Statistical Associations
Boursier, J., & Diehl, A. M. (2014) · Hepatology · doi:10.1002/hep.27445 · Cited by 7
Statin‐associated regulation of hepatic PNPLA3 in patients without known liver disease
Osman, A., Shavva, V. S., Tarnawski, L., Dai, W., Borg, F., Olofsson, V. V., Liu, T., Saliba‐Gustafsson, P., Simini, C., Pedrelli, M., et al. (2024) · Journal of Internal Medicine · doi:10.1111/joim.20032 · Cited by 6
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Absence of Adiponutrin (PNPLA3) and Monoacylglycerol Lipase Synergistically Increases Weight Gain and Aggravates Steatohepatitis in Mice
Tardelli, M., Bruschi, F. V., Fuchs, C. D., Claudel, T., Auer, N., Kunczer, V., Ronda, O. A. H. O., Verkade, H. J., Stojaković, T., Scharnagl, H., et al. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22042126 · Cited by 6
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Background
The HepG2 Cell Line as a Model for Studying Metabolic Dysfunction-Associated Steatotic Liver Disease
Kotlyarova, A., Iskrina, A., & Kotlyarov, S. (2026) · International journal of molecular sciences · doi:10.3390/ijms27083399 · Cited by 10
Tissue-specific regulation of PNPLA3 promotes lipid remodeling in response to dietary and environmental challenges
Wu, P., Wang, Y., Cohen, J. C., & Hobbs, H. H. (2026) · Journal of Hepatology · doi:10.1016/j.jhep.2026.02.029 · Cited by 5
“7 Hepatic PNPLA3 is stabilized on lipid droplets (LDs) 7 and degraded by the ubiquitin-proteasome system.”
Self-citation
Role of genetics in diagnosis and therapy of acquired liver disease
Zimmer, V., & Lammert, F. (2013) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2013.10.004 · Cited by 5
Responsiveness of PNPLA3 and lipid-related transcription factors is dependent upon fatty acid profile in primary bovine hepatocytes
Erb, S. J., Chandler, T. L., & White, H. M. (2022) · Scientific Reports · doi:10.1038/s41598-021-04755-x · Cited by 6
Difference in lifestyle and metabolic profile of non-alcoholic fatty liver disease with raised alanine amino-transferases between obese and non-overweight subjects
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“3 (PNPLA3), also called adiponutrin, is a protein expressed on endoplasmic reticulum, and on lipid droplets in hepatocytes and adipocytes [183].”
Background
Genetic and metabolic factors: the perfect combination to treat metabolic associated fatty liver disease
Meroni, M., Longo, M., & Dongiovanni, P. (2020) · Exploration of Medicine · doi:10.37349/emed.2020.00015 · Cited by 5
“Moreover, PNPLA3 protein is post-transcriptionally modified by the presence of fatty acids, hindering its degradation [34, 35].”
Background

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)
ORCID: He, Shaoqing
Li, John Zhong
Seo, Young-Kyo
Osborne, Timothy F.
Cohen, Jonathan C.
Hobbs, Helen H.
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
DOI: 10.1073/pnas.1003585107
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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A feed-forward loop amplifies nutritional regulation of PNPLA3

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