The DOI matches its Crossref record; 48 of the 49 references it cites were found in a registry or an index.
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]
Citations
Cites
SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver
Horton, J. D., Goldstein, J. L., & Brown, M. S. (2002) · Journal of Clinical Investigation · doi:10.1172/jci15593 · Cited by 4,794
Steatohepatitis: A tale of two “hits”?
Day, C. P., & James, O. F. W. (1998) · Gastroenterology · doi:10.1016/s0016-5085(98)70599-2 · Cited by 4,285
SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver
Horton, J. D., Goldstein, J. L., & Brown, M. S. (2002) · Journal of Clinical Investigation · doi:10.1172/jci0215593 · Cited by 4,092
Prevalence of Hepatic Steatosis in An Urban Population in the United States: Impact of Ethnicity
Browning, J. D., Szczepaniak, L. S., Dobbins, R., Nuremberg, P., Horton, J. D., Cohen, J. C., Grundy, S. M., & Hobbs, H. H. (2004) · Hepatology · doi:10.1002/hep.20466 · Cited by 3,664
Self-citationGenetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease
Romeo, S., Kozlitina, J., Xing, C., Pertsemlidis, A., Cox, D., Pennacchio, L. A., Boerwinkle, E., Cohen, J. C., & Hobbs, H. H. (2008) · Nature Genetics · doi:10.1038/ng.257 · Cited by 3,416
Self-citationFat Mobilization in Adipose Tissue Is Promoted by Adipose Triglyceride Lipase
Zimmermann, R., Bogner‐Strauß, J. G., Haemmerle, G., Schoiswohl, G., Birner‐Gruenberger, R., Riederer, M., Lass, A., Neuberger, G., Eisenhaber, F., Hermetter, A., et al. (2004) · Science · doi:10.1126/science.1100747 · Cited by 2,121
Structure and function of the feed-forward loop network motif
Mangan, S., & Alon, U. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2133841100 · Cited by 1,827
Repa, J. J., Liang, G., Ou, J., Bashmakov, Y. K., Lobaccaro, J. A., Shimomura, I., Shan, B., Brown, M. S., Goldstein, J. L., & Mangelsdorf, D. J. (2000) · Genes & Development · doi:10.1101/gad.844900 · Cited by 1,724
Role of LXRs in control of lipogenesis
Schultz, J. R., Tu, H., Luk, A., Repa, J. J., Medina, J. C., Li, L., Schwendner, S., Wang, S., Thoolen, M., Mangelsdorf, D. J., et al. (2000) · Genes & Development · doi:10.1101/gad.850400 · Cited by 1,499
Shimano, H., Horton, J. D., Hammer, R. E., Shimomura, I., Brown, M. S., & Goldstein, J. L. (1996) · Journal of Clinical Investigation · doi:10.1172/jci118951 · Cited by 817
Research works printed but not linked: 1
- 10.2337/diabetes.55.01.06.db05-0982 · DOI
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Mechanisms for Insulin Resistance: Common Threads and Missing Links
Samuel, V. T., & Shulman, G. I. (2012) · Cell · doi:10.1016/j.cell.2012.02.017 · Cited by 2,294
“PNPLA3 expression in adipose tissue (Caimari et al., 2007; Kershaw et al., 2006) and liver (Huang et al., 2010) decreases with fasting and increases in response to insulin and glucose—the opposite of what would be expected from a triglyceride lipase and more consistent with a potential role in…”
InfluentialHuman Fatty Liver Disease: Old Questions and New Insights
Cohen, J. C., Horton, J. D., & Hobbs, H. H. (2011) · Science · doi:10.1126/science.1204265 · Cited by 2,089
Self-citationNon-alcoholic fatty liver disease as a cause and a consequence of metabolic syndrome
Yki‐Järvinen, H. (2014) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(14)70032-4 · Cited by 1,296
Sookoian, S. C., & Pirola, C. J. (2011) · Hepatology · doi:10.1002/hep.24283 · Cited by 917
“Despite the explanation on the gene by sex interaction cannot be given by the present study, some evidence exists that the PNLPA3 gene is under the control of several factors, for instance, nutritional control in close relationship with SREBP-1c and liver X receptor.(27) Interestingly, sexual hormones, like estrogen,…”
BackgroundPeroxisome Proliferator-Activated Receptor Alpha Target Genes
Rakhshandehroo, M., Knoch, B., Müller, M., & Kersten, S. (2010) · PPAR Research · doi:10.1155/2010/612089 · Cited by 1,020
“Which other lipases importantly contribute to intracellular lipolysis of hepatic TG stores remains unclear, but lipases active in adipocytes likely play a role, including Ces3, Lipe, Pnpla2, Mgll, and perhaps Pnpla3 [195–200].”
Background
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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