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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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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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