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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“This regulatory mode ensures that the system can respond flexibly and accurately when faced with changes in external signals [26, 27], significantly accelerating/s-lowing down the accumulation/reduction of downstream genes [28, 29].”
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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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