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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PNPLA3 expression differs between humans and mice: in mice it is predominantly in adipose tissue with 50-100 times higher expression than liver; in humans it is highest in liver, and in human liver stellate cells express more than twice as much as hepatocytes.
“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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BackgroundInfluentialAdvances in Pediatric Nonalcoholic Fatty Liver Disease†
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“As summarized in Table 2 [56,58–62,67–74], the two abovementionedmissense genetic variants may play important roles in the regulation of hepatic lipid metabolism.”
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“PNPLA3 is an SREBP-1c target gene (30), and it is possible that the PNPLA3 gene is sensitive to small changes in SREBP-1c activity.”
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“Based on the recent findings that carbohydrates and fatty acids increase PNPLA3 protein levels in liver cells (53), PNPLA3 may rather have a more important role in lipid remodeling than lipid catabolism.”
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“PNPLA3 is regulated by the lipogenic program [34] and is highly expressed in the liver and adipose tissue at the level of the endoplasmic reticulum and the surface of lipid droplets, where it seems to be involved in the metabolism of triglycerides [35].”
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“PNPLA3 is expressed in the skin (13) and in A431 cells at levels roughly comparable with”
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“In mice Pnpla3 is upregulated in the liver after feeding and during insulin resistance by fatty acids and the master regulator of lipogenesis SREBP-1c [41].”
BackgroundGenetic determinants of alcoholic liver disease
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“Expression of PNPLA3 among species is distinct, with high hepatic expression in humans whereas expression is low in mice and rat livers from normal animals in which adipose tissues account for the magnitude of PNPLA3.(76) 77 However, fat challenge upregulates hepatic PNPLA3 expression in mice whereas starving leads to…”
BackgroundInfluentialHepatic lipid droplet biology: Getting to the root of fatty liver
Mashek, D. G., Khan, S. A., Sathyanarayan, A., Ploeger, J. M., & Franklin, M. P. (2015) · Hepatology · doi:10.1002/hep.27839 · Cited by 149 · see citing works
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“PNPLA3 encodes for a transmembrane protein which, in humans, is most prominently expressed in hepatocytes [19].”
BackgroundHepatocellular carcinoma in nonalcoholic fatty liver: role of environmental and genetic factors
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“The PNPLA3 gene is regulated by glucose and insulin via sterol regulatory element binding protein 1c (SREBP-1c) in mouse liver and human hepatocytes and is highly influenced by nutritional status [58,66].”
BackgroundGenetic determinants of hepatic steatosis in man
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“SREBP-1c is the only known transcriptional activator of PNPLA3 expression (Huang et al., 2010).”
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“…animal models with inhibition of VLDL secretion, the TM6SF2 gene variant carriers present liver steatosis with no disorders of glucose metabolism (Jacobs et al., 2010), which may be related to the deficiency of polyunsaturated phosphatidylcholines and excess polyunsaturated FFA in the liver of…”
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“(26-30) Pathophysiological studies established that during obesity and insulin resistance PNPLA3 protein expression is induced in hepatocytes, hepatic stellate cells, and adipocytes and is localized on LDs, where it represents the dominant surface protein.(31,32) PNPLA3 has intrinsic lipase activity on triglycerides,…”
BackgroundHepatic transcriptional responses to fasting and feeding
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“…regulates the expression of genes encoding proteins linked to triglyceride synthesis, including patatin-like phospholipase domain containing 3 (PNPLA3), mitochondrial glycerol-3-phosphate acyltransferase (GPAM), malic enzyme (ME), and glucose-6-phosphate dehydrogenase (G6PD) (Huang et al. 2010).”
BackgroundNutrition and Genetics in NAFLD: The Perfect Binomium
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“Moreover, PNPLA3 protein degradation can be inhibited by the presence of fatty acids [51,52].”
BackgroundEffects of PNPLA3 on Liver Fat and Metabolic Profile in Hispanic Children and Adolescents
Goran, M. I., Walker, R. W., Lê, K., Mahurkar‐Joshi, S., Vikman, S., Davis, J. N., Spruijt‐Metz, D., Weigensberg, M. J., & Allayee, H. (2010) · Diabetes · doi:10.2337/db10-0554 · Cited by 121 · see citing works
Dynamic interactions of ABHD5 with PNPLA3 regulate triacylglycerol metabolism in brown adipocytes
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SIRT1 Mediates the Effect of GLP-1 Receptor Agonist Exenatide on Ameliorating Hepatic Steatosis
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“PNPLA3, a target gene of SREBP-1c, also plays a role in lipogenesis in mouse liver (23).”
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PNPLA3 mediates hepatocyte triacylglycerol remodeling
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Toward Genetic Prediction of Nonalcoholic Fatty Liver Disease Trajectories: PNPLA3 and Beyond
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Metabolic dysfunction–associated fatty liver disease and the risk of 24 specific cancers
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“In fact, while knock out mice for the pnpla3 do not show any increased fat accumulation into the liver with respect to the wild types [25,26], the administration through viral vectors of the mutated PNPLA3 confers to wild type mice a higher susceptibility to fatty liver [24].”
BackgroundMitsche, M. A., Hobbs, H. H., & Cohen, J. C. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.002333 · Cited by 109 · see citing works
Self-citationHepatic steatosis in Wilson disease – Role of copper and PNPLA3 mutations
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“Its expression was regulated by sterol regulatory element-binding protein 1 (SREBP1c)/liver X receptor (LXR) and by carbohydrate response element-binding protein (ChREBP), and activated by post-prandial or pathological hyperinsulinemia [73].”
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“In the liver, carbohydrate feeding triggers increased PNPLA3 expression through the LXR/SREBP-1c pathway 60 , suggesting PNPLA3 functions under lipogenic rather than lipolytic conditions.”
Rong, S., Xia, M., Vale, G., Wang, S., Kim, C.-W., Li, S., McDonald, J. G., Radhakrishnan, A., & Horton, J. D. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2024.01.011 · Cited by 102 · see citing works
“65 A single-nucleotide polymorphism that results in a single amino acid change in PNPLA3 (I148M) is strongly associated with increased liver TG, fibrosis, cirrhosis, and hepatocellular carcinoma.”
TTC39B deficiency stabilizes LXR reducing both atherosclerosis and steatohepatitis
Hsieh, J., Koseki, M., Molusky, M. M., Yakushiji, E., Ichi, I., Westerterp, M., Iqbal, J., Chan, R., Abramowicz, S., Tascau, L., et al. (2016) · Nature · doi:10.1038/nature18628 · Cited by 99 · see citing works
“…carboxylase α (Acc α ), Glycerol-3-phosphate acyltransferase (Gpat1, Gpam), and Glucose-6-phosphate dehydrogenase (G6pd), as well as Patatin-like phospholipase domain-containing protein 3 (Pnpla3, Adiponutrin), which is an SREBP-1 target implicated in human hepatic steatosis 17,18 (Fig 3b).”
PNPLA3/adiponutrin functions in lipid droplet formation
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“, 2010) and liver in human (Huang et al., 2010) and is tightly controlled by changes in the nutritional status (Baulande et al.”
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“PNPLA3 is a membrane bound protein highly expressed in hepatocytes [35].”
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Krawczyk, M. J., Portincasa, P., & Lammert, F. (2013) · Seminars in Liver Disease · doi:10.1055/s-0033-1358525 · Cited by 92 · see citing works
Eicosanoids in Metabolic Syndrome
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“Normally, activation of the IR results in phosphorylation and activation of IRS-1 toward SREBP1c increase in lipogenesis, while IRS-2 activation mediates phosphorylation of FOXO-1 and exclusion from the nucleus where it activates the transcription of genes involved in gluconeogenesis.”
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“Rat pnpla3 is more abundant in adipose tissue than in liver and more abundant in cytosol than in membrane or lipid droplets, which is different from what has been reported in humans.(14,37) However, our findings demonstrating a strong positive correlation between hepatic PNPLA3 expressions and hepatic lipid content an…”
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PNPLA3—A Potential Therapeutic Target for Personalized Treatment of Chronic Liver Disease
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“In addition to hepatocytes, human PNPLA3 gene is also abundantly expressed in HSCs (121, 139).”
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“To this end, primary hepatocytes prepared from wild-type and SREBP-1c-null mouse livers were treated with insulin or the LXR agonist, TO901317.”
BackgroundInfluentialAbsence of adipose triglyceride lipase protects from hepatic endoplasmic reticulum stress in mice
Fuchs, C. D., Claudel, T., Kumari, P., Haemmerle, G., Pollheimer, M. J., Stojaković, T., Scharnagl, H., Halilbasic, E., Gumhold, J., Silbert, D., et al. (2012) · Hepatology · doi:10.1002/hep.25601 · Cited by 84 · see citing works
“PNPLA3 (the closest homolog to ATGL/PNPLA2) has recently been implicated in NAFLD in humans, because a missense mutation [I148M] is associated with increased steatosis and progression to NASH and fibrosis.1,27-29 However, PNPLA3 KO mice do not show altered susceptibility to steatosis,40 which could be the result of sp…”
BackgroundA Nutrigenomic Approach to Non-Alcoholic Fatty Liver Disease
Dongiovanni, P., & Valenti, L. V. C. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18071534 · Cited by 84 · see citing works
- 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 › Epidemiology › 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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