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Cited by 100Lipid metabolism and disordersLiver Disease Diagnosis and TreatmentLipid metabolism and biosynthesis

PNPLA3 is a triglyceride lipase that mobilizes polyunsaturated fatty acids to facilitate hepatic secretion of large-sized very low-density lipoprotein

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Johnson, Scott M., Bao, Hanmei, McMahon, Cailin E., Chen, Yongbin, Burr, Stephanie D., Anderson, Aaron M., Madeyski-Bengtson, Katja, Lindén, Daniel +2 more·2024·Nature Communications
DOI 10.1038/s41467-024-49224-xPMC PMC11156938
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Abstract

The I148M variant of PNPLA3 is closely associated with hepatic steatosis. Recent evidence indicates that the I148M mutant functions as an inhibitor of PNPLA2/ATGL-mediated lipolysis, leaving the role of wild-type PNPLA3 undefined. Despite showing a triglyceride hydrolase activity in vitro, PNPLA3 has yet to be established as a lipase in vivo. Here, we show that PNPLA3 preferentially hydrolyzes polyunsaturated triglycerides, mobilizing polyunsaturated fatty acids for phospholipid desaturation and enhancing hepatic secretion of triglyceride-rich lipoproteins. Under lipogenic conditions, mice with liver-specific knockout or acute knockdown of PNPLA3 exhibit aggravated liver steatosis and reduced plasma VLDL-triglyceride levels. Similarly, I148M-knockin mice show decreased hepatic triglyceride secretion during lipogenic stimulation. Our results highlight a specific context whereby the wild-type PNPLA3 facilitates the balance between hepatic triglyceride storage and secretion, and suggest the potential contribution of a loss-of-function by the I148M variant to the development of fatty liver disease in humans.

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  • The two variants with the highest significance in nearly all GWAS - PNPLA3 and TM6SF2 - both affect hepatic lipid disposal.

    “the two variants with the highest significance in nearly all GWAS — PNPLA3 (patatin-like phospholipase domain-containing protein 3) and TM6SF2 — both affect hepatic lipid disposal (16, 17).”

    From Loss of function of T-box 3 in the liver protects against MASLD (2025) · cites this paper as [16]

    The Introduction and Discussion (page unavailable) link the PNPLA3 I148M variant to fatty liver and describe reduced hepatic triglyceride secretion during lipogenic stimulation. The Discussion also addresses TM6SF2 in relation to hepatic lipid metabolism, but the paper does not establish that PNPLA3 and TM6SF2 are the two most significant variants in nearly all GWAS. (LLM, conf=0.85)

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References 88 · Cited by 100

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Authors
Johnson, S. M., Bao, H., McMahon, C. E., Chen, Y., Burr, S. D., Anderson, A. M., Madeyski-Bengtson, K., Lindén, D., Han, X., & Liu, J.
Affiliations
  • Mayo Clinic (US)
  • The University of Texas at San Antonio Health Science Center (US)
  • Cornell University (US)
  • Washington University in St. Louis (US)
  • AstraZeneca (Sweden) (SE)
Corresponding author
Liu, Jun
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2024-06-06
Volume
15
Issue
1
Pages
4847-4847
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-024-49224-x
PMC
PMC11156938
OpenAlex
W4399395069
Cited by
100
References
88
Citations by year
2026: 34 · 2025: 51 · 2024: 15
FWCI
29.96
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (DK089178, DK109096, DK124190)
  • Mayo Graduate School of Biomedical Sciences
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
Keywords
PNPLA3, triacylglycerol lipase, polyunsaturated fatty acids, hepatic steatosis, very low density lipoprotein secretion, triglyceride-rich lipoproteins, lipolysis, I148M variant, liver-specific knockout mice
MeSH terms
Acyltransferases, Animals, Fatty Acids, Unsaturated, Fatty Liver, Humans, Lipase, Lipolysis, Lipoproteins, VLDL, Liver, Male, Membrane Proteins, Mice, Inbred C57BL, Triglycerides, Mice, Knockout, Mice, Phospholipases A2, Calcium-Independent

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