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- Title
PNPLA3 is a triglyceride lipase that mobilizes polyunsaturated fatty acids to facilitate hepatic secretion of large-sized very low-density lipoprotein.
- Authors
Johnson, Scott M.; Bao, Hanmei; McMahon, Cailin E.; Chen, Yongbin; Burr, Stephanie D.; Anderson, Aaron M.; Madeyski-Bengtson, Katja; Lindén, Daniel; Han, Xianlin; Liu, Jun
- 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. The PNPLA3 gene is associated with fatty liver disease. Here, the authors define a role for PNPLA3 as a polyunsaturated triglyceride lipase that maintains the balance between hepatic triglyceride storage and secretion.
- Subjects
UNSATURATED fatty acids; FATTY liver; TRIGLYCERIDES; SECRETION; LOW density lipoproteins
- Publication
Nature Communications, 2024, Vol 15, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-024-49224-x