Pla2g12b drives expansion of triglyceride-rich lipoproteins

James H. Thierer, Ombretta Foresti, Pradeep Kumar Yadav, Meredith H. Wilson, Tabea O. C. Moll, Meng-Chieh Shen, Elisabeth M. Busch-Nentwich, Margaret Morash, Karen L. Mohlke, John F. Rawls, Vivek Malhotra, M. Mahmood Hussain and Steven A. Farber ()
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James H. Thierer: Carnegie Institution for Science
Ombretta Foresti: The Barcelona Institute for Science and Technology
Pradeep Kumar Yadav: NYU Long Island School of Medicine
Meredith H. Wilson: Carnegie Institution for Science
Tabea O. C. Moll: Carnegie Institution for Science
Meng-Chieh Shen: Carnegie Institution for Science
Elisabeth M. Busch-Nentwich: Queen Mary University of London
Margaret Morash: Duke University
Karen L. Mohlke: University of North Carolina
John F. Rawls: Duke University
Vivek Malhotra: The Barcelona Institute for Science and Technology
M. Mahmood Hussain: NYU Long Island School of Medicine
Steven A. Farber: Carnegie Institution for Science

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Vertebrates transport hydrophobic triglycerides through the circulatory system by packaging them within amphipathic particles called Triglyceride-Rich Lipoproteins. Yet, it remains largely unknown how triglycerides are loaded onto these particles. Mutations in Phospholipase A2 group 12B (PLA2G12B) are known to disrupt lipoprotein homeostasis, but its mechanistic role in this process remains unclear. Here we report that PLA2G12B channels lipids within the lumen of the endoplasmic reticulum into nascent lipoproteins. This activity promotes efficient lipid secretion while preventing excess accumulation of intracellular lipids. We characterize the functional domains, subcellular localization, and interacting partners of PLA2G12B, demonstrating that PLA2G12B is calcium-dependent and tightly associated with the membrane of the endoplasmic reticulum. We also detect profound resistance to atherosclerosis in PLA2G12B mutant mice, suggesting an evolutionary tradeoff between triglyceride transport and cardiovascular disease risk. Here we identify PLA2G12B as a key driver of triglyceride incorporation into vertebrate lipoproteins.

Date: 2024
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DOI: 10.1038/s41467-024-46102-4

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