Key result
Pla2g12b disruption confers profound atherosclerosis resistance by blocking triglyceride-rich lipoprotein expansion in preclinical models.
Why the study?
Triglyceride-rich lipoproteins promote atherosclerotic cardiovascular disease, but very little is known about how lipids are loaded onto nascent triglyceride-rich lipoproteins prior to secretion.
Identifying Pla2g12b as an essential component of TRL expansion provides a novel mechanistic target for modifying serum lipoproteins to prevent atherosclerotic cardiovascular disease.
Does not support clinical use of Pla2g12b targeting; leaves open its therapeutic potential pending human studies.
SUMMARY Triglyceride-rich lipoproteins (TRLs) are micelle-like particles that enable efficient transport of lipids throughout the bloodstream, but also promote atherosclerotic cardiovascular disease. Despite this central relevance to cardiovascular disease, very little is known about how lipids are loaded onto nascent TRLs prior to secretion. Here we show that Pla2g12b, a gene with no previously described function, concentrates components of the TRL biogenesis machinery along the ER membrane to ensure efficient delivery of lipids to nascent TRLs. We find that the lipid-poor TRLs secreted in PLA2G12B -/- mice and zebrafish support surprisingly normal growth and physiology while conferring profound resistance to atherosclerosis, and demonstrate that these same processes are conserved in human cells. Together these findings shed new light on the poorly understood process of TRL expansion, ascribe function to the previously uncharacterized gene Pla2g12b, and reveal a promising new strategy to remodel serum lipoproteins to prevent cardiovascular disease.
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Thierer et al. (2022) studied Atherosclerotic cardiovascular disease (preclinical models). Pla2g12b knockout or disruption vs. Wild-type controls was evaluated on Triglyceride-rich lipoprotein biogenesis and atherosclerosis development. Disruption of Pla2g12b prevents the expansion of nascent triglyceride-rich lipoproteins and confers profound resistance to atherosclerosis in preclinical models.
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