Pla2g12b is Essential for Expansion of Nascent Lipoprotein Particles

Abstract

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.

VLDL Biogenesis and Secretion: It Takes a Village

“…The list of proteins required for actual VLDL biogenesis in the ER has been expanded with LAP1/TORSINA, PLA2G12B, SMLR1, ERLIN1/2, and TM6SF2. 21,23,24,50 While hepatic ablation of TORSINA profoundly affects hepatic and plasma lipids through affecting VLDL biogenesis, 21 the molecular mechanism remains to be elucidated. Much more is known about PLA2G12B.…”

“…Zebra fish larvae with complete loss of Pla2g12b were shown to accumulate large lipid droplets in the lumen of the ER associated with abnormally small lipoproteins in the circulation, suggesting a defect in the second-stage formation of mature, larger apoB-containing lipoproteins. 23 Pla2g12b −/− mice were moreover shown to be protected against hyperlipidemia and atherosclerosis but at the expense of hepatic steatosis. Additional studies in HepG2 and Caco-2 (intestinal) cells implicated a role for PLA2G12B in calcium and MTP recruitment to the ER membrane to enhance lipid transfer and expansion of triglyceride-rich lipoproteins.…”

“…Additional studies in HepG2 and Caco-2 (intestinal) cells implicated a role for PLA2G12B in calcium and MTP recruitment to the ER membrane to enhance lipid transfer and expansion of triglyceride-rich lipoproteins. 23 These results led the authors to propose PLA2G12B as a key molecule for transferring triglycerides from a luminal lipid droplet to nascent VLDL. This work provides support for predictions and questions first raised in an early review on luminal lipid metabolism.…”

“…The figure illustrates that many other proteins are implicated in biogenesis of nascent lipid-poor VLDL and its conversion to more mature, well-lipidated VLDL. Newly proposed players in the first steps of this pathway are an AAA+ ATPase called TORSINA (activated by LAP1 [lamina-associated polypeptide 1] 21 ), PRAP1 (proline-rich acidic protein 1 22 ), PLA2G12B (phospholipase A2, group XIIB 23 ), ERLINs (ER lipid raft proteins) 1 and 2 24 , and TM6SF2 (transmembrane 6 superfamily member 2). 25 Triglycerides added during the later or second stage of lipidation of nascent are believed to derive from both the ER membrane and from lipid droplets in a process involving TGH (triglyceride hydrolase 26,27 ).…”

Sex-Specific Differences in Lipoprotein Production and Clearance

“…ERRα also stimulates Pla2g12b (phospholipase A2 G12B) expression, a relatively uncharacterized phospholipase lacking catalytical activity. In 2019, Thierer et al 28 identified Pla2g12b as regulator of lipoprotein size to later show that it interacts with apoB and MTP at the level of the endoplasmic reticulum membrane to promote lipoprotein expansion 29 (Figure [A]).…”