A Catalytically Inactive Phospholipase A2 Homologue Facilitates Triacylglycerol-rich Lipoprotein Production in the Liver and Intestine

The small intestine and liver produce triacylglycerol-rich lipoproteins (TRLs)—chylomicrons and very low-density lipoproteins (VLDLs), respectively—to distribute dietary and endogenously synthesized lipids needed for membrane synthesis, signaling, and energy production.¹ In the circulation, the triacylglycerol (TG) core of TRLs is hydrolyzed by lipoprotein lipases, releasing fatty acids for tissue uptake, while TRL remnants are cleared by the liver through receptor-mediated processes.^1,2 Elevated plasma TRLs are common in metabolic diseases such as obesity and insulin resistance and, when persistently increased, contribute causally to atherosclerotic cardiovascular disease.³

The assembly of TRLs begins with the translation of apolipoprotein B (ApoB) at the endoplasmic reticulum (ER). As ApoB enters the ER lumen, microsomal triglyceride transfer protein (MTP) mediates the initial addition of phospholipids and neutral lipids to nascent ApoB, forming primordial TRL particles.^1,2 Pla2g12b, a protein associated with MTP, has emerged as a mediator of lipid loading onto nascent particles, promoting TRL expansion while limiting the accumulation of cytosolic lipid droplets.

Although Pla2g12b shares sequence homology with secreted phospholipase A2 enzymes, it lacks the canonical catalytic residues and is enzymatically inactive, leaving its molecular function unresolved.^4,5 In both humans and mice, Pla2g12b is highly expressed in the liver and proximal small intestine, with minimal expression in other tissues. Multiple genetic models support its physiological role in lipoprotein metabolism. Global deletion of Pla2g12b in mice markedly reduces hepatic lipoprotein secretion and lowers circulating TG and cholesterol levels.⁶ In an ENU-induced mutant screening, a missense mutation replacing cysteine with tyrosine at position 129 (C129Y) similarly reduces plasma lipid levels while promoting hepatic lipid accumulation in mice.⁷ Biochemical and cell-biological studies localize Pla2g12b to the ER and demonstrate its association with canonical VLDL biogenesis factors such as MTP. Consistent with these findings, loss of Pla2g12b function in larval zebrafish blocks TRL generation.⁸

In this issue of Cellular and Molecular Gastroenterology and Hepatology, Prakash et al extend these observations by identifying an additional role for Pla2g12b in intestinal lipid handling, with implications for dietary fat absorption and systemic lipid homeostasis. The authors confirm that Pla2g12b protein is highly expressed in the liver and small intestine but is not detected in plasma, indicating that Pla2g12b is unlikely to function as a circulating signal. The C129Y mutation in mice does not affect this tissue expression pattern or Pla2g12b protein abundance, and it does not impact the expression of several genes involved in lipid metabolism or lipoprotein production.

Consistent with prior work, Pla2g12b C129Y mutant mice exhibit impaired hepatic TG secretion accompanied by increased hepatic TG and cholesterol accumulation. Primary hepatocytes isolated from mutant mice do not display increased fatty acid re-esterification or reduced fatty acid oxidation, supporting the conclusion that hepatic lipid accumulation arises primarily from defective lipoprotein production rather than altered intracellular lipid metabolism.

In addition to hepatic effects, Pla2g12b mutant mice also accumulate intracellular lipid droplets in the small intestine. When challenged with an oral lipid load, with or without a fluorescent tracer, these mice show blunted postprandial TG excursions, increased lipid droplet accumulation in the proximal intestine, and elevated fecal fat content—findings indicative of impaired absorption of dietary fat. In contrast to hepatocytes, where the dominant defect appears to be impaired TRL secretion, primary enterocytes from Pla2g12b mutant mice also exhibit reduced fatty acid uptake and TG synthesis, suggesting a broader disruption of intracellular lipid handling.

Transcriptomic analyses further underscore tissue-specific differences. Although global RNA-sequencing revealed few differences between mutant and control livers, duodenal samples of mutant mice showed substantial changes, including downregulation of genes encoding digestive enzymes, many of which are expressed predominantly in the pancreas rather than the intestine. Reduced mRNA levels of several lipid digestion enzymes were confirmed by quantitative polymerase chain reaction in both the intestine and pancreas of mutant mice. Because Pla2g12b is also expressed in the pancreas, these findings raise the possibility that the mutant protein may directly or indirectly reduce lipid digestion. However, intestinal luminal lipase activity was not reduced in mutant mice, leaving the physiological significance of these transcriptional changes unresolved.

Together, the findings reported by Prakash et al reinforce Pla2g12b as a central regulator of hepatic lipid metabolism while identifying a previously underappreciated role in intestinal fat absorption. By enabling efficient chylomicron and VLDL biogenesis, Pla2g12b may influence dietary lipid intake and systemic lipid distribution. Lacking enzymatic activity, Pla2g12b likely serves as a scaffold or regulatory protein that coordinates key components of the lipoprotein assembly machinery. The conservation of PLA2G12B expression with ApoB and MTP in humans suggests that these mechanisms may be conserved. Further studies will be required to define the molecular function of Pla2g12b and to determine whether modulation of this pathway has therapeutic potential.