PGAM5 deficiency is associated with enhanced endocytic function of liver sinusoidal endothelial cells and circulating lipid remodeling, which may contribute to ameliorated atherosclerosis.
Hepatic PGAM5 expression was increased in atherosclerotic mice.
Western diet-fed AAV-PCSK9 mice developed more severe atherosclerosis, hepatic steatosis and LDL-C abnormalities than normal controls.
PGAM5 knockout reduced aortic lipid deposition and enhanced plaque stability in AS mice.
PGAM5 knockout lowered plasma LDL-C and improved hepatic steatosis.
Liver proteomics showed that differentially expressed proteins after PGAM5 deficiency were enriched in fatty acid metabolism and endocytosis pathways.
Single-cell RNA-seq showed that the relative proportion of LSECs changed after PGAM5 deficiency.
Plasma metabolomics showed reduced L-palmitoylcarnitine and arachidonic acid in PGAM5-/- mice.
Plasma lipidomics showed that the circulating lipid profile was altered following PGAM5 deficiency.
PGAM5 knockdown enhanced oxLDL uptake by immortalized human LSECs, and arachidonic acid or L-palmitoylcarnitine inhibited this uptake.
This study in mice looked at a protein called PGAM5, found in mitochondria, and whether it affects atherosclerosis, the buildup of fatty plaques in artery walls. The researchers induced atherosclerosis using a viral vector that raises cholesterol plus a Western-style diet. Liver PGAM5 levels were higher in the diseased mice. Mice lacking PGAM5 had less fat in the aorta, more stable plaques, lower LDL cholesterol and less fatty liver than diseased mice with PGAM5. The team examined how this might work. Liver protein and single-cell gene analyses pointed to fatty acid metabolism and endocytosis (cells taking in material) in liver sinusoidal endothelial cells, which line the liver's small blood vessels. Blood from mice without PGAM5 had lower levels of two fat-related molecules, L-palmitoylcarnitine and arachidonic acid, and an altered overall lipid profile. In human liver endothelial cells grown in the lab, reducing PGAM5 increased uptake of oxidized LDL, a harmful form of cholesterol, and adding either molecule blunted this uptake. This research suggests that PGAM5 may influence atherosclerosis by changing how liver endothelial cells clear oxidized LDL and by reshaping circulating lipids. The findings come from mice and cultured cells, so they do not show that targeting PGAM5 would work in people. The authors describe the link as an association.
Tan H, Jin J, Yang M, Wang J, Zhou F, Zeng P, et al.. (2026). [PGAM5 deficiency attenuates atherosclerosis, enhances oxidized LDL uptake by liver sinusoidal endothelial cells and reshapes circulating lipidome in mice].. Nan fang yi ke da xue xue bao = Journal of Southern Medical University. https://doi.org/10.12122/j.issn.1673-4254.2026.10.05