PGAM5 deficiency attenuates atherosclerosis, enhances oxidized LDL uptake by liver sinusoidal endothelial cells and reshapes circulating lipidome in mice

To investigate the effects of mitochondrial phosphoglycerate mutase 5 (PGAM5) deficiency on endocytic function of liver sinusoidal endothelial cells (LSECs) and circulating lipid remodeling and their association with atherosclerosis (AS).

AS was induced by tail vein injection of AAV-PCSK9 combined with Western diet (WD) feeding. Mice were divided into 5 groups: NC (negative control, normal chow feeding), ND (normal chow feeding after AAV-PCSK9 injection), WD (WD feeding after AAV-PCSK9 injection), ATOR (WD feeding plus atorvastatin calcium gavage after AAV-PCSK9 injection), and PGAM5 KO (PGAM5^-/- mice fed WD after AAV-PCSK9 injection). Aortic plaques, hepatic lipid deposition, and plasma lipids were assessed by Oil Red O, HE, Masson staining, and lipid assays. Liver proteomics and single-cell RNA-seq were used to screen the pathways and analyze cell subsets. Plasma metabolomics and lipidomics screened key differential metabolites. In immortalized human LSECs (HLSECs), PGAM5 knockdown was used to assess oxidized low-density lipoprotein (oxLDL) uptake under metabolite interventions.

Hepatic PGAM5 expression increased in AS. Compared with NC, WD mice showed increased aortic plaque burden, hepatic steatosis, and LDL-C abnormalities. Compared with WD, PGAM5 KO mice showed reduced aortic lipid deposition, enhanced plaque stability, decreased plasma low-density lipoprotein cholesterol (LDL-C) levels, and improved hepatic steatosis. Liver proteomics revealed differential protein enrichment in fatty acid metabolism and endocytosis pathways. Single-cell RNA-seq showed altered relative LSEC proportions following PGAM5 deficiency. Plasma metabolomics showed decreased L-palmitoylcarnitine (L-PC) and arachidonic acid (AA) levels in PGAM5^-/- mice. Plasma lipidomics showed altered lipid profiles following PGAM5 deficiency. PGAM5 knockdown enhanced oxLDL uptake by HLSECs, while AA or L-PC inhibited this process.

PGAM5 deficiency is associated with enhanced endocytic function of LSECs and circulating lipid remodeling, which may contribute to ameliorated AS.