Zdhhc1 deficiency mitigates foam cell formation and atherosclerosis by inhibiting PI3K-Akt-mTOR signaling pathway through facilitating the nuclear translocation of p110α

Biochim Biophys Acta Mol Basis Dis. 2025 Feb;1871(2):167577. doi: 10.1016/j.bbadis.2024.167577. Epub 2024 Nov 19.

Abstract

Monocyte-to-macrophage differentiation and subsequent foam cell formation are key processes that contribute to plaque build-up during the progression of atherosclerotic lesions. Palmitoylation enzymes are known to play pivotal roles in the development and progression of inflammatory diseases. However, their specific impact on atherosclerosis development remains unclear. In this study, we discovered that the knockout of zDHHC1 in THP-1 cells, as well as Zdhhc1 in mice, markedly reduces the uptake of oxidized low-density lipoprotein (ox-LDL) by macrophages, thereby inhibiting foam cell formation. Moreover, the absence of Zdhhc1 in ApoE-/- mice significantly suppresses atherosclerotic plaque formation. Mass spectrometry coupled with bioinformatic analysis revealed an enrichment of the PI3K-Akt-mTOR signaling pathway. Consistent with this, we observed that knockout of zDHHC1 significantly decreases the palmitoylation levels of p110α, a crucial subunit of PI3K. Notably, the deletion of Zdhhc1 facilitates the nuclear translocation of p110α in macrophages, leading to a significant reduction in the downstream phosphorylation of Akt at Ser473 and mTOR at Ser2448. This cascade results in a decreased number of macrophages within plaques and ultimately mitigates the severity of atherosclerosis. These findings unveil a novel role for zDHHC1 in regulating foam cell formation and the progression of atherosclerosis, suggesting it as a promising target for clinical intervention in atherosclerosis therapy.

Keywords: Atherosclerosis; Foam cell formation; PI3K-Akt-mTOR signaling pathway; Palmitoylation; Zdhhc1.

MeSH terms

  • Active Transport, Cell Nucleus
  • Acyltransferases* / deficiency
  • Acyltransferases* / genetics
  • Acyltransferases* / metabolism
  • Animals
  • Apolipoproteins E / deficiency
  • Apolipoproteins E / genetics
  • Apolipoproteins E / metabolism
  • Atherosclerosis* / genetics
  • Atherosclerosis* / metabolism
  • Atherosclerosis* / pathology
  • Cell Nucleus / metabolism
  • Class I Phosphatidylinositol 3-Kinases / genetics
  • Class I Phosphatidylinositol 3-Kinases / metabolism
  • Foam Cells* / metabolism
  • Foam Cells* / pathology
  • Humans
  • Lipoproteins, LDL* / metabolism
  • Lipoylation
  • Macrophages / metabolism
  • Macrophages / pathology
  • Male
  • Mice
  • Mice, Knockout
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Plaque, Atherosclerotic / genetics
  • Plaque, Atherosclerotic / metabolism
  • Plaque, Atherosclerotic / pathology
  • Proto-Oncogene Proteins c-akt* / metabolism
  • Signal Transduction*
  • THP-1 Cells
  • TOR Serine-Threonine Kinases* / metabolism

Substances

  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Lipoproteins, LDL
  • oxidized low density lipoprotein
  • Acyltransferases
  • Class I Phosphatidylinositol 3-Kinases
  • Phosphatidylinositol 3-Kinases
  • mTOR protein, mouse
  • Apolipoproteins E
  • PIK3CA protein, human
  • MTOR protein, human