Myeloid-associated lipin-1 transcriptional co-regulatory activity is atheroprotective

Atherosclerosis. 2021 Aug:330:76-84. doi: 10.1016/j.atherosclerosis.2021.06.927. Epub 2021 Jul 1.

Abstract

Background and aims: Atherosclerosis is the most prominent underlying cause of cardiovascular disease (CVD). It is initiated by cholesterol deposition in the arterial intima, which causes macrophage recruitment and proinflammatory responses that promote plaque growth, necrotic core formation, and plaque rupture. Lipin-1 is a phosphatidic acid phosphohydrolase for glycerolipid synthesis. We have shown that lipin-1 phosphatase activity promotes macrophage pro-inflammatory responses when stimulated with modified low-density lipoprotein (modLDL) and accelerates atherosclerosis. Lipin-1 also independently acts as a transcriptional co-regulator where it enhances the expression of genes involved in β-oxidation. In hepatocytes and adipocytes, lipin-1 augments the activity of transcription factors such as peroxisome proliferator-activated receptor (PPARs). PPARs control the expression of anti-inflammatory genes in macrophages and slow or reduce atherosclerotic progression. Therefore, we hypothesize myeloid-derived lipin-1 transcriptional co-regulatory activity reduces atherosclerosis.

Methods: We used myeloid-derived lipin-1 knockout (lipin-1mKO) and littermate control mice and AAV8-PCSK9 along with high-fat diet to elicit atherosclerosis.

Results: Lipin-1mKO mice had larger aortic root plaques than littermate control mice after 8 and 12 weeks of a high-fat diet. Lipin-1mKO mice also had increased serum proinflammatory cytokine concentrations, reduced apoptosis in plaques, and larger necrotic cores in the plaques compared to control mice.

Conclusions: Combined, the data suggest lipin-1 transcriptional co-regulatory activity in myeloid cells is atheroprotective.

Keywords: Atherosclerosis; IL-23; Lipin-1 transcriptional co-regulatory activity; Macrophage; Necrotic core.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nuclear Proteins* / genetics
  • Organic Chemicals
  • Phosphatidate Phosphatase / genetics
  • Phosphatidate Phosphatase / metabolism*
  • Proprotein Convertase 9*

Substances

  • Nuclear Proteins
  • Organic Chemicals
  • lipine
  • Lpin1 protein, mouse
  • Phosphatidate Phosphatase
  • PCSK9 protein, human
  • Proprotein Convertase 9