Novel Role of CETP in Macrophages: Reduction of Mitochondrial Oxidants Production and Modulation of Cell Immune-Metabolic Profile

Author(s)

Dorighello, Gabriel G. ; Assis, Leandro H. P. ; Rentz, Thiago ; Morari, Joseane ; Santana, Monique F. M. ; Passarelli, Marisa ; Ridgway, Neale D. ; Vercesi, Anibal E. ; Oliveira, Helena C. F.

• Document type: Journal article
• Source: ANTIOXIDANTS; v. 11, n. 9, p. 17-pg., 2022-09-01.

Abstract

Plasma cholesteryl ester transfer protein (CETP) activity diminishes HDL-cholesterol levels and thus may increase atherosclerosis risk. Experimental evidence suggests CETP may also exhibit anti-inflammatory properties, but local tissue-specific functions of CETP have not yet been clarified. Since oxidative stress and inflammation are major features of atherogenesis, we investigated whether CETP modulates macrophage oxidant production, inflammatory and metabolic profiles. Comparing macrophages from CETP-expressing transgenic mice and non-expressing littermates, we observed that CETP expression reduced mitochondrial superoxide anion production and H2O2 release, increased maximal mitochondrial respiration rates, and induced elongation of the mitochondrial network and expression of fusion-related genes (mitofusin-2 and OPA1). The expression of pro-inflammatory genes and phagocytic activity were diminished in CETP-expressing macrophages. In addition, CETP-expressing macrophages had less unesterified cholesterol under basal conditions and after exposure to oxidized LDL, as well as increased HDL-mediated cholesterol efflux. CETP knockdown in human THP1 cells increased unesterified cholesterol and abolished the effects on mitofusin-2 and TNF alpha. In summary, the expression of CETP in macrophages modulates mitochondrial structure and function to promote an intracellular antioxidant state and oxidative metabolism, attenuation of pro-inflammatory gene expression, reduced cholesterol accumulation, and phagocytosis. These localized functions of CETP may be relevant for the prevention of atherosclerosis and other inflammatory diseases. (AU)

• FAPESP's process: 13/07607-8 - OCRC - Obesity and Comorbidities Research Center
• Grantee: Licio Augusto Velloso
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 17/17728-8 - Mitochondrial function and dysfunction: implications for aging and associated diseases
• Grantee: Aníbal Eugênio Vercesi
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 17/02903-9 - Role of CETP expression in the macrophage redox state: possible consequences to inflammation and atherosclerosis
• Grantee: Gabriel de Gabriel Taffarello Dorighello
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 19/18431-4 - High-density lipoprotein, advanced glycation endproducts and oxysterols in Breast Cancer: association with the molecular classification of tumor and disease prognosis
• Grantee: Marisa Passarelli
• Support Opportunities: Regular Research Grants
• FAPESP's process: 21/02401-9 - Anti-inflammatory activity and transport of microRNA by High-Density Lipoproteins (HDL) in Breast Câncer: association with the prognosis of the disease predicted by tumor molecular classification
• Grantee: Monique de Fatima Mello Santana
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 17/03402-3 - Study of the association of mitochondrial and endoplasmic reticulum membranes in macrophages in the context of hypercholesterolemia: possible relevance for atherosclerosis
• Grantee: Leandro Henrique de Paula Assis
• Support Opportunities: Scholarships in Brazil - Post-Doctoral