CETP Expression in Bone-Marrow-Derived Cells Reduces the Inflammatory Features of Atherosclerosis in Hypercholesterolemic Mice

Rentz, Thiago; Dorighello, Gabriel G.; dos Santos, Renata R.; Barreto, Lohanna M.; Freitas, Israelle N.; Lazaro, Carolina M.; Razolli, Daniela S.; Cazita, Patricia M.; Oliveira, Helena C. F.

doi:10.3390/biom13101556

Cited by 3 publications

(1 citation statement)

References 51 publications

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“…However, in addition to being an important component of reverse cholesterol transport, recent discoveries have shown its importance in playing an anti-inflammatory role, influencing the development of infections in experimental studies of endotoxemia and sepsis ( 11 – 13 ). Further, the expression of CETP in macrophages promotes an intracellular antioxidant state, reduces the accumulation of free cholesterol and phagocytosis, and attenuates pro-inflammatory gene expression ( 14 , 15 ).…”

Section: Introductionmentioning

confidence: 99%

The impact of cholesteryl ester transfer protein on the progression of cutaneous leishmaniasis

Batista-Dantas,

Ozaki,

Santana

et al. 2024

Front. Immunol.

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IntroductionPathogenesis of cutaneous leishmaniases involves parasite growth, persistent inflammation, and likely participation of lipoproteins (LP). The cholesteryl ester transfer protein (CETP), involved in LP remodeling, has been shown to participate in the inflammatory response and the evolution of infectious conditions. MethodsWe evaluated the impact of the presence of CETP on infection by Leishmania (L.) amazonensis in an experimental model of cutaneous leishmaniasis using C57BL6/J mice transgenic for human CETP (CETP), having as control their littermates that do not express the protein, wild-type (WT) mice. The progression of the lesion after infection in the footpad was monitored for 12 weeks. Two groups of animals were formed to collect the plantar pad in the 4th and 12th week post-infection. ResultsThe lesion increased from the 3rd week onwards, in both groups, with a gradual decrease from the 10th week onwards in the CETP group compared to the WT group, showing a reduction in parasitism and an improvement in the healing process, a reduction in CD68+ cells, and an increase in CD163+ and CD206, characterizing a population of M2 macrophages. A reduction in ARG1+ cells and an increase in INOS+ cells were observed. During infection, the LP profile showed an increase in triglycerides in the VLDL fraction in the CETP group at 12 weeks. Gene expression revealed a decrease in the CD36 receptor in the CETP group at 12 weeks, correlating with healing and parasite reduction. In vitro, macrophages derived from bone marrow cells from CETP mice showed lower parasite load at 48 h and, a reduction in arginase activity at 4 h accompanied by increased NO production at 4 and 24 h compared to WT macrophages, corroborating the in vivo findings.DiscussionThe data indicate that the presence of CETP plays an important role in resolving Leishmania (L.) amazonensis infection, reducing parasitism, and modulating the inflammatory response in controlling infection and tissue repair.

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Section: Introductionmentioning

confidence: 99%

The impact of cholesteryl ester transfer protein on the progression of cutaneous leishmaniasis

Batista-Dantas,

Ozaki,

Santana

et al. 2024

Front. Immunol.

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Sex-Specific Effects of Cholesteryl Ester Transfer Protein (CETP) on the Perivascular Adipose Tissue

Lazaro,

Freitas,

Nunes

et al. 2024

Function

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Cholesteryl ester transfer protein (CETP) increases the atherosclerosis risk by lowering HDL-cholesterol levels. It also exhibits tissue-specific effects independent of HDL. However, sexual dimorphism of CETP effects remains largely unexplored. Here, we hypothesized that CETP impacts the perivascular adipose tissue (PVAT) phenotype and function in a sex-specific manner. PVAT function, gene and protein expression, and morphology were examined in male and female transgenic mice expressing human or simian CETP and their non-transgenic counterparts (NTg). PVAT exerted its anticontractile effect in aortas from NTg males, NTg females, and CETP females, but not in CETP males. CETP male PVAT had reduced NO levels, decreased eNOS and phospho-eNOS levels, oxidative stress, increased NOX1 and 2, and decreased SOD2 and 3 expressions. In contrast, CETP-expressing female PVAT displayed increased NO and phospho-eNOS levels with unchanged NOX expression. NOX inhibition and the antioxidant tempol restored PVAT anticontractile function in CETP males. Ex vivo estrogen treatment also restored PVAT function in CETP males. Moreover, CETP males, but not female PVAT, show increased inflammatory markers. PVAT lipid content increased in CETP males but decreased in CETP females, while PVAT cholesterol content increased in CETP females. CETP male PVAT exhibited elevated leptin and reduced Prdm16 (brown adipocyte marker) expression. These findings highlight CETP sex-specific impact on PVAT. In males, CETP impaired PVAT anticontractile function, accompanied by oxidative stress, inflammation, and whitening. Conversely, in females, CETP expression increased NO levels, induced an anti-inflammatory phenotype, and preserved the anticontractile function. This study reveals sex-specific vascular dysfunction mediated by CETP.

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CETP expression in females increases body metabolism under both cold exposure and thermoneutrality contributing to a leaner phenotype

Castelli,

Raposo,

Navarro

et al. 2024

Preprint

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Susceptibility to obesity differs depending on the genetic background and housing temperatures. We have recently reported that CETP expressing female mice are leaner due to increased lipolysis, brown adipose tissue (BAT) activity and body energy expenditure compared to non-transgenic (NTg) littermates under standard housing temperature (22 C). The aim of this study is to evaluate how CETP expression affect body temperature, composition and metabolism during cold exposure (4 C) and thermoneutrality (30 C). When submitted to cold, CETP mice maintained rectal temperature, body weight and food intake similarly to NTg mice along acute or chronic exposure to 4 C. The body oxygen consumption in response to an isoproterenol challenge was 21% higher at 22 C, and 41% higher after 7 days of cold exposure in CETP than in NTg mice. In addition, BAT biopsies from CETP mice showed reduced lipid content and increased basal oxygen consumption rates. Under thermoneutrality (30 C), when BAT activity is inhibited, CETP mice showed higher rectal and tail temperatures, increased food intake and increased energy expenditure. Lean mass was elevated and fat mass reduced in CETP mice kept at 30 C. In this thermoneutrality condition, soleus muscle, but not gastrocnemius or liver of CETP mice showed increased mitochondrial respiration rates. These data indicate that CETP expression confers a greater capacity of elevating body metabolic rates at both cold exposure, through BAT activity, and at thermoneutrality, through increased muscle metabolism. Thus, the CETP expression levels in females should be considered as a new influence in the contexts of obesity and metabolic disorders propensity.

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CETP Expression in Bone-Marrow-Derived Cells Reduces the Inflammatory Features of Atherosclerosis in Hypercholesterolemic Mice

Cited by 3 publications

References 51 publications

The impact of cholesteryl ester transfer protein on the progression of cutaneous leishmaniasis

The impact of cholesteryl ester transfer protein on the progression of cutaneous leishmaniasis

Sex-Specific Effects of Cholesteryl Ester Transfer Protein (CETP) on the Perivascular Adipose Tissue

CETP expression in females increases body metabolism under both cold exposure and thermoneutrality contributing to a leaner phenotype

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