Dataset Information

FcγRIIb on CD11c⁺ cells modulates serum cholesterol and triglyceride levels and differentially affects atherosclerosis in male and female Ldlr^-/- mice.

ABSTRACT:

Background and aims

Circulating levels of oxidized lipoprotein (oxLDL) correlate with myocardial infarction risk and atherosclerosis severity. Our previous study demonstrates that oxLDL immune complexes (oxLDL-ICs) can signal through FcγRs on bone marrow-derived dendritic cells (BMDCs) and enhance their activation and inflammatory cytokine secretion. While global FcγR^-/- studies have shown that activating FcγRs are proatherogenic, the role of the inhibitory FcγRIIb is unclear. We sought to determine the role of DC-specific FcγRIIb in atherosclerosis.

Methods

Bone marrow chimeras were generated by rescuing lethally irradiated Ldlr^-/- mice with hematopoietic cells from littermate CD11c-Cre⁺ or CD11c-Cre^-Fcgr2b^fl/fl donors. Four weeks following transplant, recipients were placed on a Western diet for eight weeks. Various tissues and organs were analyzed for differences in inflammation.

Results

Quantitation of atherosclerosis in the proximal aorta demonstrated a 58% increase in female CD11c-Cre⁺Fcgr2b^fl/fl recipients, but a surprising 44% decrease in male recipients. Hepatic cholesterol and triglycerides were increased in female CD11c-Cre⁺Fcgr2b^fl/fl recipients. This was associated with an increase in CD36 and MHC Class II expression on hepatic CD11c⁺CD11b⁺ DCs in female livers. In contrast, male CD11c-Cre⁺Fcgr2b^fl/fl recipients had decreased hepatic lipids with a corresponding decrease in CD36 and MHC Class II expression on CD11c⁺ cells. Interestingly, both sexes of CD11c-Cre⁺Fcgr2b^fl/fl recipients had significant decreases in serum cholesterol and TGs with corresponding decreases in liver Fasn transcripts.

Conclusions

The absence of FcγRIIb expression on CD11c⁺ cells results in sex-dependent alteration in liver inflammation influencing atherogenesis and sex-independent modulation of serum cholesterol and TGs.

SUBMITTER: Marvin J

PROVIDER: S-EPMC8086422 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Publications

FcγRIIb on CD11c<sup>+</sup> cells modulates serum cholesterol and triglyceride levels and differentially affects atherosclerosis in male and female Ldlr<sup>-/-</sup> mice.

Marvin Jennifer J Rhoads Jillian P JP Major Amy S AS

Atherosclerosis 20190413

<h4>Background and aims</h4>Circulating levels of oxidized lipoprotein (oxLDL) correlate with myocardial infarction risk and atherosclerosis severity. Our previous study demonstrates that oxLDL immune complexes (oxLDL-ICs) can signal through FcγRs on bone marrow-derived dendritic cells (BMDCs) and enhance their activation and inflammatory cytokine secretion. While global FcγR<sup>-/-</sup> studies have shown that activating FcγRs are proatherogenic, the role of the inhibitory FcγRIIb is unclear. ...[more]

PMID: 31051414

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Project description:IntroductionLecithin cholesterol acyltransferase (LCAT) plays a crucial role in acyl-esterifying cholesterol in plasma, which is essential for reverse cholesterol transport (RCT). Previous studies indicated that its activity on both α and β lipoproteins interpret its effects on lipoproteins for many controversial investigations of atherosclerosis.ObjectivesTo better understand the relationship between LCAT, diet-induced dyslipidemia and atherosclerosis, we developed a double knockout (LCAT-/-&LDLR-/-, DKO) hamster model to evaluate the specific role of LCAT independent of LDL clearance effects.MethodsPlasma triglyceride (TG), total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-C), and free cholesterol (FC) levels were measured using biochemical reagent kits. FPLC was performed to analyze the components of lipoproteins. Apolipoprotein content was assessed using western blotting (WB). The hamsters were fed a high cholesterol/high fat diet (HCHFD) to induce atherosclerosis. Oil Red O staining was employed to detect plaque formation. Peritoneal macrophages were studied to investigate the effects of LCAT on cholesterol uptake and efflux.ResultsOn HCHFD, DKO hamsters exhibited significantly elevated levels of TG and FC, while HDL-C was nearly undetectable without affecting TC levels, as compared to low-density lipoprotein receptor (LDLR)-deficient (LDLR-/-, LKO) hamsters. Lipoprotein profiling revealed a marked increase in plasma chylomicron/very low-density lipoprotein (CM/VLDL) fractions, along with an unexpected reduction in LDL fraction in DKO hamsters. Furthermore, DKO hamsters displayed aggravated atherosclerotic lesions in the aorta, aortic root, and coronary artery relative to LKO hamsters, attributed to a pro-atherogenic lipoprotein profile and impaired cholesterol efflux in macrophages.ConclusionsOur study demonstrates the beneficial role of LCAT in inhibiting atherosclerotic development and highlights the distinctive lipid metabolism characteristics in hamsters with familial hypercholesterolemia.

Project description:Background: Tanshinone IIA (TIIA) is the major lipid-soluble active ingredient of the traditional Chinese medicine Salvia miltiorrhiza, which slows down atherosclerosis (AS). However, it remains unclear whether TIIA has the potential to enhance macrophage efferocytosis and thereby improve atherosclerosis. Objective: The focus of this examination was to determine if TIIA could reduce lipid accumulation and treat AS by enhancing efferocytosis. Methods: Firstly, we conducted in vivo experiments using LDLR knockout (LDLR-/-) mice for a period of 24 weeks, using histopathological staining, immunofluorescence and Western blot experiments to validate from the efficacy and mechanism parts, respectively; in addition, we utilized cells to validate our study again in vitro. The specific experimental design scheme is as follows: In vivo, Western diet-fed LDLR-/- mice for 12 weeks were constructed as an AS model, and normal diet-fed LDLR-/- mice were taken as a blank control group. The TIIA group and positive control group (atorvastatin, ATO) were intervened for 12 weeks by intraperitoneal injection (15 mg/kg/d) and gavage (1.3 mg/kg/d), respectively. In vitro, RAW264.7 cells were cultured with ox-LDL (50 ug/mL) or ox-LDL (50 ug/mL) + TIIA (20 uM/L or 40 uM/L). Pathological changes in aortic plaques and foam cell formation in RAW264.7 cells were evaluated using Masson and Oil Red O staining, respectively. Biochemical methods were used to detect lipid levels in mice. The immunofluorescence assay was performed to detect apoptotic cells and efferocytosis-related signal expression at the plaques. RT-qPCR and Western blot were carried out to observe the trend change of efferocytosis-related molecules in both mouse aorta and RAW264.7 cells. We also used the neutral red assay to assess RAW264.7 cells' phagocytic capacity. Results: Compared with the model group, TIIA decreased serum TC, TG, and LDL-C levels (p < 0.01), reduced the relative lumen area of murine aortic lipid-rich plaques (p < 0.01), enhanced the stability of murine aortic plaques (p < 0.01), reduced ox-LDL-induced lipid build-up in RAW264.7 cells (p < 0.01), and upregulated efferocytosis-related molecules expression and enhance the efferocytosis rate of ox-LDL-induced RAW264.7 cells. Conclusion: TIIA might reduce lipid accumulation by enhancing the efferocytosis of macrophages and thus treat AS.

Dataset Information

FcγRIIb on CD11c⁺ cells modulates serum cholesterol and triglyceride levels and differentially affects atherosclerosis in male and female Ldlr^-/- mice.

Background and aims

Methods

Results

Conclusions

Publications

FcγRIIb on CD11c<sup>+</sup> cells modulates serum cholesterol and triglyceride levels and differentially affects atherosclerosis in male and female Ldlr<sup>-/-</sup> mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

FcγRIIb on CD11c+ cells modulates serum cholesterol and triglyceride levels and differentially affects atherosclerosis in male and female Ldlr-/- mice.

Background and aims

Methods

Results

Conclusions

Publications

FcγRIIb on CD11c<sup>+</sup> cells modulates serum cholesterol and triglyceride levels and differentially affects atherosclerosis in male and female Ldlr<sup>-/-</sup> mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

FcγRIIb on CD11c⁺ cells modulates serum cholesterol and triglyceride levels and differentially affects atherosclerosis in male and female Ldlr^-/- mice.