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ApoE-/- PGC-1α-/- mice display reduced IL-18 levels and do not develop enhanced atherosclerosis.

Stein S, Lohmann C, Handschin C, Stenfeldt E, Borén J, Lüscher TF, Matter CM - PLoS ONE (2010)

Bottom Line: The PPARγ coactivator 1 alpha (Ppargc1a or PGC-1α) was identified as an important transcriptional cofactor of PPARγ and is activated by SIRT1.Despite having more macrophages and a higher ICAM-1 expression in plaques, ApoE(-/-) PGC-1α(-/-) did not display more or larger atherosclerotic plaques than their ApoE(-/-) PGC-1α(+/+) littermates.VLDL/LDL-cholesterol and triglyceride contents were also reduced.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular Research, Institute of Physiology, and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.

ABSTRACT

Background: Atherosclerosis is a chronic inflammatory disease that evolves from the interaction of activated endothelial cells, macrophages, lymphocytes and modified lipoproteins (LDLs). In the last years many molecules with crucial metabolic functions have been shown to prevent important steps in the progression of atherogenesis, including peroxisome proliferator activated receptors (PPARs) and the class III histone deacetylase (HDAC) SIRT1. The PPARγ coactivator 1 alpha (Ppargc1a or PGC-1α) was identified as an important transcriptional cofactor of PPARγ and is activated by SIRT1. The aim of this study was to analyze total PGC-1α deficiency in an atherosclerotic mouse model.

Methodology/principal findings: To investigate if total PGC-1α deficiency affects atherosclerosis, we compared ApoE(-/-) PGC-1α(-/-) and ApoE(-/-) PGC-1α(+/+) mice kept on a high cholesterol diet. Despite having more macrophages and a higher ICAM-1 expression in plaques, ApoE(-/-) PGC-1α(-/-) did not display more or larger atherosclerotic plaques than their ApoE(-/-) PGC-1α(+/+) littermates. In line with the previously published phenotype of PGC-1α(-/-) mice, ApoE(-/-) PGC-1α(-/-) mice had marked reduced body, liver and epididymal white adipose tissue (WAT) weight. VLDL/LDL-cholesterol and triglyceride contents were also reduced. Aortic expression of PPARα and PPARγ, two crucial regulators for adipocyte differentiation and glucose and lipid metabolism, as well as the expression of some PPAR target genes was significantly reduced in ApoE(-/-) PGC-1α(-/-) mice. Importantly, the epididymal WAT and aortic expression of IL-18 and IL-18 plasma levels, a pro-atherosclerotic cytokine, was markedly reduced in ApoE(-/-) PGC-1α(-/-) mice.

Conclusions/significance: ApoE(-/-) PGC-1α(-/-) mice, similar as PGC-1α(-/-) mice exhibit markedly reduced total body and visceral fat weight. Since inflammation of visceral fat is a crucial trigger of atherogenesis, decreased visceral fat in PGC-1α-deficient mice may explain why these mice do not develop enhanced atherosclerosis.

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Plasma lipid levels.(A, B) Cholesterol and triglyceride distribution in the plasma lipoprotein fractions of ApoE−/− PGC-1α−/− and ApoE−/− PGC-1α+/+ mice. Plasma samples were pooled (n = 14 per genotype) and fractionated on a HPLC column. (C) Total cholesterol and triglycerides concentrations were measured with an enzymatic colorimetric assay. n = 14 per genotype. HPLC, high pressure liquid chromatography; HDL, high-density lipoproteins; IDL, intermediate-density lipoproteins; LDL, low-density lipoproteins; VLDL, very-low-density lipoproteins. ** p<0.01.
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pone-0013539-g004: Plasma lipid levels.(A, B) Cholesterol and triglyceride distribution in the plasma lipoprotein fractions of ApoE−/− PGC-1α−/− and ApoE−/− PGC-1α+/+ mice. Plasma samples were pooled (n = 14 per genotype) and fractionated on a HPLC column. (C) Total cholesterol and triglycerides concentrations were measured with an enzymatic colorimetric assay. n = 14 per genotype. HPLC, high pressure liquid chromatography; HDL, high-density lipoproteins; IDL, intermediate-density lipoproteins; LDL, low-density lipoproteins; VLDL, very-low-density lipoproteins. ** p<0.01.

Mentions: ApoE−/− PGC-1α−/− mice had a lower body, liver, and epididymal fat weight than ApoE−/− PGC-1α+/+ mice (Fig. 3A–D). Spleen weight did not differ between the two groups (Fig. 3E). These data match the published phenotype of PGC-1α−/− mice [11]. We next analyzed total cholesterol and triglyceride plasma levels and their distribution in lipoprotein fractions. Both cholesterol and triglyceride contents were lower in VLDL and IDL/LDL particles, whereas their content in HDL particles did not differ (Fig. 4A, B). Total plasma cholesterol showed a clear trend, whereas total triglyceride levels were markedly lower in ApoE−/− PGC-1α−/− compared to ApoE−/− PGC-1α+/+ mice (Fig. 4C).


ApoE-/- PGC-1α-/- mice display reduced IL-18 levels and do not develop enhanced atherosclerosis.

Stein S, Lohmann C, Handschin C, Stenfeldt E, Borén J, Lüscher TF, Matter CM - PLoS ONE (2010)

Plasma lipid levels.(A, B) Cholesterol and triglyceride distribution in the plasma lipoprotein fractions of ApoE−/− PGC-1α−/− and ApoE−/− PGC-1α+/+ mice. Plasma samples were pooled (n = 14 per genotype) and fractionated on a HPLC column. (C) Total cholesterol and triglycerides concentrations were measured with an enzymatic colorimetric assay. n = 14 per genotype. HPLC, high pressure liquid chromatography; HDL, high-density lipoproteins; IDL, intermediate-density lipoproteins; LDL, low-density lipoproteins; VLDL, very-low-density lipoproteins. ** p<0.01.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2962638&req=5

pone-0013539-g004: Plasma lipid levels.(A, B) Cholesterol and triglyceride distribution in the plasma lipoprotein fractions of ApoE−/− PGC-1α−/− and ApoE−/− PGC-1α+/+ mice. Plasma samples were pooled (n = 14 per genotype) and fractionated on a HPLC column. (C) Total cholesterol and triglycerides concentrations were measured with an enzymatic colorimetric assay. n = 14 per genotype. HPLC, high pressure liquid chromatography; HDL, high-density lipoproteins; IDL, intermediate-density lipoproteins; LDL, low-density lipoproteins; VLDL, very-low-density lipoproteins. ** p<0.01.
Mentions: ApoE−/− PGC-1α−/− mice had a lower body, liver, and epididymal fat weight than ApoE−/− PGC-1α+/+ mice (Fig. 3A–D). Spleen weight did not differ between the two groups (Fig. 3E). These data match the published phenotype of PGC-1α−/− mice [11]. We next analyzed total cholesterol and triglyceride plasma levels and their distribution in lipoprotein fractions. Both cholesterol and triglyceride contents were lower in VLDL and IDL/LDL particles, whereas their content in HDL particles did not differ (Fig. 4A, B). Total plasma cholesterol showed a clear trend, whereas total triglyceride levels were markedly lower in ApoE−/− PGC-1α−/− compared to ApoE−/− PGC-1α+/+ mice (Fig. 4C).

Bottom Line: The PPARγ coactivator 1 alpha (Ppargc1a or PGC-1α) was identified as an important transcriptional cofactor of PPARγ and is activated by SIRT1.Despite having more macrophages and a higher ICAM-1 expression in plaques, ApoE(-/-) PGC-1α(-/-) did not display more or larger atherosclerotic plaques than their ApoE(-/-) PGC-1α(+/+) littermates.VLDL/LDL-cholesterol and triglyceride contents were also reduced.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular Research, Institute of Physiology, and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.

ABSTRACT

Background: Atherosclerosis is a chronic inflammatory disease that evolves from the interaction of activated endothelial cells, macrophages, lymphocytes and modified lipoproteins (LDLs). In the last years many molecules with crucial metabolic functions have been shown to prevent important steps in the progression of atherogenesis, including peroxisome proliferator activated receptors (PPARs) and the class III histone deacetylase (HDAC) SIRT1. The PPARγ coactivator 1 alpha (Ppargc1a or PGC-1α) was identified as an important transcriptional cofactor of PPARγ and is activated by SIRT1. The aim of this study was to analyze total PGC-1α deficiency in an atherosclerotic mouse model.

Methodology/principal findings: To investigate if total PGC-1α deficiency affects atherosclerosis, we compared ApoE(-/-) PGC-1α(-/-) and ApoE(-/-) PGC-1α(+/+) mice kept on a high cholesterol diet. Despite having more macrophages and a higher ICAM-1 expression in plaques, ApoE(-/-) PGC-1α(-/-) did not display more or larger atherosclerotic plaques than their ApoE(-/-) PGC-1α(+/+) littermates. In line with the previously published phenotype of PGC-1α(-/-) mice, ApoE(-/-) PGC-1α(-/-) mice had marked reduced body, liver and epididymal white adipose tissue (WAT) weight. VLDL/LDL-cholesterol and triglyceride contents were also reduced. Aortic expression of PPARα and PPARγ, two crucial regulators for adipocyte differentiation and glucose and lipid metabolism, as well as the expression of some PPAR target genes was significantly reduced in ApoE(-/-) PGC-1α(-/-) mice. Importantly, the epididymal WAT and aortic expression of IL-18 and IL-18 plasma levels, a pro-atherosclerotic cytokine, was markedly reduced in ApoE(-/-) PGC-1α(-/-) mice.

Conclusions/significance: ApoE(-/-) PGC-1α(-/-) mice, similar as PGC-1α(-/-) mice exhibit markedly reduced total body and visceral fat weight. Since inflammation of visceral fat is a crucial trigger of atherogenesis, decreased visceral fat in PGC-1α-deficient mice may explain why these mice do not develop enhanced atherosclerosis.

Show MeSH
Related in: MedlinePlus