Therapeutic silencing of FSP27 reduces the progression of atherosclerosis in Ldlr–/– mice

Rajamoorthi, Ananthi; Lee, Richard G.; Baldán, Ángel

doi:10.1016/j.atherosclerosis.2018.05.045

Cited by 9 publications

(8 citation statements)

References 38 publications

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“…This points out toward a “systemic” effect of the beneficial Q1 AMD CIDEC variants. Interestingly, a similar indirect and systemic favorable effect has recently been reported in mouse models of vascular inflammation and atherogenesis after Fsp27 silencing 38; 39 . Many studies on dietary or circulating lipids, as well as genetic studies support a role for not only local lipid trafficking in the retina but also for circulating lipoproteins in AMD pathogenesis 40 .…”

Section: Discussionsupporting

confidence: 74%

Age-related Macular Degeneration patient deep phenotyping and whole genome sequencing analysis identifies coding variants linking small low-luminance visual deficit to fat storage defects

Kim

Stockwell²,

Qin³

et al. 2022

Preprint

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Background: The basis of Age-related macular degeneration (AMD) genetic risk has been well documented; however, few studies have looked at genetic biomarkers of disease progression or treatment response within advanced AMD patients. Here we report the first genome-wide analysis of genetic determinants of low-luminance vision deficit (LLD), which is seen as predictive of visual acuity loss and anti-VEGF treatment response in neovascular AMD patients. Methods: AMD patients were separated into small- and large-LLD groups for comparison and whole genome sequencing was performed. Genetic determinants of LLD were assessed by common and rare variant genetic analysis. Follow-up functional analysis of rare coding variants identified by the burden test was then performed in vitro. Results: We identified four coding variants in the CIDEC gene. These rare variants were only present in patients with a small LLD, which has been previously shown to indicate better prognosis and better treatment response. Our in vitro functional characterization of these CIDEC alleles revealed that all decrease the binding affinity between CIDEC and the lipid droplet fusion effectors PLIN1, RAB8A and AS160. The rare CIDEC alleles all cause a hypomorphic defect in lipid droplet fusion and enlargement, resulting in a decreased fat storage capability in adipocytes. Conclusions: As we did not detect CIDEC expression in the ocular tissue affected by AMD, our results suggest that the CIDEC variants do not play a direct role in the eye and influence low-luminance vision deficit via an indirect and systemic effect related to fat storage capacity.

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Section: Discussionsupporting

confidence: 74%

Age-related Macular Degeneration patient deep phenotyping and whole genome sequencing analysis identifies coding variants linking small low-luminance visual deficit to fat storage defects

Kim

Stockwell²,

Qin³

et al. 2022

Preprint

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show abstract

“…This points out toward a “systemic” effect of the beneficial Q1 AMD CIDEC variants. Interestingly, a similar indirect and systemic favorable effect has recently been reported in mouse models of vascular inflammation and atherogenesis after Fsp27 silencing [ 39 , 40 ]. Many studies on dietary or circulating lipids, as well as genetic studies support a role for not only local lipid trafficking in the retina but also for circulating lipoproteins in AMD pathogenesis [ 41 ].…”

Section: Discussionsupporting

confidence: 63%

Rare CIDEC coding variants enriched in age-related macular degeneration patients with small low-luminance deficit cause lipid droplet and fat storage defects

Kim¹,

Stockwell²,

Qin³

et al. 2023

PLoS ONE

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Background The basis of Age-related macular degeneration (AMD) genetic risk has been well documented; however, few studies have looked at genetic biomarkers of disease progression or treatment response within advanced AMD patients. Here we report the first genome-wide analysis of genetic determinants of low-luminance vision deficit (LLD), which is seen as predictive of visual acuity loss and anti-VEGF treatment response in neovascular AMD patients. Methods AMD patients were separated into small- and large-LLD groups for comparison and whole genome sequencing was performed. Genetic determinants of LLD were assessed by common and rare variant genetic analysis. Follow-up functional analysis of rare coding variants identified by the burden test was then performed in vitro. Results We identified four coding variants in the CIDEC gene. These rare variants were only present in patients with a small LLD, which has been previously shown to indicate better prognosis and better anti-VEGF treatment response. Our in vitro functional characterization of these CIDEC alleles revealed that all decrease the binding affinity between CIDEC and the lipid droplet fusion effectors PLIN1, RAB8A and AS160. The rare CIDEC alleles all cause a hypomorphic defect in lipid droplet fusion and enlargement, resulting in a decreased fat storage capability in adipocytes. Conclusions As we did not detect CIDEC expression in the ocular tissue affected by AMD, our results suggest that the CIDEC variants do not play a direct role in the eye and influence low-luminance vision deficit via an indirect and systemic effect related to fat storage capacity.

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“…A homozygous human mutation of CIDEC has been reported to induce lipodystrophy and insulin-resistant diabetes (40,48). Reduced expression of hepatic Fsp27 abolished fasting-induced liver steatosis (23) and the former condition in combination with a PPARalpha agonist was also found to reduce hepatic steatosis (45) and even atherosclerosis (46) in Ldlr-deficient mice, a model of atherosclerosis and hepatosteatosis (49).…”

Section: Introductionmentioning

confidence: 99%

Pgc1ais responsible for the sex differences in hepaticCidec/Fsp27βmRNA expression in hepatic steatosis of mice fed a Western diet

Herrera-Marcos

Sancho-Knapik

Gabás‐Rivera

et al. 2020

American Journal of Physiology-Endocrinology and Metabolism

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Hepatic fat-specific protein 27 [cell death-inducing DNA fragmentation effector protein C ( Cidec)/ Fsp27] mRNA levels have been associated with hepatic lipid droplet extent under certain circumstances. To address its hepatic expression under different dietary conditions and in both sexes, apolipoprotein E ( Apoe) -deficient mice were subjected to different experimental conditions for 11 wk to test the influence of cholesterol, Western diet, squalene, oleanolic acid, sex, and surgical castration on Cidec/Fsp27 mRNA expression. Dietary cholesterol increased hepatic Cidec/Fsp27β expression, an effect that was suppressed when cholesterol was combined with saturated fat as represented by Western diet feeding. Using the latter diet, neither oleanolic acid nor squalene modified its expression. Females showed lower levels of hepatic Cidec/Fsp27β expression than males when they were fed Western diets, a result that was translated into a lesser amount of CIDEC/FSP27 protein in lipid droplets and microsomes. This was also confirmed in low-density lipoprotein receptor ( Ldlr)-deficient mice. Incubation with estradiol resulted in decreased Cidec/Fsp27β expression in AML12 cells. Whereas male surgical castration did not modify the expression, ovariectomized females did show increased levels compared with control females. Females also showed increased expression of peroxisome proliferator-activated receptor-γ coactivator 1-α ( Pgc1a), suppressed by ovariectomy, and the values were significantly and inversely associated with those of Cidec/Fsp27β. When Pgc1a-deficient mice were used, the sex differences in Cidec/Fsp27β expression disappeared. Therefore, hepatic Cidec/Fsp27β expression has a complex regulation influenced by diet and sex hormonal milieu. The mRNA sex differences are controlled by Pgc1a.

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Therapeutic silencing of FSP27 reduces the progression of atherosclerosis in Ldlr–/– mice

Abstract: Our findings suggest that therapeutic silencing of Fsp27 with ASOs may be beneficial in the prevention and management of atherogenic disease in patients with metabolic syndrome.

Cited by 9 publications

References 38 publications

Age-related Macular Degeneration patient deep phenotyping and whole genome sequencing analysis identifies coding variants linking small low-luminance visual deficit to fat storage defects

Age-related Macular Degeneration patient deep phenotyping and whole genome sequencing analysis identifies coding variants linking small low-luminance visual deficit to fat storage defects

Rare CIDEC coding variants enriched in age-related macular degeneration patients with small low-luminance deficit cause lipid droplet and fat storage defects

Pgc1ais responsible for the sex differences in hepaticCidec/Fsp27βmRNA expression in hepatic steatosis of mice fed a Western diet

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