Lipid metabolism, inflammation, and foam cell formation in health and metabolic disorders: targeting mTORC1

Cheon, So Yeong; Cho, Kyoungjoo

doi:10.1007/s00109-021-02117-8

Cited by 26 publications

(35 citation statements)

References 138 publications

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“…Studies have shown that lipid metabolism disorder is an important risk factor for AS ( 30 ). Dyslipidemia usually refers to the abnormality of the lipid quality and quality in the plasma, including the increase of TC, TG, and LDL-C, and the decrease of HDL-C ( 31 , 32 ). The deposition of LDL-C on the intima of the arterial wall contributes to plaque formation and AS, restricting blood flow to vital organs, and increasing the risk of atherosclerotic thrombosis and sequelae of AS ( 33 ).…”

Section: Discussionmentioning

confidence: 99%

PCSK9 inhibitor inclisiran for treating atherosclerosis via regulation of endothelial cell pyroptosis

Kong¹,

Xu²,

Cui³

et al. 2022

Ann Transl Med

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Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) belongs to an intracellular invertase or decarboxylase and is an independent risk factor for atherosclerosis (AS). This study aimed to investigate the therapeutic potential of the PCSK9 inhibitor, inclisiran, and its underlying mechanism in AS.Methods: ApoE -/mice were fed with a high-fat diet (HFD) and intraperitoneally injected with 1, 5, or 10 mg/kg inclisiran. Low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglyceride (TG), and high-density lipoprotein cholesterol (HDL-C) levels were determined using commercially available kits. Oil Red O staining was applied to detect the aortic plaque area and oil formation. Human umbilical vein endothelial cells (HUVECs) were treated with oxidized low-density lipoprotein (ox-LDL) to induce cell injuries. Cell death was determined using a Hoechst 33342/propidium iodide (PI) dual-staining assay. Cytotoxicity was measured by lactate dehydrogenase (LDH) activity analysis. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot analyses were performed to examine the pyroptosisrelated factors. Results: Inclisiran inhibited the levels of LDL-C, TC, and TG, but increased the HDL-C level in the AS animal model. It also significantly inhibited plaque and oil droplet formation in a dose-dependent manner. Moreover, inclisiran markedly inhibited pyroptosis, as evidenced by the decreased levels of cleavedcaspase-1, NOD-like receptor family pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein containing a caspase-1 recruitment domain (ASC), gasdermin-D (GSDMD)-N, interleukin (IL)-1β, and IL-18. Furthermore, inclisiran substantially inhibited cell death and cytotoxicity induced by ox-LDL in HUVECs.Conclusions: Inclisiran exerted an anti-atherosclerotic effect by inhibiting pyroptosis. This study provides a theoretical basis for the therapeutic potential of inclisiran in AS.

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Section: Discussionmentioning

confidence: 99%

PCSK9 inhibitor inclisiran for treating atherosclerosis via regulation of endothelial cell pyroptosis

Kong¹,

Xu²,

Cui³

et al. 2022

Ann Transl Med

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“…Previous studies showed that the mechanisms of VSMC foaming mainly involved in the imbalance between lipids in and out of cells (Cheon and Cho, 2021). Ox-LDL entered the cells via LDL receptor (LDLR), and LDL was internalized and transported to the endosomes (Huang et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Protective effects of mitochondrial fission inhibition on ox-LDL induced VSMC foaming via metabolic reprogramming

Fang

Zhu

et al. 2022

Front. Pharmacol.

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Atherosclerosis (AS) is one of the most common diseases in middle-age and elderly population. Lipid metabolism disorder induced foaming of vascular smooth muscle cell (VSMC) is an important pathological process of AS. Mitochondria plays an important role in lipids metabolism. While it is not known whether regulating mitochondrial function can protect ox-LDL induced VSMC foaming via metabolic reprogramming. With ox-LDL induced mouse model of VSMC injury, the injury effect of ox-LDL and the protective effect of mdivi-1, the mitochondrial fission inhibitor on mitochondrial morphology and function of VSMC, and the formation of lipid droplet were observed. With metabonomics and proteomics techniques, the main lipid metabolites and regulation proteins were identified. The results showed that Ox-LDL induced a significant mitochondrial fission and fragmentation of VSMC, and mitochondrial function disorder along with lipid deposition and foaming. Mdivi-1 significantly antagonized the damage effect of ox-LDL on mitochondrial morphology and function of VSMC, and blocked the lipid deposition. Metabonomics analysis found 848 different metabolites between ox-LDL and mdivi-1 treatment group, in which the lipid metabolites were the main, and heptadecanoic acid, palmitoleic acid and myristic acid were the critical metabolites changed most. Proteomics results showed that there were 125 differential expressed proteins between ox-LDL and mdivi-1 treatment, acetyl -CoA carboxylase1 and fatty acid synthase were the main differential expressed proteins. This study suggest that Mitochondrial fission plays an important role in VSMC lipid deposition and foaming. Inhibition of mitochondrial fission may effectively fight against ox-LDL induced lipid deposition and foaming of VSMC via improving mitochondrial function and metabolic reprogramming. This finding provides a new insight for prevention and treatment of AS.

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“…mTOR is a serine-threonine protein kinase and functions as two distinct signaling complexes: mTOR complex 1 (mTORC1) and mTORC2 [175]. mTORC1 is involved in immune responses and lipid metabolism in the human body [176]. In the context of eye disease, several studies showed that systemic rapamycin treatment reduces retinal neovascularization in OIR mice [177,178].…”

Section: Rapamycinmentioning

confidence: 99%

Metabolism in Retinopathy of Prematurity

Tomita

Usui‐Ouchi

Nilsson

et al. 2021

Life

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Retinopathy of prematurity is defined as retinal abnormalities that occur during development as a consequence of disturbed oxygen conditions and nutrient supply after preterm birth. Both neuronal maturation and retinal vascularization are impaired, leading to the compensatory but uncontrolled retinal neovessel growth. Current therapeutic interventions target the hypoxia-induced neovessels but negatively impact retinal neurons and normal vessels. Emerging evidence suggests that metabolic disturbance is a significant and underexplored risk factor in the disease pathogenesis. Hyperglycemia and dyslipidemia correlate with the retinal neurovascular dysfunction in infants born prematurely. Nutritional and hormonal supplementation relieve metabolic stress and improve retinal maturation. Here we focus on the mechanisms through which metabolism is involved in preterm-birth-related retinal disorder from clinical and experimental investigations. We will review and discuss potential therapeutic targets through the restoration of metabolic responses to prevent disease development and progression.

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Lipid metabolism, inflammation, and foam cell formation in health and metabolic disorders: targeting mTORC1

Cited by 26 publications

References 138 publications

PCSK9 inhibitor inclisiran for treating atherosclerosis via regulation of endothelial cell pyroptosis

PCSK9 inhibitor inclisiran for treating atherosclerosis via regulation of endothelial cell pyroptosis

Protective effects of mitochondrial fission inhibition on ox-LDL induced VSMC foaming via metabolic reprogramming

Metabolism in Retinopathy of Prematurity

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