mTOR Enhances Foam Cell Formation by Suppressing the Autophagy Pathway

Wang, Xiaochuang; Li, Lingxia; Niu, Xiaolin; Dang, Xiaoyan; Li, Ping; Li, Qu; Bi, Xiaoju; Gao, Yanxia; Hu, Yanfen; Li, Manxiang; Qiao, Wan-hai; Peng, Zhuo; Pan, Longfei

doi:10.1089/dna.2013.2164

Cited by 46 publications

(51 citation statements)

References 34 publications

(36 reference statements)

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“…24, 38 To explore the molecular mechanism underlying HY-SDT-induced autophagy, we additionally analyzed the phosphorylation levels of AKT, AMPK and mTOR (p-AKT, p-AMPK and p-mTOR) at different time points following HY-SDT. As show in Figure 2a, HY-SDT induced a rapid and significant increase in p-AMPK from 1 h to 3 h, while a reduction of p-AKT with the minimum at 3 h, suggesting the involvement of AKT and AMPK in HY-SDT-induced autophagy.…”

Section: Resultsmentioning

confidence: 99%

“…22 In addition, increasing macrophage autophagy enhances LDs breakdown, facilitates lipid efflux and further decreases plaque susceptibility. 23, 24, 25 In contrast, specific deficiency of macrophage autophagy exacerbates atherosclerotic lesion in high-fat-fed LDLr −/− or ApoE −/− mice. 2, 26 While impaired hydrolysis of engulfed lipids results in progressive lysosomal dysfunction and accordingly autophagy defect.…”

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confidence: 99%

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Hypericin-mediated sonodynamic therapy induces autophagy and decreases lipids in THP-1 macrophage by promoting ROS-dependent nuclear translocation of TFEB

Zhang

Zheng

et al. 2016

Cell Death Dis

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Lipid catabolism disorder is the primary cause of atherosclerosis. Transcription factor EB (TFEB) prevents atherosclerosis by activating macrophage autophagy to promote lipid degradation. Hypericin-mediated sonodynamic therapy (HY-SDT) has been proved non-invasively inducing THP-1-derived macrophage apoptosis; however, it is unknown whether macrophage autophagy could be triggered by HY-SDT to influence cellular lipid catabolism via regulating TFEB. Here, we report that HY-SDT resulted in the time-dependent THP-1-derived macrophage autophagy activation through AMPK/AKT/mTOR pathway. Besides, TFEB nuclear translocation in macrophage was triggered by HY-SDT to promote autophagy activation and lysosome regeneration which enhanced lipid degradation in response to atherogenic lipid stressors. Moreover, following HY-SDT, the ABCA1 expression level was increased to promote lipid efflux in macrophage, and the expression levels of CD36 and SR-A were decreased to inhibit lipid uptake, both of which were prevented by TFEB knockdown. These results indicated that TFEB nuclear translocation activated by HY-SDT was not only the key regulator of autophagy activation and lysosome regeneration in macrophage to promote lipolysis, but also had a crucial role in reverse cholesterol transporters to decrease lipid uptake and increase lipid efflux. Reactive oxygen species (ROS) were adequately generated in macrophage by HY-SDT. Further, ROS scavenger N-acetyl-l-cysteine abolished HY-SDT-induced TFEB nuclear translocation and autophagy activation, implying that ROS were the primary upstream factors responsible for these effects during HY-SDT. In summary, our data indicate that HY-SDT decreases lipid content in macrophage by promoting ROS-dependent nuclear translocation of TFEB to influence consequent autophagy activation and cholesterol transporters. Thus, HY-SDT may be beneficial for atherosclerosis via TFEB regulation to ameliorate lipid overload in atherosclerotic plaques.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Hypericin-mediated sonodynamic therapy induces autophagy and decreases lipids in THP-1 macrophage by promoting ROS-dependent nuclear translocation of TFEB

Zhang

Zheng

et al. 2016

Cell Death Dis

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“…In this setting autophagy plays a positive role by promoting the clearance of intracellular lipid stores. In this condition, promoting autophagy by inhibiting mTORC1 with rapalogues or Raptor deletion reduces disease incidence that is associated with diminished chemokine gene expression and increased plasma LDL (Wang et al, 2014). There is reason to believe therefore that targeted inhibition of mTORC1 in macrophages could aid in preventing artherosclerosis.…”

Section: Mtor In the Innate Immune Systemmentioning

confidence: 99%

MenTORing Immunity: mTOR Signaling in the Development and Function of Tissue-Resident Immune Cells

2017

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Tissue-resident immune cells must balance survival in peripheral tissues with the capacity to respond rapidly upon infection or tissue damage, and in turn couple these responses with intrinsic metabolic control and conditions in the tissue microenvironment. The serine/threonine kinase mammalian/mechanistic target of rapamycin (mTOR) is a central integrator of extracellular and intracellular growth signals and cellular metabolism and plays important roles in both innate and adaptive immune responses. This review discusses the function of mTOR signaling in the differentiation and function of tissue-resident immune cells, with focus on the role of mTOR as a metabolic sensor and its impact on metabolic regulation in innate and adaptive immune cells. We also discuss the impact of metabolic constraints in tissues on immune homeostasis and disease, and how manipulating mTOR activity with drugs such as rapamycin can modulate immunity in these contexts.

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“…Upregulation of mTOR and p-mTOR protein is observed in macrophage-derived foam cells, whereas blocking mTOR expression with specific siRNA suppresses foam cell formation. 51 Thus, autophagy promotes cholesterol efflux from macrophage foam cells, thereby contributing to the regression of atherosclerotic plaques. 52 Along these lines, PPM1D phosphatase deficiency may prevent foam cell formation and ultimately plaque development by activation of autophagy-dependent cholesterol efflux via an ATM-dependent inhibition of mTOR.…”

Section: Autophagy Has Diverse Effects In Atherosclerotic Plaquesmentioning

confidence: 99%

Autophagy in Vascular Disease

Meyer

Grootaert

Michiels

et al. 2015

Circulation Research

239

179

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A utophagy is a complex intracellular process that delivers cytoplasmic constituents for degradation into lysosomes.1,2 Three main types of autophagy have been described: (1) microautophagy, comprising direct engulfment of cytoplasmic material by lysosomes via inward invaginations of the lysosomal membrane, (2) macroautophagy, characterized by formation of double-membrane sequestering compartments termed autophagosomes that fuse with lysosomes for delivery of cytoplasmic cargo, and (3) chaperone-mediated autophagy, mediated by a chaperone complex and lysosomal-associated membrane protein type 2A to degrade cytosolic proteins with a specific targeting motif. The term autophagy usually refers to macroautophagy, which is the most prevalent and beststudied form of autophagy. Also in this review, we will focus exclusively on macroautophagy, further cited as autophagy.Autophagy occurs at basal levels in most tissues to allow constitutive turnover of cytosolic components but is stimulated by environmental stress-related signals (eg, nutrient deprivation and oxidative injury) to recycle nutrients and to generate energy for maintenance of cell viability in unfavorable conditions.1 In addition to cellular stress, basal autophagy can be intensified by specific drugs, 3 indicating that the autophagic machinery is a potential therapeutic target for diverse diseases. Indeed, given that autophagy is involved in the prevention

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mTOR Enhances Foam Cell Formation by Suppressing the Autophagy Pathway

Cited by 46 publications

References 34 publications

Hypericin-mediated sonodynamic therapy induces autophagy and decreases lipids in THP-1 macrophage by promoting ROS-dependent nuclear translocation of TFEB

Hypericin-mediated sonodynamic therapy induces autophagy and decreases lipids in THP-1 macrophage by promoting ROS-dependent nuclear translocation of TFEB

MenTORing Immunity: mTOR Signaling in the Development and Function of Tissue-Resident Immune Cells

Autophagy in Vascular Disease

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