CPT1 regulates the proliferation of pulmonary artery smooth muscle cells through the AMPK-p53-p21 pathway in pulmonary arterial hypertension

Zhuang, Wenxin; Lian, Guili; Huang, Bangbang; Du, Apang; Gong, Jin; Xiao, Genfa; Xu, Changsheng; Wang, Huajun; Xie, Liangdi

doi:10.1007/s11010-018-3480-z

Cited by 48 publications

(42 citation statements)

References 44 publications

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“…Previous research uncovered that CPT1A-dependent FAO plays an important role in the cell cycle progression of CRC cells 29 and targeting CPT1A induced a cell cycle arrest 30 . Our study found etomoxir indeed blocking FAO pathway by decreasing the expression of long-chain-acyl-CoA dehydrogenase (ACADL), which is another enzyme of fatty acid oxidation (FAO).…”

Section: Resultsmentioning

confidence: 99%

Simultaneously targeting SOAT1 and CPT1A ameliorates hepatocellular carcinoma by disrupting lipid homeostasis

Ren

Xiao

et al. 2021

Cell Death Discov.

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Lipid homeostasis plays a fundamental role in the development of hepatocellular carcinoma (HCC). However, the mechanisms that regulate lipid homeostasis to avoid lipotoxicity in HCC remain elusive. Here, we found high-fat diet (HFD) improved the expression of sterol o-acyltransferase1 (SOAT1) and carnitine palmitoyltransferase 1A (CPT1A) in diethylnitrosamine-induced HCC. Bioinformatic analysis showed that SOAT1-mediated fatty acid storage and CPT1A-mediated fatty acids oxidation (FAO) formed a double-negative feedback loop in HCC. We verified that SOAT1 inhibition enhanced CPT1A protein, which shuttled the released fatty acids into the mitochondria for oxidation in vivo and in vitro. Besides, we further confirmed that CPT1A inhibition converted excess fatty acids into lipid drops by SOAT1 in vitro. Simultaneously targeting SOAT1 and CPT1A by the small-molecule inhibitors avasimibe and etomoxir had synergistic anticancer efficacy in HCC in vitro and in vivo. Our study provides new mechanistic insights into the regulation of lipid homeostasis and suggests the combination of avasimibe and etomoxir is a novel strategy for HCC treatment.

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Section: Resultsmentioning

confidence: 99%

Simultaneously targeting SOAT1 and CPT1A ameliorates hepatocellular carcinoma by disrupting lipid homeostasis

Ren

Xiao

et al. 2021

Cell Death Discov.

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“…The SD rats were anesthetized with 30 mg/kg sodium pentobarbital and killed by cervical dislocation. The isolation of PASMCs from the pulmonary arterioles was described in our previous study [ 14 ]. The identification of PASMCs was performed by staining of α-smooth muscle actin (α-SMA), a specific biomarker for vascular smooth muscle cells, using α-SMA antibody (Abcam, USA, 1:200).…”

Section: Methodsmentioning

confidence: 99%

“…The cell proliferation was assessed by measurement of proliferating cell nuclear antigen (PCNA) expression by western blot and methyl thiazolyl tetrazolium bromide (MTT) assay. The MTT assay has been used in our previous study [ 14 ]. Briefly, PASMCs were seeded in the 96-well plates at a density of 1 × 10 4 per well and cultured for 24 h. After treatment with the indicated reagents including TPEN (Sigma-Aldrich, USA) and FK506 (MedChemExpress LLC, USA), 20 μl MTT (5 mg/ml; Solarbio, Shanghai, China) was added to each well for 4 h of incubation.…”

Section: Methodsmentioning

confidence: 99%

“…Immunofluorescence staining was described previously [ 14 ]. The deparaffinized and dehydrated sections (5 μm) from lung tissues or glass coverslips with cells were fixed with 4% formaldehyde in phosphate buffer saline (PBS) for 10 min at room temperature.…”

Section: Methodsmentioning

confidence: 99%

“…Previously, we have showed the important role of CPT1, a CREB target gene, in regulating PASMC proliferation in PH [ 14 ]. In the present study, we applied a series of techniques, such as bioinformatics analysis, western blot and luciferase reporter assay to explore the expression and regulation of CREB in PH, aiming to provide a full understanding of the CREB pathway in proliferation of PASMCs.…”

Section: Introductionmentioning

confidence: 99%

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Zinc-mediated activation of CREB pathway in proliferation of pulmonary artery smooth muscle cells in pulmonary hypertension

et al. 2021

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Background Transcription factor CREB is involved in the development of pulmonary hypertension (PH). However, little is known about the role and regulatory signaling of CREB in PH. Methods A series of techniques, including bioinformatics methods, western blot, cell proliferation and luciferase reporter assay were used to perform a comprehensive analysis of the role and regulation of CREB in proliferation of pulmonary artery smooth muscle cells (PASMCs) in PH. Results Using bioinformatic analysis of the differentially expressed genes (DEGs) identified in the development of monocrotaline (MCT)- and hypoxia-induced PH, we found the overrepresentation of CRE-containing DEGs. Western blot analysis revealed a sustained increase in total- and phosphorylated-CREB in PASMCs isolated from rats treated with MCT. Similarly, an enhanced and prolonged serum-induced CREB phosphorylation was observed in hypoxia-pretreated PASMCs. The sustained CREB phosphorylation in PASMCs may be associated with multiple protein kinases phosphorylated CREB. Additionally, hierarchical clustering analysis showed reduced expression of the majority of CREB phosphatases in PH, including regulatory subunits of PP2A, Ppp2r2c and Ppp2r3a. Cell proliferation analysis showed increased PASMCs proliferation in MCT-induced PH, an effect relied on CREB-mediated transcriptional activity. Further analysis revealed the raised intracellular labile zinc possibly from ZIP12 was associated with reduced phosphatases, increased CREB-mediated transcriptional activity and PASMCs proliferation. Conclusions CREB pathway was overactivated in the development of PH and contributed to PASMCs proliferation, which was associated with multiple protein kinases and/or reduced CREB phosphatases and raised intracellular zinc. Thus, this study may provide a novel insight into the CREB pathway in the pathogenesis of PH.

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Metabolic Reprogramming in Cancer

Prusty

Manna

2022

Drug Metabolism Handbook

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CPT1 regulates the proliferation of pulmonary artery smooth muscle cells through the AMPK-p53-p21 pathway in pulmonary arterial hypertension

Cited by 48 publications

References 44 publications

Simultaneously targeting SOAT1 and CPT1A ameliorates hepatocellular carcinoma by disrupting lipid homeostasis

Simultaneously targeting SOAT1 and CPT1A ameliorates hepatocellular carcinoma by disrupting lipid homeostasis

Zinc-mediated activation of CREB pathway in proliferation of pulmonary artery smooth muscle cells in pulmonary hypertension

Metabolic Reprogramming in Cancer

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