Poly-ion complex micelles effectively deliver CoA-conjugated CPT1A inhibitors to modulate lipid metabolism in brain cells

Paraiso, West Kristian D.; García-Chica, Jesús; Ariza, Xavier; Zagmutt, Sebastián; Fukushima, Shigeto; García, Jordi; Mochida, Yuki; Serra, Dolors; Herrero, Laura; Kinoh, Hiroaki; Casals, Núria Camps; Kataoka, Kazunori; Rodríguez‐Rodríguez, Rosalía; Quader, Sabina

doi:10.1039/d1bm00689d

Cited by 11 publications

(13 citation statements)

References 62 publications

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“…Furthermore, inhibition of carnitine palmitoyltransferase I (CPT-1), inhibition of the mitochondrial respiratory chain, and disruption of mitochondrial DNA can all result in indirect inhibition of β-oxidation [37,[42][43][44]. The role of CPT1A, which is found in the outer mitochondrial membrane, is to transform lipid acyl-coenzyme A into lipoyl carnitine and coenzyme A, a key component of lipid metabolism that catalyzes the initial stage of fatty acid oxidation [45,46]. SLC27A2 and SLC27A5 are the fatty acid transport proteins in hepatocytes [47].…”

Section: Discussionmentioning

confidence: 99%

Psoraleae Fructus Ethanol Extract Induced Hepatotoxicity via Impaired Lipid Metabolism Caused by Disruption of Fatty Acid β-Oxidation

Guo

Shi

Jiang

et al. 2023

Oxidative Medicine and Cellular Longevity

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Herb-induced liver injury (HILI) is gradually increasing, and Psoraleae Fructus (PF) has been reported to induce hepatotoxicity. However, its underlying toxicity mechanism has been only poorly revealed. In this paper, we attempted to explore the liver injury and mechanism caused by Psoraleae Fructus ethanol extract (PFE). First, we administered PFE to mice for 4 weeks and evaluated their serum liver function indices. H&E staining was performed to observe the pathological changes of the livers. Oil red O staining was used to visualize hepatic lipids. Serum-untargeted metabolomics and liver proteomics were used to explore the mechanism of PF hepatotoxicity, and transmission electron microscopy was determined to assess mitochondria and western blot to determine potential target proteins expression. The results showed that PFE caused abnormal liver biochemical indicators and liver tissue injury in mice, and there was substantial fat accumulation in liver tissue in this group. Furthermore, metabolomic analysis showed that PFE changed bile acid synthesis, lipid metabolism, etc., and eight metabolites, including linoleic acid, which could be used as potential biomarkers of PFE hepatotoxicity. Proteomic analysis revealed that differential proteins were clustered in the mitochondrial transmembrane transport, the long-chain fatty acid metabolic process and purine ribonucleotide metabolic process. Multiomics analysis showed that eight pathways were enriched in both metabolomics and proteomics, such as bile secretion, unsaturated fatty acid biosynthesis, and linoleic acid metabolism. The downregulation of SLC27A5, CPT1A, NDUFB5, and COX6A1 and upregulation of cytochrome C and ABCC3 expressions also confirmed the impaired fatty acid oxidative catabolism. Altogether, this study revealed that PFE induced hepatotoxicity by damaging mitochondria, reducing fatty acid β-oxidation levels, and inhibiting fatty acids ingested by bile acids.

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Section: Discussionmentioning

confidence: 99%

Psoraleae Fructus Ethanol Extract Induced Hepatotoxicity via Impaired Lipid Metabolism Caused by Disruption of Fatty Acid β-Oxidation

Guo

Shi

Jiang

et al. 2023

Oxidative Medicine and Cellular Longevity

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“…The combination of CPT1C inhibitors with DOX and PARP1 inhibitors, could be advantageous for HER2- patients and should require further research. Our group is developing nanomedicine strategies to target CPT1 proteins with potential use in tumors [ 54 ].…”

Section: Discussionmentioning

confidence: 99%

Cpt1c Downregulation Causes Plasma Membrane Remodelling and Anthracycline Resistance in Breast Cancer

Muley

Valencia

Casas

et al. 2023

IJMS

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Breast cancer (BC) is the most common malignancy in women worldwide. While the main systemic treatment option is anthracycline-containing chemotherapy, chemoresistance continues to be an obstacle to patient survival. Carnitine palmitoyltransferase 1C (CPT1C) has been described as a poor-prognosis marker for several tumour types, as it favours tumour growth and hinders cells from entering senescence. At the molecular level, CPT1C has been associated with lipid metabolism regulation and important lipidome changes. Since plasma membrane (PM) rigidity has been associated with reduced drug uptake, we explored whether CPT1C expression could be involved in PM remodelling and drug chemoresistance. Liquid chromatography-high resolution mass spectrometry (LC-HRMS) lipid analysis of PM-enriched fractions of MDA-MB-231 BC cells showed that CPT1C silencing increased PM phospholipid saturation, suggesting a rise in PM rigidity. Moreover, CPT1C silencing increased cell survival against doxorubicin (DOX) treatment in different BC cells due to reduced drug uptake. These findings, further complemented by ROC plotter analysis correlating lower CPT1C expression with a lower pathological complete response to anthracyclines in patients with more aggressive types of BC, suggest CPT1C as a novel predictive biomarker for BC chemotherapy.

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“…To track its cellular uptake, we prepared PMs from a fluorescent derivative of CoA, Fluor-CoA, 28 with a size profile similar to (±)-C75-CoA-PM (Fig. S4A, ESI †).…”

Section: Papermentioning

confidence: 99%

“…27 We used this particular property in designing a poly-ion complex (PIC) micelle, a polymeric formulation that allows for a direct and specific cellular transport of (±)-C75-CoA, demonstrating an efficient inhibition of CPT1A-dependent lipid metabolism in cellular models of neurons and glioma cells. 28 In the present study, we have developed a more robust core-crosslinked polymeric micelle (PM)-type nano-medicine, with a high entrapment efficiency of the specific CPT1A inhibitor (±)-C75-CoA (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

Nanomedicine targeting brain lipid metabolism as a feasible approach for controlling the energy balance

et al. 2023

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Poly-ion complex micelles effectively deliver CoA-conjugated CPT1A inhibitors to modulate lipid metabolism in brain cells

Abstract: Carnitine palmitoyltransferase 1A (CPT1A) is a central player in lipid metabolism, catalyzing the first committed step to fatty acid oxidation (FAO). Inhibiting CPT1A, especially in the brain, can have several...

Cited by 11 publications

References 62 publications

Psoraleae Fructus Ethanol Extract Induced Hepatotoxicity via Impaired Lipid Metabolism Caused by Disruption of Fatty Acid β-Oxidation

Psoraleae Fructus Ethanol Extract Induced Hepatotoxicity via Impaired Lipid Metabolism Caused by Disruption of Fatty Acid β-Oxidation

Cpt1c Downregulation Causes Plasma Membrane Remodelling and Anthracycline Resistance in Breast Cancer

Nanomedicine targeting brain lipid metabolism as a feasible approach for controlling the energy balance

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