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1.
Elife ; 132024 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-38602170

RESUMEN

Statins are known to be anti-inflammatory, but the mechanism remains poorly understood. Here, we show that macrophages, either treated with statin in vitro or from statin-treated mice, have reduced cholesterol levels and higher expression of Jmjd3, a H3K27me3 demethylase. We provide evidence that lowering cholesterol levels in macrophages suppresses the adenosine triphosphate (ATP) synthase in the inner mitochondrial membrane and changes the proton gradient in the mitochondria. This activates nuclear factor kappa-B (NF-κB) and Jmjd3 expression, which removes the repressive marker H3K27me3. Accordingly, the epigenome is altered by the cholesterol reduction. When subsequently challenged by the inflammatory stimulus lipopolysaccharide (M1), macrophages, either treated with statins in vitro or isolated from statin-fed mice, express lower levels proinflammatory cytokines than controls, while augmenting anti-inflammatory Il10 expression. On the other hand, when macrophages are alternatively activated by IL-4 (M2), statins promote the expression of Arg1, Ym1, and Mrc1. The enhanced expression is correlated with the statin-induced removal of H3K27me3 from these genes prior to activation. In addition, Jmjd3 and its demethylase activity are necessary for cholesterol to modulate both M1 and M2 activation. We conclude that upregulation of Jmjd3 is a key event for the anti-inflammatory function of statins on macrophages.


Asunto(s)
Colesterol , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Histona Demetilasas con Dominio de Jumonji , Macrófagos , Mitocondrias , Regulación hacia Arriba , Histona Demetilasas con Dominio de Jumonji/metabolismo , Histona Demetilasas con Dominio de Jumonji/genética , Animales , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Colesterol/metabolismo , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Antiinflamatorios/farmacología , Ratones Endogámicos C57BL , Masculino
2.
Cell Chem Biol ; 30(2): 214-229.e18, 2023 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-36758549

RESUMEN

Glioblastoma (GBM) is an aggressive adult brain cancer with few treatment options due in part to the challenges of identifying brain-penetrant drugs. Here, we investigated the mechanism of MM0299, a tetracyclic dicarboximide with anti-glioblastoma activity. MM0299 inhibits lanosterol synthase (LSS) and diverts sterol flux away from cholesterol into a "shunt" pathway that culminates in 24(S),25-epoxycholesterol (EPC). EPC synthesis following MM0299 treatment is both necessary and sufficient to block the growth of mouse and human glioma stem-like cells by depleting cellular cholesterol. MM0299 exhibits superior selectivity for LSS over other sterol biosynthetic enzymes. Critical for its application in the brain, we report an MM0299 derivative that is orally bioavailable, brain-penetrant, and induces the production of EPC in orthotopic GBM tumors but not normal mouse brain. These studies have implications for the development of an LSS inhibitor to treat GBM or other neurologic indications.


Asunto(s)
Glioblastoma , Glioma , Adulto , Humanos , Lanosterol/farmacología , Lanosterol/metabolismo , Encéfalo/metabolismo , Glioma/tratamiento farmacológico , Glioma/metabolismo , Colesterol , Glioblastoma/tratamiento farmacológico
3.
Elife ; 122023 01 25.
Artículo en Inglés | MEDLINE | ID: mdl-36695568

RESUMEN

Most of the cholesterol in the plasma membranes (PMs) of animal cells is sequestered through interactions with phospholipids and transmembrane domains of proteins. However, as cholesterol concentration rises above the PM's sequestration capacity, a new pool of cholesterol, called accessible cholesterol, emerges. The transport of accessible cholesterol between the PM and the endoplasmic reticulum (ER) is critical to maintain cholesterol homeostasis. This pathway has also been implicated in the suppression of both bacterial and viral pathogens by immunomodulatory oxysterols. Here, we describe a mechanism of depletion of accessible cholesterol from PMs by the oxysterol 25-hydroxycholesterol (25HC). We show that 25HC-mediated activation of acyl coenzyme A: cholesterol acyltransferase (ACAT) in the ER creates an imbalance in the equilibrium distribution of accessible cholesterol between the ER and PM. This imbalance triggers the rapid internalization of accessible cholesterol from the PM, and this depletion is sustained for long periods of time through 25HC-mediated suppression of SREBPs and continued activation of ACAT. In support of a physiological role for this mechanism, 25HC failed to suppress Zika virus and human coronavirus infection in ACAT-deficient cells, and Listeria monocytogenes infection in ACAT-deficient cells and mice. We propose that selective depletion of accessible PM cholesterol triggered by ACAT activation and sustained through SREBP suppression underpins the immunological activities of 25HC and a functionally related class of oxysterols.


Asunto(s)
Oxiesteroles , Infección por el Virus Zika , Virus Zika , Animales , Humanos , Ratones , Oxiesteroles/metabolismo , Aciltransferasas/metabolismo , Colesterol/metabolismo , Membrana Celular/metabolismo , Bacterias/metabolismo
4.
Cell Rep ; 41(3): 111493, 2022 10 18.
Artículo en Inglés | MEDLINE | ID: mdl-36261024

RESUMEN

Cells sense stress and initiate response pathways to maintain lipid and protein homeostasis. However, the interplay between these adaptive mechanisms is unclear. Herein, we demonstrate how imbalances in cytosolic protein homeostasis affect intracellular lipid surveillance. Independent of its ancient thermo-protective properties, the heat shock factor, HSF-1, modulates lipid metabolism and age regulation through the metazoan-specific nuclear hormone receptor, NHR-49. Reduced hsf-1 expression destabilizes the Caenorhabditis elegans enteric actin network, subsequently disrupting Rab GTPase-mediated trafficking and cell-surface residency of nutrient transporters. The ensuing malabsorption limits lipid availability, thereby activating the intracellular lipid surveillance response through vesicular release and nuclear translocation of NHR-49 to both increase nutrient absorption and restore lipid homeostasis. Overall, cooperation between these regulators of cytosolic protein homeostasis and lipid surveillance ensures metabolic health and age progression through actin integrity, endocytic recycling, and lipid sensing.


Asunto(s)
Proteínas de Caenorhabditis elegans , Animales , Proteínas de Caenorhabditis elegans/metabolismo , Actinas/metabolismo , Caenorhabditis elegans/metabolismo , Respuesta al Choque Térmico , Factores de Transcripción/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Lípidos , Proteínas de Unión al GTP rab/metabolismo
5.
Sci Adv ; 8(28): eabn5295, 2022 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-35857506

RESUMEN

27-Hydroxycholesterol (27-HC) is the most abundant oxysterol that increases the risk of breast cancer progression. However, little is known about epigenetic regulation of 27-HC metabolism and its role in breast tumor initiation. Using genetic mouse mammary tumor and human breast cancer models, we showed here that the histone reader ZMYND8 was selectively expressed in breast cancer stem cells (BCSCs) and promoted epithelial-mesenchymal transition (EMT), BCSC maintenance and self-renewal, and oncogenic transformation through its epigenetic functions, leading to breast tumor initiation. Mechanistically, ZMYND8 was a master transcriptional regulator of 27-HC metabolism. It increased cholesterol biosynthesis and oxidation but blocked cholesterol efflux and 27-HC catabolism, leading to accumulation of 27-HC in BCSCs. Consequently, 27-HC promoted EMT, oncogenic transformation, and tumor initiation through activation of liver X receptor. These findings reveal that ZMYND8 is an epigenetic booster that drives breast tumor initiation through metabolic reprogramming.


Asunto(s)
Neoplasias de la Mama , Animales , Neoplasias de la Mama/patología , Carcinogénesis/patología , Línea Celular Tumoral , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Colesterol/metabolismo , Epigénesis Genética , Femenino , Humanos , Hidroxicolesteroles , Ratones , Células Madre Neoplásicas/metabolismo
6.
Nature ; 605(7911): 736-740, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35585236

RESUMEN

Imbalances in lipid homeostasis can have deleterious effects on health1,2. Yet how cells sense metabolic demand due to lipid depletion and respond by increasing nutrient absorption remains unclear. Here we describe a mechanism for intracellular lipid surveillance in Caenorhabditis elegans that involves transcriptional inactivation of the nuclear hormone receptor NHR-49 through its cytosolic sequestration to endocytic vesicles via geranylgeranyl conjugation to the small G protein RAB-11.1. Defective de novo isoprenoid synthesis caused by lipid depletion limits RAB-11.1 geranylgeranylation, which promotes nuclear translocation of NHR-49 and activation of rab-11.2 transcription to enhance transporter residency at the plasma membrane. Thus, we identify a critical lipid sensed by the cell, its conjugated G protein, and the nuclear receptor whose dynamic interactions enable cells to sense metabolic demand due to lipid depletion and respond by increasing nutrient absorption and lipid metabolism.


Asunto(s)
Proteínas de Caenorhabditis elegans , Proteínas de Unión al GTP Monoméricas , Animales , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Lípidos , Proteínas de Unión al GTP Monoméricas/metabolismo , Prenilación de Proteína , Receptores Citoplasmáticos y Nucleares/metabolismo
7.
Methods Mol Biol ; 2295: 417-438, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34047991

RESUMEN

Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) has emerged as a major analytical platform for the determination and localization of lipid metabolites directly from tissue sections. Unlike analysis of lipid extracts, where lipid localizations are lost due to homogenization and/ or solvent extraction, MALDI-MSI analysis is capable of revealing spatial localization of metabolites while simultaneously collecting high chemical resolution mass spectra. Important considerations for obtaining high quality MALDI-MS images include tissue preservation, section preparation, MS data collection and data processing. Errors in any of these steps can lead to poor quality metabolite images and increases the chance for metabolite misidentification and/ or incorrect localization. Here, we present detailed methods and recommendations for specimen preparation, MALDI-MS instrument parameters, software analysis platforms for data processing, and practical considerations for each of these steps to ensure acquisition of high-quality chemical and spatial resolution data for reconstructing MALDI-MS images of plant tissues.


Asunto(s)
Lípidos/química , Plantas/química , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodos , Diagnóstico por Imagen/métodos , Técnicas Histológicas/métodos , Procesamiento de Imagen Asistido por Computador/métodos , Metabolismo de los Lípidos/fisiología , Plantas/metabolismo , Programas Informáticos
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