RESUMEN
X-linked adrenoleukodystrophy (ALD) is a progressive neurodegenerative disease caused by mutations in ABCD1, the peroxisomal very long-chain fatty acid (VLCFA) transporter. ABCD1 deficiency results in accumulation of saturated VLCFAs. A drug screen using a phenotypic motor assay in a zebrafish ALD model identified chloroquine as the top hit. Chloroquine increased expression of stearoyl-CoA desaturase-1 (scd1), the enzyme mediating fatty acid saturation status, suggesting that a shift toward monounsaturated fatty acids relieved toxicity. In human ALD fibroblasts, chloroquine also increased SCD1 levels and reduced saturated VLCFAs. Conversely, pharmacological inhibition of SCD1 expression led to an increase in saturated VLCFAs, and CRISPR knockout of scd1 in zebrafish mimicked the motor phenotype of ALD zebrafish. Importantly, saturated VLCFAs caused ER stress in ALD fibroblasts, whereas monounsaturated VLCFA did not. In parallel, we used liver X receptor (LXR) agonists to increase SCD1 expression, causing a shift from saturated toward monounsaturated VLCFA and normalizing phospholipid profiles. Finally, Abcd1-/y mice receiving LXR agonist in their diet had VLCFA reductions in ALD-relevant tissues. These results suggest that metabolic rerouting of saturated to monounsaturated VLCFAs may alleviate lipid toxicity, a strategy that may be beneficial in ALD and other peroxisomal diseases in which VLCFAs play a key role.
Asunto(s)
Adrenoleucodistrofia/enzimología , Cloroquina/farmacología , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Receptores X del Hígado/agonistas , Estearoil-CoA Desaturasa/biosíntesis , Proteínas de Pez Cebra/metabolismo , Miembro 1 de la Subfamilia D de Transportador de Casetes de Unión al ATP/genética , Miembro 1 de la Subfamilia D de Transportador de Casetes de Unión al ATP/metabolismo , Adrenoleucodistrofia/tratamiento farmacológico , Adrenoleucodistrofia/genética , Animales , Línea Celular , Ácidos Grasos/metabolismo , Humanos , Receptores X del Hígado/genética , Receptores X del Hígado/metabolismo , Ratones , Ratones Noqueados , Mutación , Estearoil-CoA Desaturasa/genética , Pez Cebra , Proteínas de Pez Cebra/genéticaRESUMEN
PURPOSE OF REVIEW: There is convincing evidence for benefit from lung-protective mechanical ventilation with lower tidal volumes in patients with the acute respiratory distress syndrome (ARDS). It is uncertain whether this strategy benefits critically ill patients without ARDS as well. This manuscript systematically reviews recent preclinical studies of ventilation in animals with uninjured lungs, and clinical trials of ventilation in ICU patients without ARDS on the association between tidal volume size and pulmonary complications and outcome. RECENT FINDINGS: Successive preclinical studies almost without exception show that ventilation with lower tidal volumes reduces the injurious effects of ventilation in animals with uninjured lungs. This finding is in line with results from recent trials in ICU patients without ARDS, demonstrating that ventilation with lower tidal volumes has a strong potential to prevent development of pulmonary complications and maybe even to improve survival. However, evidence mostly comes from nonrandomized clinical trials, and concerns are expressed regarding unselected use of lower tidal volumes in the ICU, that is, in all ventilated critically ill patients, since this strategy could also increase needs for sedation and/or neuromuscular blockade, and maybe even cause respiratory muscle fatigue. These all then could in fact worsen outcome, possibly counteracting the beneficial effects of ventilation with lower tidal volumes. SUMMARY: Ventilation with lower tidal volumes protects against pulmonary complications, but well-powered randomized controlled trials are urgently needed to determine whether this ventilation strategy truly benefits all ventilated ICU patients without ARDS.
