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1.
Biochim Biophys Acta Mol Basis Dis ; 1870(7): 167283, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-38851305

RESUMEN

Obesity represents a significant health challenge, intricately linked to conditions such as type II diabetes, metabolic syndrome, and hepatic steatosis. Several existing obesity treatments exhibit limited efficacy, undesirable side effects or a limited capability to maintain therapeutics effects in the long-term. Recently, modulation Coenzyme Q (CoQ) metabolism has emerged as a promising target for treatment of metabolic syndrome. This potential intervention could involve the modulation of endogenous CoQ biosynthesis by the use of analogs of the precursor of its biosynthesis, such as ß-resorcylic acid (ß-RA). Here, we show that oral supplementation with ß-RA, incorporated into the diet of diet-induced obese (DIO) mice, leads to substantial weight loss. The anti-obesity effects of ß-RA are partially elucidated through the normalization of mitochondrial CoQ metabolism in white adipose tissue (WAT). Additionally, we identify an HFN4α/LXR-dependent transcriptomic activation of the hepatic lipid metabolism that contributes to the anti-obesity effects of ß-RA. Consequently, ß-RA mitigates WAT hypertrophy, prevents hepatic steatosis, counteracts metabolic abnormalities in WAT and liver, and enhances glucose homeostasis by reducing the insulin/glucagon ratio and plasma levels of gastric inhibitory peptide (GIP). Moreover, pharmacokinetic evaluation of ß-RA supports its translational potential. Thus, ß-RA emerges as an efficient, safe, and translatable therapeutic option for the treatment and/or prevention of obesity, metabolic dysfunction-associated steatotic liver disease (MASLD).


Asunto(s)
Ratones Endogámicos C57BL , Obesidad , Animales , Obesidad/metabolismo , Obesidad/tratamiento farmacológico , Ratones , Masculino , Ubiquinona/análogos & derivados , Ubiquinona/farmacología , Ubiquinona/metabolismo , Ubiquinona/administración & dosificación , Tejido Adiposo Blanco/metabolismo , Tejido Adiposo Blanco/efectos de los fármacos , Tejido Adiposo Blanco/patología , Hígado/metabolismo , Hígado/patología , Metabolismo de los Lípidos/efectos de los fármacos , Administración Oral , Dieta Alta en Grasa/efectos adversos , Humanos
2.
Cell Rep ; 43(5): 114148, 2024 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-38697100

RESUMEN

Coenzyme Q (CoQ) deficiency syndrome is conventionally treated with limited efficacy using exogenous CoQ10. Poor outcomes result from low absorption and bioavailability of CoQ10 and the clinical heterogenicity of the disease. Here, we demonstrate that supplementation with 4-hydroxybenzoic acid (4HB), the precursor of the benzoquinone ring in the CoQ biosynthetic pathway, completely rescues multisystemic disease and perinatal lethality in a mouse model of CoQ deficiency. 4HB stimulates endogenous CoQ biosynthesis in tissues of Coq2 mutant mice, normalizing mitochondrial function and rescuing cardiac insufficiency, edema, and neurodevelopmental delay. In contrast, exogenous CoQ10 supplementation falls short in fully restoring the phenotype. The treatment is translatable to human use, as proven by in vitro studies in skin fibroblasts from patients with pathogenic variants in COQ2. The therapeutic approach extends to other disorders characterized by deficiencies in the production of 4HB and early steps of CoQ biosynthesis and instances of secondary CoQ deficiency.


Asunto(s)
Modelos Animales de Enfermedad , Enfermedades Mitocondriales , Parabenos , Ubiquinona , Animales , Enfermedades Mitocondriales/tratamiento farmacológico , Enfermedades Mitocondriales/patología , Enfermedades Mitocondriales/metabolismo , Parabenos/farmacología , Ubiquinona/análogos & derivados , Ubiquinona/farmacología , Ubiquinona/metabolismo , Ubiquinona/deficiencia , Ratones , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Humanos , Fibroblastos/metabolismo , Fibroblastos/efectos de los fármacos , Ratones Endogámicos C57BL , Debilidad Muscular/tratamiento farmacológico , Debilidad Muscular/metabolismo , Debilidad Muscular/patología , Ataxia/tratamiento farmacológico , Ataxia/patología , Ataxia/metabolismo
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