EPHX1 mutations cause a lipoatrophic diabetes syndrome due to impaired epoxide hydrolysis and increased cellular senescence.
Elife
; 102021 08 03.
Article
em En
| MEDLINE
| ID: mdl-34342583
ABSTRACT
Epoxide hydrolases (EHs) regulate cellular homeostasis through hydrolysis of epoxides to less-reactive diols. The first discovered EH was EPHX1, also known as mEH. EH functions remain partly unknown, and no pathogenic variants have been reported in humans. We identified two de novo variants located in EPHX1 catalytic site in patients with a lipoatrophic diabetes characterized by loss of adipose tissue, insulin resistance, and multiple organ dysfunction. Functional analyses revealed that these variants led to the protein aggregation within the endoplasmic reticulum and to a loss of its hydrolysis activity. CRISPR-Cas9-mediated EPHX1 knockout (KO) abolished adipocyte differentiation and decreased insulin response. This KO also promoted oxidative stress and cellular senescence, an observation confirmed in patient-derived fibroblasts. Metreleptin therapy had a beneficial effect in one patient. This translational study highlights the importance of epoxide regulation for adipocyte function and provides new insights into the physiological roles of EHs in humans.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Senescência Celular
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Diabetes Mellitus Lipoatrófica
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Epóxido Hidrolases
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Compostos de Epóxi
Limite:
Adolescent
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Adult
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Female
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Humans
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article