Lipodystrophic syndromes: From diagnosis to treatment

Sollier, Camille; Vatier, Camille; Capel, Émilie; Lascols, Olivier; Auclair, Martine; Janmaat, Sonja; Fève, Bruno; Jéru, Isabelle; Vigouroux, Corinne

doi:10.1016/j.ando.2019.10.003

Cited by 32 publications

(32 citation statements)

References 51 publications

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“…In accordance, the insulin-mediated signaling pathways were strongly impaired in cells harboring pathogenic LIPE variants. All these data were in agreement with the pathophysiology of other geneticallydetermined lipodystrophic syndromes, which is mainly driven by primary defects in differentiation, maintenance and/or functions of adipocytes (30). The mechanistic link between HSL deficiency and adipocyte differentiation defects remains to be clarified.…”

Section: Discussionsupporting

confidence: 85%

LIPE-related lipodystrophic syndrome: clinical features and disease modeling using adipose stem cells

Sollier

Capel

Aguilhon

et al. 2021

European Journal of Endocrinology

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Objective The term Multiple Symmetric Lipomatosis (MSL) describes a heterogeneous group of rare monogenic disorders and multifactorial conditions, characterized by upper-body adipose masses. Biallelic variants in LIPE encoding hormone sensitive lipase (HSL), a key lipolytic enzyme, were implicated in three families worldwide. We aimed to further delineate LIPE-related clinical features and pathophysiological determinants. Methods A gene panel was used to identify pathogenic variants. The disease features were reviewed at the French lipodystrophy reference center. The immunohistological, ultrastructural, and protein expression characteristics of lipomatous tissue were determined in surgical samples from one patient. The functional impact of variants was investigated by developing a model of adipose stem cells (ASCs) isolated from lipomatous tissue. Results We identified new biallelic LIPE null variants in three unrelated patients referred for MSL and/or partial lipodystrophy. The hallmarks of the disease, appearing in adulthood, included lower-limb lipoatrophy, upper-body and abdominal pseudolipomatous masses, diabetes and/or insulin resistance, hypertriglyceridemia, liver steatosis, high blood pressure, and neuromuscular manifestations. Ophthalmological investigations revealed numerous auto-fluorescent drusen-like retinal deposits in all patients. Lipomatous tissue and patient ASCs showed loss of HSL and decreased expression of adipogenic and mature adipocyte markers. LIPE-mutated ASCs displayed impaired adipocyte differentiation, decreased insulin response, defective lipolysis, and mitochondrial dysfunction. Conclusions Biallelic LIPE null variants result in a multisystemic disease requiring multidisciplinary care. Loss of HSL expression impairs adipocyte differentiation, consistent with the lipodystrophy/MSL phenotype and associated metabolic complications. Detailed ophthalmological examination could reveal retinal damage, further pointing to the nervous tissue as an important disease target.

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Section: Discussionsupporting

confidence: 85%

LIPE-related lipodystrophic syndrome: clinical features and disease modeling using adipose stem cells

Sollier

Capel

Aguilhon

et al. 2021

European Journal of Endocrinology

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“…About 30 genes have been implicated in lipoatrophic diabetes ( Brown et al, 2016 ). Although these disorders remain genetically unexplained in the vast majority of cases, there is growing interest in identifying their molecular and cellular bases to improve genetic counseling and personalize treatment ( Letourneau and Greeley, 2018 ; Sollier et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

EPHX1 mutations cause a lipoatrophic diabetes syndrome due to impaired epoxide hydrolysis and increased cellular senescence

Gautheron

Morisseau

Chung

et al. 2021

eLife

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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.

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“…About 30 genes have been implicated in lipoatrophic diabetes (11). Although these disorders remain genetically unexplained in the vast majority of cases, there is growing interest in identifying their molecular and cellular bases to improve genetic counseling and personalize treatment (12, 13).…”

Section: Introductionmentioning

confidence: 99%

EPHX1 mutations cause a lipoatrophic diabetes syndrome due to impaired epoxide hydrolysis and increased cellular senescence

Gautheron

Morisseau

Chung

et al. 2021

Preprint

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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 remains 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. A major beneficial effect of metreleptin therapy was observed. This translational study highlights the importance of epoxide regulation for adipocyte function, and provides new insights into the physiological roles of EHs in humans.

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Lipodystrophic syndromes: From diagnosis to treatment

Cited by 32 publications

References 51 publications

LIPE-related lipodystrophic syndrome: clinical features and disease modeling using adipose stem cells

LIPE-related lipodystrophic syndrome: clinical features and disease modeling using adipose stem cells

EPHX1 mutations cause a lipoatrophic diabetes syndrome due to impaired epoxide hydrolysis and increased cellular senescence

EPHX1 mutations cause a lipoatrophic diabetes syndrome due to impaired epoxide hydrolysis and increased cellular senescence

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