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

in European Journal of Endocrinology
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  • 1 Sorbonne Université, Inserm UMRS_938, Centre de Recherche Saint Antoine, Paris, France
  • 2 CHU de Montpellier, Hôpital Lapeyronie, Service d’Endocrinologie-Diabétologie-Nutrition, and Institut de Génomique Fonctionnelle, CNRS, INSERM, Université de Montpellier, Montpellier, France
  • 3 CHU de Lille, Exploration de la Vision et Neuro-Ophtalmologie, Lille, France
  • 4 Université de Lille, Faculté de Médecine, Lille, France
  • 5 Hopital Huriez-CHU Lille, Service d’Endocrinologie-Diabétologie-Métabolisme, et Hôpital Jeanne de Flandres, Centre de Référence des Maladies Héréditaires du Métabolisme, Clinique de Pédiatrie, Lille, France
  • 6 Hôpital Jean Bernard, Service d’Endocrinologie-Diabétologie, Venciennes, France
  • 7 Inserm U955, Faculté de Médecine, Université Paris-Est, Créteil, France
  • 8 Assistance Publique-Hôpitaux de Paris, Hôpital Saint Antoine, Centre National de Référence des Pathologies Rares de l’Insulino-Sécrétion et de l’Insulino-Sensibilité (PRISIS), Service de Diabétologie et Endocrinologie de la Reproduction, Paris, France
  • 9 Assistance Publique-Hôpitaux de Paris, Hôpital Saint Antoine, Laboratoire commun de Biologie et Génétique Moléculaires, Paris, France

Correspondence should be addressed to C Vigouroux or I Jéru; Email: corinne.vigouroux@inserm.fr or isabelle.jeru@aphp.fr
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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 pseudo-lipomatous 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.

Conslusions

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.

Supplementary Materials

 

     European Society of Endocrinology

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