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

Abstract

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.

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

“…This is consistent with the lipoatrophic phenotype observed in the two patients carrying de novo EPHX1 pathogenic variants. Such an adipocyte differentiation defect has been reported in several other lipoatrophic diabetes of various genetic origins ( Akinci et al, 2018a ; Capel et al, 2018 ; Sollier et al, 2021 ). Lipoatrophic diabetes are indeed characterized by an incapacity of adipose tissue to store triglycerides, leading to ectopic fat depots and insulin resistance.…”

Identification of Co-Expression Network Correlated With Different Periods of Adipogenic and Osteogenic Differentiation of BMSCs by Weighted Gene Co-Expression Network Analysis (WGCNA)

“…Other hub genes in module red, such as LIPE, had intimate interactions with these validated biomarkers, suggesting their unignorable position during the late stage of adipogenesis. LIPE, a kind of lipase encoding gene, has been reported to be involved in various lipid metabolism-related syndrome (Sollier et al, 2021;Wu et al, 2017). However, few study reports the relationship between LIPE and adipogenic differentiation.…”

Rare Forms of Lipomatosis: Dercum’s Disease and Roch-Leri Mesosomatous Lipomatosis

“…Madelung disease, also known as Launois-Bensaude syndrome, is a form of multiple symmetric lipomatosis that is mainly localized in the upper body (shoulders, neck, head) and occurs preferentially in men with chronic excessive alcohol consumption. Multiple deletions of mitochondrial DNA, MERRF, LIPE, and MNF2 mutations have been identified in non-alcoholic cases [47]. The mutation described in Launois-Bensaude syndrome (mitochondrial DNA) has never been reported in cases of Dercum's disease [20].…”