Impact of Combined Baricitinib and FTI Treatment on Adipogenesis in Hutchinson-Gilford Progeria Syndrome and Other Lipodystrophic Laminopathies

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disease that causes premature aging symptoms, such as vascular diseases, lipodystrophy, loss of bone mineral density, and alopecia. HGPS is mostly linked to a heterozygous and de novo mutation in the LMNA gene (c.1824 C > T; p.G608G),...

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Published in:Cells (Basel, Switzerland) Switzerland), 2023-05, Vol.12 (10), p.1350
Main Authors: Hartinger, Ramona, Lederer, Eva-Maria, Schena, Elisa, Lattanzi, Giovanna, Djabali, Karima
Format: Article
Language:English
Subjects:
Abdomen
Adipocytes
Adipogenesis
Amino acids
Apoptosis
baricitinib
Body fat
Bone mineral density
Cell cycle
Diagnosis
Dosage and administration
Drug therapy
Drug therapy, Combination
Enzymes
Genetic disorders
Humans
Inflammation
Insulin resistance
lamin A
Lipodystrophy
Lipodystrophy - drug therapy
lonafarnib
Metabolism
Mortality
Mutation
Patient outcomes
Progeria
Progeria - genetics
progerin
Senescence
Skin
Thermogenesis
Vascular diseases
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Summary:Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disease that causes premature aging symptoms, such as vascular diseases, lipodystrophy, loss of bone mineral density, and alopecia. HGPS is mostly linked to a heterozygous and de novo mutation in the LMNA gene (c.1824 C > T; p.G608G), resulting in the production of a truncated prelamin A protein called "progerin". Progerin accumulation causes nuclear dysfunction, premature senescence, and apoptosis. Here, we examined the effects of baricitinib (Bar), an FDA-approved JAK/STAT inhibitor, and a combination of Bar and lonafarnib (FTI) treatment on adipogenesis using skin-derived precursors (SKPs). We analyzed the effect of these treatments on the differentiation potential of SKPs isolated from pre-established human primary fibroblast cultures. Compared to mock-treated HGPS SKPs, Bar and Bar + FTI treatments improved the differentiation of HGPS SKPs into adipocytes and lipid droplet formation. Similarly, Bar and Bar + FTI treatments improved the differentiation of SKPs derived from patients with two other lipodystrophic diseases: familial partial lipodystrophy type 2 (FPLD2) and mandibuloacral dysplasia type B (MADB). Overall, the results show that Bar treatment improves adipogenesis and lipid droplet formation in HGPS, FPLD2, and MADB, indicating that Bar + FTI treatment might further ameliorate HGPS pathologies compared to lonafarnib treatment alone.
ISSN:2073-4409
2073-4409
DOI:10.3390/cells12101350