Age-Related Lipid Metabolic Signature in Human LMNA-Lipodystrophic Stem Cell-Derived Adipocytes.

Abstract

CONTEXT:

Lamin A (LMNA)-linked lipodystrophies belong to a group of clinical disorders characterized by a redistribution of adipose tissue with a variable range of metabolic complications. The leading cause of these disorders is the nonphysiological accumulation of the lamin A precursor, prelamin A. However, the molecular mechanisms by which prelamin A induces the pathology remain unclear.

OBJECTIVE:

The aim of this study is to use an experimental LMNA-lipodystrophy model based on human mesenchymal stem cell (hMSC)-derived adipocytes that accumulate prelamin A to gain deeper insights into the mechanisms governing these diseases.

DESIGN/SETTING/PARTICIPANTS:

Prelamin A-induced or -noninduced hMSC-derived adipocytes were obtained from healthy donors. The study was performed at the Biocruces Health Research Institute.

MAIN OUTCOME MEASURES:

Lipolytic activity was determined by the measurement of glycerol and free fatty acids. Ultrastructural analysis was performed by electron microscopy. Flow cytometry was used to assess mitochondrial membrane potential, and ultra-performance liquid chromatography coupled to mass spectrometry was used to explore lipid profiles.

RESULTS:

Prelamin A accumulating hMSC-derived adipocytes revealed increased lipolysis, mitochondrial dysfunction, and endoplasmic reticulum stress. Accumulation of prelamin A induces an altered lipid profile characterized by reduced diacylglyceride content, a higher ratio of monounsaturated over polyunsaturated fatty acids, and decreased stearoyl-coenzyme A desaturase-1 activity. In contrast, the ratio of diacylglycerophosphatidylcholine over diacylglycerophosphatidylethanolamine and the activity of phosphatidylethanolamine-methyltransferase were increased.

CONCLUSIONS:

Prelamin A accumulation causes mitochondrial dysfunction, endoplasmic reticulum stress, and altered lipid metabolism resembling a premature aging phenotype.

• Authors: Patricia Sánchez, Arantza Infante, Garbiñe Ruiz de Eguino, Jorge A Fuentes-Maestre, José Manuel García-Verdugo, Clara I Rodríguez
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 100 Issue 7 Pg. E964-73 (Jul 2015) ISSN: 1945-7197 [Electronic] United States
• PMID: 25961135 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• LMNA protein, human
• Lamin Type A

Topics

• Adipocytes (metabolism, physiology)
• Adolescent
• Adult
• Aging (metabolism)
• Cell Differentiation
• Female
• Humans
• Lamin Type A (genetics)
• Lipid Metabolism
• Lipodystrophy (genetics, metabolism, pathology)
• Lipolysis
• Male
• Metabolome
• Metabolomics
• Middle Aged
• Stem Cells (pathology, physiology)
• Young Adult