Integrated Metabolomics and Lipidomics Reveal High Accumulation of Glycerophospholipids in Human Astrocytes under the Lipotoxic Effect of Palmitic Acid and Tibolone Protection.

Ricardo Cabezas,George E Barreto,Cynthia Martin-Jiménez,Martha Zuluaga,Janneth González,Andrés Pinzón

doi:10.3390/ijms23052474

Abstract

Lipotoxicity is a metabolic condition resulting from the accumulation of free fatty acids in non-adipose tissues which involves a series of pathological responses triggered after chronic exposure to high levels of fatty acids, severely detrimental to cellular homeostasis and viability. In brain, lipotoxicity affects both neurons and other cell types, notably astrocytes, leading to neurodegenerative processes, such as Alzheimer (AD) and Parkinson diseases (PD). In this study, we performed for the first time, a whole lipidomic characterization of Normal Human Astrocytes cultures exposed to toxic concentrations of palmitic acid and the protective compound tibolone, to establish and identify the set of potential metabolites that are modulated under these experimental treatments. The study covered 3843 features involved in the exo- and endo-metabolome extracts obtained from astrocytes with the mentioned treatments. Through multivariate statistical analysis such as PCA (principal component analysis), partial least squares (PLS-DA), clustering analysis, and machine learning enrichment analysis, it was possible to determine the specific metabolites that were affected by palmitic acid insult, such as phosphoethanolamines, phosphoserines phosphocholines and glycerophosphocholines, with their respective metabolic pathways impact. Moreover, our results suggest the importance of tibolone in the generation of neuroprotective metabolites by astrocytes and may be relevant to the development of neurodegenerative processes.

Highlights

Lipotoxicity is a metabolic condition resulting from the accumulation of free fatty acids in non-adipose tissues [1,2]
This condition involves a series of pathological responses triggered after chronic exposure to high levels of fatty acids, which may be detrimental to cellular homeostasis and viability, leading to cellular dysfunction, lipid droplet formation, and cell death [3,4]
This study presents a lipidomic profile of the exo- and endo-metabolome of astrocytic cells, which were generated by means of different treatments: (i) Tibolone; (ii) palmitic acid (PA) and (iii) PA + tibolone

Summary

Introduction

Lipotoxicity is a metabolic condition resulting from the accumulation of free fatty acids in non-adipose tissues [1,2]. The exact mechanisms related to a lipotoxic event have not been thoroughly characterized, this process is a well-known factor present in obesity and neurodegenerative diseases (NDs) [5,6,7] In these aspects, lipotoxicity may affect both neurons and astrocytes in the central nervous system (CNS). Lipid metabolism is crucial to the normal astrocytic function and in neuron-astrocyte crosstalk during processes such membrane fluidity, cell signalling, inflammation, and energy generation During pathological processes such as obesity, ischemia/reoxygenation, multiple sclerosis and Parkinson and Alzheimer diseases, the normal homeostatic functions of the astrocytes are significantly impaired, which can lead to neurodegeneration and related processes [15,16,17]

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Results

Conclusion