Impaired Membrane Lipid Homeostasis in Schizophrenia

Abstract

Background and hypothesis: Multiple lines of clinical, biochemical, and genetic evidence suggest that disturbances of membrane lipids and their metabolism are probably involved in the etiology of schizophrenia (SCZ). Lipids in the membrane are essential to neural development and brain function, however, their role in SCZ remains largely unexplored.

Study design: Here we investigated the lipidome of the erythrocyte membrane of 80 patients with SCZ and 40 healthy controls using ultra-performance liquid chromatography-mass spectrometry. Based on the membrane lipids profiling, we explored the potential mechanism of membrane phospholipids metabolism.

Study results: By comparing 812 quantified lipids, we found that in SCZ, membrane phosphatidylcholines and phosphatidylethanolamines, especially the plasmalogen, were significantly decreased. In addition, the total polyunsaturated fatty acids (PUFAs) in the membrane of SCZ were significantly reduced, resulting in a decrease in membrane fluidity. The accumulation of membrane oxidized lipids and the level of peripheral lipid peroxides increased, suggesting an elevated level of oxidative stress in SCZ. Further study of membrane-phospholipid-remodeling genes showed that activation of PLA2s and LPCATs expression in patients, supporting the imbalance of unsaturated and saturated fatty acyl remodeling in phospholipids of SCZ patients.

Conclusions: Our results suggest that the mechanism of impaired membrane lipid homeostasis is related to the activated phospholipid remodeling caused by excessive oxidative stress in SCZ. Disordered membrane lipids found in this study may reflect the membrane dysfunction in the central nervous system and impact neurotransmitter transmission in patients with SCZ, providing new evidence for the membrane lipids hypothesis of SCZ.

Keywords: lipidome; membrane fatty acids; membrane lipids; oxidative stress; phospholipid remodeling; schizophrenia.

Fig. 1.

Predominant lipid classes in RBC membrane. Characterizing the number and diversity of lipids detected in erythrocyte membrane based on classifications in the LipidSearch database. Percentage (%) indicates the proportion of the number of lipids in different classes to the total lipids.

Fig. 2.

Membrane lipids were obviously different between SCZ patients and HCs. (A) The PLS-DA model was used to distinguish RBC membrane lipids between in SCZ patients and in HCs. (B) Percentage of the 11 major lipid classes within the RBC membrane between SCZ patients and HCs (Percentage: mean ± SD; unit: %). (C) Differences in 812 lipids between SCZ patients and HCs (The q-value corrected by FDR).

Fig. 3.

The level of unsaturated fatty acids in the RBC membrane of SCZ patients was decreased, and FA indices differed in SCZ. (A) Membrane lipidome results showed that acyl chains of 11 lipid classes, described by the number of double bonds and chain length. The direction of the fold change and significance by heat map. The bubble size represents the mean of different fatty acyl chain concentration percentages in the same lipid classes in HCs. SFA, MUFA, and PUFA represent the total content of three types of fatty acyl chains in different lipid classes (The q-values were corrected by FDR, q < 0.05). Data in (B-G) represent FA indexes of the membrane, the calculation method please see the additional methods in Supplementary Materials. (B-D) Membrane fluidity indexes: total SFA%/MUFA%, total SFA%/PUFA%, and the lipophilic index. (E). The unsaturation index. (F) The chain length index. (G) The peroxidation index, showing FA susceptibility to peroxidation by calculating the double bond content. The p-values were corrected by two-tailed T-test (P < .05).

Fig. 4.

Impaired membrane lipid homeostasis was related to the increase of oxidative stress and abnormal phospholipid remodeling. (A) Significant changes in oxidized lipids of erythrocyte membrane in SCZ patients (The p-values corrected by Mann-Whitney U-test and the q-values were corrected by FDR, details are in supplementary table S6). (B) The total amount of plasmalogen ethanolamine in SCZ patients was significantly reduced. (FC = 0.91, P-value = 3.51E-06). (C) Plasma lipid peroxides (4-HNE) were significantly elevated in SCZ (FC = 1.49, P = 6.11E-05). (D) The plasma activity of SOD was significantly decreased in SCZ (FC = 0.84, P = .012). (E) The mRNA levels of LPCATs and PLA2s were detected in patients with SCZ (n = 80) and HCs (n = 60). The p-values were calculated based on logistic regression correction for age, BMI and sex. One asterisk indicates the P-value < .05, two asterisks indicate the P-value < .01, three asterisks indicate the P-value < .001, and four asterisks indicate the P-value < .0001.

Fig. 5.

Related mechanisms and pathology of membrane lipid homeostasis disorder in SCZ. Membrane lipid homeostasis was impaired in patients with schizophrenia. Excessive oxidative stress resulted in membrane lipid peroxidation. During the remodeling process of membrane phospholipids, the expression of PLA2s and LPCATs is activated, resulting in an imbalance of SFA and PUFA composition in membrane phospholipids, which further leads to the decrease of membrane fluidity. Disturbance of the membrane-lipid system is pervasive throughout the body of SCZ patients, leading to membrane dysfunction (such as abnormal neurotransmitter transmission between synapses), and subsequent development of schizophrenia. PLs, glycerophospholipids; LPLs, lysophospholipids; OxPLs, oxidized phospholipids; OxFAs, oxidized fatty acids; PLA2s, iPLA2, and cPLA2; LPCATs, LPCAT1, and LPCAT4; 4-HNE, 4-hydroxynonenonic acid; ROS, reactive oxygen species.