Brain-Specific Oxysterols and Risk of Schizophrenia in Clinical High-Risk Subjects and Patients With Schizophrenia

Abstract

Accumulating evidence from clinical, genetic, and epidemiologic studies suggest that schizophrenia might be a neuronal development disorder. While oxysterols are important factors in neurodevelopment, it is unknown whether oxysterols might be involved in development of schizophrenia. The present study investigated the relationship between tissue-specifically originated oxysterols and risk of schizophrenia. A total of 216 individuals were recruited in this study, including 76 schizophrenia patients, 39 clinical high-risk (CHR) subjects, and 101 healthy controls (HC). We investigated the circulating levels of brain-specific oxysterol 24(S)-hydroxycholesterol (24OHC) and peripheral oxysterol 27-hydroxycholesterol (27OHC) in all participants and analyzed the potential links between the oxysterols and specific clinical symptoms in schizophrenic patients and CHR. Our data showed an elevation of 24OHC in both schizophrenia patients and CHR than that in HC, while a lower level of 27OHC in the schizophrenia group only. The ratio of 24OHC to 27OHC was only increased in the schizophrenic group compared with CHR and HC. For the schizophrenic patients, the circulating 24OHC levels are significantly associated with disease duration, positively correlated with the positive and negative syndrome total scores, while the 27OHC levels were inversely correlated with the positive symptom scores. Together, our data demonstrated the disruption of tissue-specifically originated cholesterol metabolism in schizophrenia and CHR, suggesting the circulating 24OHC or 24OHC/27OHC ratio might not only be a potential indicator for risk for schizophrenia but also be biomarkers for functional abnormalities in neuropathology of schizophrenia.

Tissue-Specific Oxysterols as Predictors of Antidepressant (Escitalopram) Treatment Response in Patients With Major Depressive Disorder

“…24OHC plays a critical role in the physiological cholesterol homeostasis within the brain, and abnormal changes in 24OHC levels are associated with diseases such as Alzheimer's disease ( 32 , 33 , 34 ), amyotrophic lateral sclerosis ( 35 ), Parkinson's disease ( 14 ), and autism spectrum disorders ( 36 ). Our previous study also indicated an important role of oxysterols in schizophrenia ( 37 ). However, there have been limited studies on brain cholesterol metabolism in MDD ( 5 , 10 ).…”

“…( 46 ). Plasma oxysterol levels were detected using high-performance liquid chromatography – mass spectrometry as described previously ( 37 ). In general, 50 μL of plasma or standard sample (with 5% bovine serum albumin) was mixed with 200 μL of acidic buffer solution (50 mM ammonium acetate, 1% formic acid, pH 3) and 1 mL methyl tert-butyl ether in a microcentrifuge tube, while 100 ng D5/D7 deuterium cholesterol was spiked in as an internal standard.…”

Peppers in Diet: Genome-Wide Transcriptome and Metabolome Changes in Drosophila melanogaster

“…For instance, the metabolites cholesterol and linoleic acid (both upregulated), and L-tyrosine (downregulated), were associated with schizophrenia. Disturbed cholesterol homeostasis in the brain might increase the risk of many neurodevelopmental disorders [ 48 , 49 ], whereas the level of tyrosine, an essential amino acid, is altered in people with schizophrenia [ 50 ]. Moreover, mannitol was found upregulated on flies fed the pepper diet.…”

Oxysterol-liver X receptor signaling mediates CYFIP1 regulation of cortical neurogenesis

“…Altered oxysterol levels have been described in patients with several neurodegenerative disorders, including Alzheimer's disease, Amyotrophic Lateral Sclerosis, Parkinson's disease, and Huntington's disease [51][52][53] . While investigations into steroldysregulation in neuropsychiatric and neurodevelopmental disorders is in its infancy, changes of plasma 24S-hydroxycholesterol, a primarily neuron derived oxysterol, is found in patients with schizophrenia 54 , ASD 55 , and bipolar disorders 56 .…”