Changes in regulators of lipid metabolism in the brain: a study of animal models of depression and hypothyroidism

Abstract

Metabolic disturbances in the brain are assumed to be early changes involved in the pathogenesis of depression, and these alterations may be intensified by a deficiency of thyroid hormones. In contrast to glucose metabolism, the link between altered brain lipids and the pathogenesis of depression is poorly understood, therefore in the present study, we determine transcription factors and enzymes regulating cholesterol and fatty acid biosynthesis in the brain structures in an animal model of depression, hypothyroidism and the coexistence of these diseases.In used model of depression, a decrease in the active form of the transcription factor SREBP-2 in the hippocampus was demonstrated, thus suggesting a reduction in cholesterol biosynthesis. In turn, in the hypothyroidism model, the reduction of cholesterol biosynthesis in the frontal cortex was demonstrated by both the reduction of mature SREBP-2 and the concentration of enzymes involved in cholesterol biosynthesis. The lower expression of LDL receptors in the frontal cortex indicates the restriction of cholesterol uptake into the cells in the model of coexistence of depression and hypothyroidism. Moreover, the identified changes in the levels of SNAP-25, GLP-1R and GLP-2R pointed to disturbances in synaptic plasticity and neuroprotection mechanisms in the examined brain structures.In conclusion, a reduction in cholesterol synthesis in the hippocampus in the model of depression may be the reason for the reduction of synaptic plasticity, whereas a lower level of LDL-R occurring in the frontal cortex in rats from the model of depression and hypothyroidism coexistence could be the reason of anxiogenic and depression-like behaviors.

St. John's wort extract Ze 117 alters the membrane fluidity of C6 glioma cells by influencing cellular cholesterol metabolism

“…As expected, inhibition of HMG-CoA reductase by simvastatin also reduced the total cholesterol found in C6 cells, indicating the reliability of the experimental setup. Interestingly, Glombik et al 47 found a reduction in sterol regulatory element-binding protein (SREBP-2), a regulator of cholesterol biosynthesis, but no change in SCD in the hippocampi of WKY rats, an animal model for depression, fitting perfectly to the results in our study.…”

“…The 5-HT 1A receptor is a GPCR for which involvement in depression pathology has been shown in multiple studies 51 . In addition, its functionality was demonstrated to be dependent on the cellular cholesterol content 47 , 52 . We therefore investigated whether Ze 117, simvastatin, or dexamethasone not only change the total cellular cholesterol content but also affect the signaling ability of this receptor.…”

Effects of (S)-ketamine on depression-like behaviors in a chronic variable stress model: a role of brain lipidome

“…In the central nervous system (CNS), lipid populations play an increasingly recognized role in the maintenance and modulation of energy metabolism, synaptic plasticity, neurotransmission, and regulation of multiple signaling pathways (Hussain et al, 2019 ; Glombik et al, 2022 ). These cascades of biological processes influenced by lipids are associated with a range of emotional behaviors and cognitive functions (Hashimoto et al, 2015 ; Egawa et al, 2016 ).…”

Impaired Cholesterol Metabolism, Neurons, and Neuropsychiatric Disorders

“…In particular, the myelin contents of the lateral prefrontal cortex, insula, and whole brain reflect the severity of depression [79]. SREBP-2 was decreased in the hippocampus of an animal model of depression, thereby reducing of cholesterol synthesis [80]. Hypercholesterolaemic mice with knockout of the LDLR show depression-like behaviour and altered monoaminergic metabolism [17].…”