Abstract
Previous findings suggested that a four-protein complex, including sterol-regulatory element-binding protein (SREBP), SREBP-cleavage-activating protein (SCAP), insulin-induced gene (INSIG) and progesterone receptor membrane component 1 (PGRMC1), within the endoplasmic reticulum appears to be an important regulator responsible for atypical antipsychotic drug (AAPD)-induced lipid disturbances. In the present study, effects of typical antipsychotic drug and AAPDs as well as treatment outcome of steroid antagonist mifepristone (MIF) on the PGRMC1/INSIG/SCAP/SREBP pathway were investigated in rat liver using real-time quantitative polymerase chain reaction (qPCR) and western blot analysis. In addition, serum triacylglycerol, total cholesterol, free fatty acids and various hormones including progesterone, corticosterone and insulin were measured simultaneously. Following treatment with clozapine or risperidone, both lipogenesis and cholesterogenesis were enhanced via inhibition of PGRMC1/INSIG-2 and activation of SCAP/SREBP expressions. Such metabolic disturbances, however, were not demonstrated in rats treated with aripiprazole (ARI) or haloperidol (HAL). Moreover, the add-on treatment of MIF was effective in reversing the AAPD-induced lipid disturbances by upregulating the expression of PGRMC1/INSIG-2 and subsequent downregulation of SCAP/SREBP. Taken together, our findings suggest that disturbances in lipid metabolism can occur at an early stage of AAPD treatment before the presence of weight gain. Such metabolic defects can be modified by an add-on treatment of steroid antagonist MIF enhancing the PGRMC1 pathway. Thus, it is likely that PGRMC1/INSIG-2 signaling may be a therapeutic target for AAPD-induced weight gain.
Highlights
High rates of comorbidity with metabolic disturbances have been associated with schizophrenia (SZ) patients following treatment with atypical antipsychotic drugs (AAPDs).[1]
First-episode SZ patients who started with AAPDs had a three times higher incidence rate of metabolic syndrome (MetS) as compared with the firstepisode SZ patients treated with typical antipsychotics.[1]
Our findings were in accordance with those animal studies conducted in less than 1-month treatment with AAPDs such as olanzapine,[33] CLO34 or other typical antipsychotic drugs.[35]
Summary
High rates of comorbidity with metabolic disturbances have been associated with schizophrenia (SZ) patients following treatment with atypical antipsychotic drugs (AAPDs).[1] The review by De Hert et al.[2] found that the prevalence rate of the metabolic syndrome (MetS) was two to three times higher in patients with SZ or schizoaffective disorder than in the general population. First-episode SZ patients who started with AAPDs had a three times higher incidence rate of MetS as compared with the firstepisode SZ patients treated with typical antipsychotics.[1] Such MetS3 consisting of high blood pressure, hyperglycemia, insulin resistance, weight gain and dyslipidemia may contribute to the increased cardiovascular mortality in this debilitating disease. 4) and histamine H1 receptors[5] to AAPD-induced weight gain, possibly resulting from an increased dietary intake. Excess SREBP activity could account for elevated circulating cholesterol, free fatty acids (FFAs) and triacylglycerols.[6]
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