A potential mechanism underlying atypical antipsychotics-induced lipid disturbances

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.

Figure 1

Schematic diagrams illustrating the mechanism of (a) the involvement of PGRMC1/INSIG/SCAP/SREBP signaling in the lipid biosynthesis. (b) AAPD-induced hepatic inhibition of PGRMC1/INSIG-2 and subsequent activation of SCAP/SREBP that contributes to the increased biosynthesis of lipids in the liver. The add-on MIF treatment can reverse AAPD-induced metabolic disturbances by upregulating the expression of PGRMC1/INSIG-2 followed by downregulation of SCAP/SREBP. AAPD, atypical antipsychotic drug; aSREBP, active sterol-regulatory element-binding protein; ER, endoplasmic reticulum; FA, fatty acid; iaSREBP, inactive sterol-regulatory element-binding protein; INSIG, insulin-induced gene; MIF, mifepristone; PGRMC1, progesterone receptor membrane component 1; SCAP, SREBP-cleavage activating protein; TAG, triacylglycerol.

Figure 2

Hepatic expression of PGRMC1/INSIG/SCAP/SREBP mRNA in rats after 4-week treatment with different antipsychotic drugs (a, b); add-on MIF medication with AAPD monotherapy (c, d) using real-time qPCR. *P<0.05, **P<0.01 and ***P<0.0001 as compared with controls. ⁺P<0.05 and ⁺⁺P<0.01 in parentheses as compared with corresponding AAPD monotherapy group. Relative expression values were presented as a normalized ratio to the β-actin mRNA level. AAPD, atypical antipsychotic drug; ARI, aripiprazole; CLO, clozapine; CLO+MIF, clozapine with add-on MIF treatment; HAL, haloperidol; MIF, mifepristone; NC, normal control; qPCR, quantitative polymerase chain reaction; RIS, risperidone; RIS+MIF, risperidone with add-on MIF treatment.

Figure 3

Quantification of the PGRMC1/INSIG/SCAP/SREBP protein in the rat liver by western blotting following 4-week treatment of various antipsychotic drugs (HAL, ARI, RIS and CLO): (a) PGRMC1, (b) INSIG-1, (c) INSIG-2, (d) SCAP, (e) SREBP-1 and (f) SREBP-2. *P<0.05, **P<0.01 and ***P<0.0001 as compared with controls. Relative expression data were calculated based on normalized ratio to the β-actin protein level. ARI, aripiprazole; CLO, clozapine; CLO+MIF, clozapine with add-on MIF treatment; HAL, haloperidol; MIF, mifepristone; NC, normal control; RIS, risperidone; RIS+MIF, risperidone with add-on MIF treatment.

Figure 4

Comparisons of hepatic expression of PGRMC1/INSIG/SCAP/SREBP protein in CLO- or RIS-treated rats before and after the add-on MIF treatment using western blotting: (a) PGRMC1, (b) INSIG-1, (c) INSIG-2, (d) SCAP, (e) SREBP-1 and (f) SREBP-2. *P<0.05, **P<0.01 and ***P<0.0001 as compared with controls. +P<0.05 and ++P<0.01 in parentheses as compared with corresponding AAPD monotherapy group. Relative expression data were normalized from β-actin protein level. ARI, aripiprazole; CLO, clozapine; CLO+MIF, clozapine with add-on MIF treatment; HAL, haloperidol; MIF, mifepristone; NC, normal control; RIS, risperidone; RIS+MIF, risperidone with add-on MIF treatment.