A potential mechanism underlying atypical antipsychotics-induced lipid disturbances.
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.
Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, China.|The Institute of Clinical Pharmacy, Central South University, Changsha, China.|Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA.|Medical Research Service, VA Pittsburgh Healthcare System, University of Pittsburgh, Pittsburgh, PA, USA.
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Cai
School of Pharmacy, Guilin Medical University, Guilin, China.
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Tan
Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, China.|The Institute of Clinical Pharmacy, Central South University, Changsha, China.|School of Pharmacy, Central South University, Changsha, China.
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Jiang
Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, China.|The Institute of Clinical Pharmacy, Central South University, Changsha, China.|School of Pharmacy, Central South University, Changsha, China.
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Dang
Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, China.|The Institute of Clinical Pharmacy, Central South University, Changsha, China.|School of Pharmacy, Central South University, Changsha, China.
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Xue
Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, China.|The Institute of Clinical Pharmacy, Central South University, Changsha, China.|School of Pharmacy, Central South University, Changsha, China.
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Tang
Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, China.|The Institute of Clinical Pharmacy, Central South University, Changsha, China.
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Xu
Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, China.|The Institute of Clinical Pharmacy, Central South University, Changsha, China.
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Deng
Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, China.|The Institute of Clinical Pharmacy, Central South University, Changsha, China.
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Li
Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA.|Medical Research Service, VA Pittsburgh Healthcare System, University of Pittsburgh, Pittsburgh, PA, USA.|Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
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Yao
D000818:Animals; D014150:Antipsychotic Agents / Q000097:blood / Q000494:pharmacology*; D015153:Blotting, Western; D002784:Cholesterol / Q000097:blood; D003024:Clozapine / Q000494:pharmacology; D003345:Corticosterone / Q000097:blood; D004195:Disease Models, Animal; D005230:Fatty Acids, Nonesterified / Q000097:blood; D007328:Insulin / Q000097:blood; D050356:Lipid Metabolism / Q000187:drug effects*; D050155:Lipogenesis / Q000187:drug effects*; D008099:Liver / Q000187:drug effects; D008297:Male; D016133:Polymerase Chain Reaction; D011374:Progesterone / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D018967:Risperidone / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D014280:Triglycerides / Q000097:blood
D014150:Antipsychotic Agents; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D014280:Triglycerides; D011374:Progesterone; D002784:Cholesterol; D003024:Clozapine; D018967:Risperidone; D003345:Corticosterone