Curcumin Activates AMPK Pathway and Regulates Lipid Metabolism in Rats Following Prolonged Clozapine Exposure.

Zhen Liu,Pengfei Xu,Changmeng Cui,Pei Jiang,Dehua Liao,Qingyan Feng,Hualin Cai,Ruili Dang,Xin Yan,Mengqi Yang

doi:10.3389/fnins.2017.00558

Abstract

Clozapine (CLO) remains an ultimate option for patients with treatment resistant schizophrenia. However, the atypical antipsychotic is often associated with serious metabolic side effects, such as dyslipidemia. Hepatic sterol regulatory element-binding proteins (SREBPs) are central in the allosteric control of a variety of lipid biosynthetic pathways. There is emerging evidence that CLO can activate SREBP pathway and enhance downstream lipogenesis, whereas curcumin (CUR), a major active compound of Curcuma longa, contains hypolipidemic properties. Therefore, in the present study, we examined the protective effects of CUR against CLO-induced lipid disturbance and analyzed the expression of key components in hepatic lipid metabolism. Our data showed that 4-week treatment of CLO (15 mg/kg/day) markedly elevated serum lipid levels and resulted in hepatic lipid accumulation, whereas co-treatment of CUR (80 mg/kg/day) alleviated the CLO-induced dyslipidemia. We further demonstrated that CUR appears to be a novel AMP-activated protein kinase (AMPK) agonist, which enhanced AMPK phosphorylation and mitigated CLO-induced SREBP overexpression. Additionally, CUR also modulated the downstream SREBP-targeted genes involved in fatty acid synthesis and cholesterol metabolism, including fatty acid synthase (FAS) and HMG-CoA reductase (HMGCR). In summary, our study suggests that the suppressed AMPK activity and thereby enhanced SREBP-dependent lipid synthesis could be associated with the antipsychotic-stimulated dyslipidemia, whereas CUR may maintain lipid homeostasis by directly binding to AMPK, indicating that adjunctive use of CUR could be a promising preventive strategy for the drug-induced lipogenesis.

Highlights

High rates of comorbidity with metabolic syndrome are associated with schizophrenia patients following treatment with atypical antipsychotic drugs (AAPDs), such as clozapine (CLO) and olanzanpine (Kristóf et al, 2016)
The results were consistent with our previous findings (Cai et al, 2015; Dang et al, 2015), indicating that CLO-induced metabolic disturbance is independent of its effects on hypothalamic neurotransmission and consequent changes in food intake and obesity, but may through the direct modification on lipid metabolism in the periphery
The use of AAPDs is related to a constellation of serious metabolic side effects, which may result in comorbidities such as Type 2 diabetes mellitus and cardiovascular disease, as well as contributing to the poor treatment adherence rates (Fell et al, 2008; Henderson et al, 2015)

Summary

Introduction

High rates of comorbidity with metabolic syndrome are associated with schizophrenia patients following treatment with atypical antipsychotic drugs (AAPDs), such as clozapine (CLO) and olanzanpine (Kristóf et al, 2016). The drug-induced dyslipidemia might be secondary to hyperorexia and obesity, recent evidence highlights that the antipsychotics can exert direct effects on lipid metabolism in peripheral tissues (McNamara et al, 2011). AMP-activated protein kinase (AMPK) has emerged as a key regulator in hepatic energy metabolism and lipid homeostasis. Recent studies demonstrated that the AAPDs perturbs AMPK signaling and activates SREBP signaling, resulting in the overexpression of downstream lipogenic genes and dyslipidemia, whereas pharmaceutical means to potentiate hepatic AMPK are promising to maintain lipid homeostasis during AAPD treatment (Oh et al, 2011)

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