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

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.

Curcumin alleviates postprandial glycaemic response in healthy subjects: A cross-over, randomized controlled study

“…Curcumin, a dietary bio-active derived from turmeric, has been shown to alleviate insulin resistance and lower fasting glucose in preclinical studies 5 – 7 . These effects were hypothesised to be mediated via lowering of low grade inflammation via down-regulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) 8 , cytoprotection of pancreatic β-cells by increasing the concentrations of anti-oxidant enzymes 9 and via increasing expression of 5′ adenosine monophosphate-activated protein kinase (AMPK) 10 , a key regulator of glucose and lipid homeostasis. Clinical trials with curcumin supplementation reported positive 11 and no effect 12 on fasting glycaemic parameters in high risk and individuals with type 2 diabetes 13 – 15 .…”

Curcumin Inhibits the Proteolytic Process of SREBP-2 by First Inhibiting the Expression of S1P rather than Directly Inhibiting SREBP-2 Expression.

“…Studies have described various effects of curcumin including reducing blood fat, choleretic actions, and antitumor, anti-inflammatory, and anti-oxidation effects [13][14][15][16] . Several studies have indicated that the effect of curcumin on SREBPs is related to the mechanism of curcumin regulating blood lipid metabolism [4,5,[8][9][10][11][12] . Kumar et al [4] found that curcumin can regulate the expression of NPC1L1 through SREBP-2 to inhibit cholesterol absorption in Caco-2 cells.…”

“…Thus, the detected protein may be mSREBP-2 rather than pSREBP-2. Liu et al [10] studied the function of curcumin using antibodies against SREBP-2 purchased from Santa Cruz which have only been used to detect pSREBP-2. Our results indicate that curcumin first affects the SREBP-2 proteolysis process rather than inhibiting its protein expression.…”

“…The cells were 4% paraformaldehyde fixed (15min) at room temperature and then incubated with 0.1% TritonX-100 in PBS for 15min to permeabilize the cells and block non-specific protein-protein interaction with 5% BSA for 30min. The cells were then incubated with the antibody Many studies report inhibited expression of SREBP-2 mRNA upon curcumin treatment [4,5,[8][9][10][11][12] . Our study showed consistent results, with mRNA levels of SREBP-2, SCAP and SP-1 mRNA decreasing as the curcumin concentration increased.…”

“…Many studies have confirmed that curcumin can inhibit SREBP-2 mRNA expression [4,5,[8][9][10][11][12] . This may depend on the inhibition of specificity protein-1 (SP-1) protein expression, which can bind to the GC-box in the SREBP-2 promoter sequence [8] .…”