The effect of clozapine on the AMPK-ACC-CPT1 pathway in the rat frontal cortex

Kim, Min Kyung; Kim, Se Hyun; Yu, Hyun Sook; Park, Hong Geun; Kang, Ung Gu; Ahn, Yong Min; Kim, Yong Sik

doi:10.1017/s1461145711000976

Cited by 51 publications

(41 citation statements)

References 58 publications

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“…These results demonstrated a novel mechanism by which LBP exerts a powerful lipid-lowering effect by activating the SIRT1/AMPK pathway and reducing lipid synthesis. Moreover, other researchers have shown that activation of ACC leads to increased intracellular malonyl-CoA, which blocks CPT-1α expression and abrogates fatty acid β-oxidation32. Surprisingly, LBP strongly upregulated CPT-1α expression and boosted fatty acid β-oxidation by repressing intracellular malonyl-CoA accumulation (Figs 4G–I and 5E–G).…”

Section: Discussionmentioning

confidence: 73%

Lycium barbarum polysaccharide attenuates high-fat diet-induced hepatic steatosis by up-regulating SIRT1 expression and deacetylase activity

et al. 2016

Sci Rep

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In this study, we aimed to investigate the protective effects and underlying mechanism of Lycium barbarum polysaccharide (LBP) on high-fat-induced nonalcoholic fatty liver disease (NAFLD). Recently, sirtuin 1 (SIRT1) has been shown to play an important role in the regulation of hepatocellular lipid metabolism. Here, we demonstrated that LBP up-regulates SIRT1 deacetylase activity and protein expression by enhancing the NAD+/NADH ratio. Subsequently, LBP promoted LKB1 deacetylation and AMPK phosphorylation via SIRT1-dependent signalling. We also found that LBP increases acetyl-CoA carboxylase (ACC) phosphorylation and adipose triglyceride lipase (ATGL) protein expression and decreases fatty acid synthase (FAS) by activating the SIRT1/LKB1/AMPK pathway in vitro and in vivo. However, SIRT1 small interfering RNA (siRNA)-mediated knockdown reversed the LBP-mediated effects on ACC, FAS and ATGL. Moreover, LBP elevated carnitine palmitoyltransferase-1 alpha (CPT-1α) expression by suppressing malonyl-CoA accumulation. Taken together, our data indicate that LBP plays a vital role in the regulation of hepatic lipid metabolism and that pharmacological activation of SIRT1 by LBP may be a strategy for the prevention of NAFLD.

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Section: Discussionmentioning

confidence: 73%

Lycium barbarum polysaccharide attenuates high-fat diet-induced hepatic steatosis by up-regulating SIRT1 expression and deacetylase activity

et al. 2016

Sci Rep

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“…PPARα agonist up-regulates the expression of CPT1 [42] and inhibits TNF-α and IL-6 levels [43,44]. AMPK activation increases fatty acid oxidation likely by activating PPARα [45] and CPT1 [46]. Therefore, AMPK and PPARα are two critical regulators of hepatic lipid metabolism and may be therapeutic targets in the treatment of NAFLD.…”

Section: Discussionmentioning

confidence: 99%

Alisol A 24-Acetate Prevents Hepatic Steatosis and Metabolic Disorders in HepG2 Cells

Zeng

Tang

Yin

et al. 2016

Cell Physiol Biochem

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Background: Non-alcoholic fatty liver disease (NAFLD) is closely associated with metabolic disorders including hepatic lipid accumulation and inflammation. Alisol A 24-acetate, a triterpene from Alismatis rhizome, has multiple biologic activities such as hypolipidemic, anti-inflammatory and anti-diabetic. Thus we hypothesized that Alisol A 24 -acetate would have effect on NAFLD. The present study was conducted to investigate the therapeutic effects and potential mechanisms of Alisol A 24-acetate against hepatic steatosis in a free fatty acids (FFAs) induced NAFLD cell model. Methods: This study was divided into four groups including Control group, Model group (FFA group), Alisol A 24-acetate (FFA+A) group, Fenofibrate (FFA+F) group. Preventive role of Alisol A 24-acetate was evaluated using 10µM Alisol A 24-acetate plus 1 mM FFA (oleate:palmitate=2:1) incubated with HepG2 cells for 24 h, which was determined by Oil Red O Staining, Oil Red O based colorimetric assay and intracellular triglyceride (TG) content. Besides, the inflammatory cytokines tumor necrosis factor (TNF)- α, interleukin (IL)-6 levels as well as the protein and mRNA expressions that were involved in fatty acid synthesis and oxidation including Adiponectin, AMP-activated protein kinase (AMPK) α, peroxisome proliferator-activated receptor (PPAR) α, sterol regulatory element binding protein 1c (SREBP-1c), acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), carnitine palmitoyltransferase 1 (CPT1) and acyl coenzyme A oxidase 1 (ACOX1) were detected. Results: Alisol A 24-acetate significantly decreased the numbers of lipid droplets, Oil Red O lipid content, and intracellular TG content. Besides, inflammatory cytokines TNF-α, IL-6 levels were markedly inhibited by Alisol A 24-acetate. Furthermore, Alisol A 24-acetate effectively increased the protein and mRNA expressions of Adiponectin, the phosphorylation of AMPKα, CPT1 and ACOX1, whereas decreased SREBP-1c, the phosphorylation of ACC and FAS at both protein and mRNA levels. However, there was no significant effect on the protein and mRNA expressions of PPARα by Alisol A 24-acetate. Conclusions: These results demonstrated that Alisol A 24-acetate effectively ameliorated hepatic steatosis likely through Adiponectin, which activated AMPKα signaling pathways via down-regulating SREBP-1c, ACC, FAS and up-regulating CPT1 and ACOX1, and inhibited inflammation. Thereby, Alisol A 24-acetate could be a promising candidate for the treatment of NAFLD.

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“…However, a study in rats has reported that a single intraperitoneal injection of clozapine (5-20mg/kg) significantly activated AMPK-CPT1 signaling in the prefrontal cortex, suggesting that clozapine affects lipid metabolism in the brain. [87] In addition to the hypothalamus, H1 receptors and AMPK-CPT1 signaling in the nucleus of solitary tract (NTS) in the brainstem may also play a role in feeding regulation and contribute to SGA-induced weight gain. Previous studies in rats found that the brainstem dorsal vagal complex (DVC) is significantly involved in mediating olanzapine-induced weight gain.…”

Section: Intracellular Mechanisms For Sga-induced Weight Gain Associamentioning

confidence: 99%

The Role of Hypothalamic H1 Receptor Antagonism in Antipsychotic-Induced Weight Gain

Deng

Huang

2013

CNS Drugs

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Treatment with second generation antipsychotics (SGAs), notably olanzapine and clozapine, causes severe obesity side effects. Antagonism of histamine H1 receptors has been identified as a main cause of SGAinduced obesity, but the molecular mechanisms associated with this antagonism in different stages of SGAinduced weight gain remain unclear. This review aims to explore the potential role of hypothalamic histamine H1 receptors in different stages of SGA-induced weight gain/obesity and the molecular pathways related to SGA-induced antagonism of these receptors. Initial data have demonstrated the importance of hypothalamic H1 receptors in both short-and long-term SGA-induced obesity. Blocking hypothalamic H1 receptors by SGAs activates AMP-activated protein kinase (AMPK), a well-known feeding regulator. During short-term treatment, hypothalamic H1 receptor antagonism by SGAs may activate the AMPK-carnitine palmitoyltransferase 1 signaling to rapidly increase caloric intake and result in weight gain. During long-term SGA treatment, hypothalamic H1 receptor antagonism can reduce thermogenesis, possibly by inhibiting the sympathetic outflows to the brainstem rostral raphe pallidus and rostral ventrolateral medulla, therefore decreasing brown adipose tissue thermogenesis. Additionally, blocking of hypothalamic H1 receptors by SGAs may also contribute to fat accumulation by decreasing lipolysis but increasing lipogenesis in white adipose tissue. In summary, antagonism of hypothalamic H1 receptors by SGAs may time-dependently affect the hypothalamus-brainstem circuits to cause weight gain by stimulating appetite and fat accumulation but reducing energy expenditure. The H1 receptor and its downstream signaling molecules could be valuable targets for the design of new compounds for treating SGA-induced weight gain/obesity.

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The effect of clozapine on the AMPK-ACC-CPT1 pathway in the rat frontal cortex

Cited by 51 publications

References 58 publications

Lycium barbarum polysaccharide attenuates high-fat diet-induced hepatic steatosis by up-regulating SIRT1 expression and deacetylase activity

Lycium barbarum polysaccharide attenuates high-fat diet-induced hepatic steatosis by up-regulating SIRT1 expression and deacetylase activity

Alisol A 24-Acetate Prevents Hepatic Steatosis and Metabolic Disorders in HepG2 Cells

The Role of Hypothalamic H1 Receptor Antagonism in Antipsychotic-Induced Weight Gain

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