Acute effects of oral olanzapine treatment on the expression of fatty acid and cholesterol metabolism-related gene in rats

Liu, Xuemei; Deng, Chao; Cao, Shuang; Gong, Jingwen; Wang, Bochu; Hu, Changhua

doi:10.1016/j.lfs.2015.01.033

Cited by 24 publications

(15 citation statements)

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“…However, a strong association between the increase in lipid levels and weight gain was not found, and this suggested the possibility of a direct effect on lipid levels by multiple mechanisms including hepatic SREBP as well as ChREBP pathways 26, 28 . In this study, OLZ and CLZ augmented the abundance of SREBP-1c and SREBP-2 in the nucleus without a significant effect on their precursor form in the cytoplasm.…”

Section: Discussionmentioning

confidence: 95%

Time-dependent changes and potential mechanisms of glucose-lipid metabolic disorders associated with chronic clozapine or olanzapine treatment in rats

Liu

Lian

et al. 2017

Sci Rep

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Chronic treatment with second-generation antipsychotic drugs (SGAs) has been associated with an increased risk of metabolic syndrome. To evaluate the longitudinal changes in glucose-lipid homeostasis after SGA use, we studied the time-dependent effects of olanzapine (OLZ) (3 mg/kg, b.i.d.) or clozapine (CLZ) (20 mg/kg, b.i.d.) treatment on metabolic profiles for 9 weeks in rats. Although only OLZ significantly increased body weight in rats, both OLZ and CLZ elevated blood lipid levels. Chronic OLZ treatment induced significant weight gain leading to a higher fasting insulin level and impaired glucose tolerance, whereas CLZ lowered fasting insulin levels and impaired glucose tolerance independent of weight gain. Treatment with both drugs deranged AKT/GSK phosphorylation and up-regulated muscarinic M3 receptors in the rats’ livers. Consistent with an elevation in lipid levels, both OLZ and CLZ significantly increased the protein levels of nuclear sterol regulatory element-binding proteins (SREBPs) in the liver, which was associated with improvement in hepatic histamine H1R. However, enhanced carbohydrate response element binding protein (ChREBP) signalling was observed in only CLZ-treated rats. These results suggest that SGA-induced glucose-lipid metabolic disturbances could be independent of weight gain, possibly through activation of SREBP/ChREBP in the liver.

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Section: Discussionmentioning

confidence: 95%

Time-dependent changes and potential mechanisms of glucose-lipid metabolic disorders associated with chronic clozapine or olanzapine treatment in rats

Liu

Lian

et al. 2017

Sci Rep

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“…However, they cause troublesome metabolic side-effects such as SGA-jnduced metabolic abnormalities, increased leptin [3], and decreased adiponectin levels [4], weight gain, dyslipidemia, insulin resistance, and type II diabetes mellitus, which could further lead to the risk of cardiovascular disease and premature death [5,6,7,8]. …”

Section: Introductionmentioning

confidence: 99%

Berberine Alleviates Olanzapine-Induced Adipogenesis via the AMPKα–SREBP Pathway in 3T3-L1 Cells

Zhao

Feng

et al. 2016

IJMS

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The aim of this study was to investigate the mechanisms underlying the inhibitory effects of berberine (BBR) on olanzapine (OLZ)-induced adipogenesis in a well-replicated 3T3-L1 cell model. Oil-Red-O (ORO) staining showed that BBR significantly decreased OLZ-induced adipogenesis. Co-treatment with OLZ and BBR decreased the accumulation of triglyceride (TG) and total cholesterol (TC) by 55.58% ± 3.65% and 49.84% ± 8.31%, respectively, in 3T3-L1 adipocytes accompanied by reduced expression of Sterol regulatory element binding proteins 1 (SREBP1), fatty acid synthase (FAS), peroxisome proliferator activated receptor-γ (PPARγ), SREBP2, low-density lipoprotein receptor (LDLR), and hydroxymethylglutaryl-coenzyme A reductase (HMGR) genes compared with OLZ alone. Consistently, the co-treatment downregulated protein levels of SREBP1, SREBP2, and LDLR by 57.71% ± 9.42%, 73.05% ± 11.82%, and 59.46% ± 9.91%, respectively. In addition, co-treatment reversed the phosphorylation level of AMP-activated protein kinase-α (AMPKα), which was reduced by OLZ, determined via the ratio of pAMPKα:AMPKα (94.1%) compared with OLZ alone. The results showed that BBR may prevent lipid metabolism disorders caused by OLZ by reversing the degree of SREBP pathway upregulated and the phosphorylation of AMPKα downregulated. Collectively, these results indicated that BBR could be used as a potential adjuvant to prevent dyslipidemia and obesity caused by the use of second-generation antipsychotic medication.

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“…First, the lipogenic transcription factor sterol regulatory element binding protein 1 (SREBP-1) and target genes are thought to be one of the possible pathways involved in SGAinduced hepatic lipid dysregulation. We have recently shown that mRNA expression of SREBP-1 and target genes in the liver and fat tissue was strongly affected by a single oral olanzapine administration [11]. In addition, SGAs (especially clozapine) exposure in the cultured cells induces a time-dependent proteolytic cleavage of SREBP-1, in which mRNA expression of the cluster of lipid biosynthesis-related genes is directly up-regulated, without a preceding elevation of SREBP gene expression [12].…”

Section: Introductionmentioning

confidence: 99%

Betahistine co-treatment ameliorates dyslipidemia induced by chronic olanzapine treatment in rats through modulation of hepatic AMPKα-SREBP-1 and PPARα-dependent pathways

Liu¹,

Lian

et al. 2015

Pharmacological Research

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Second-generation antipsychotics including olanzapine are associated with weight gain, dyslipidemia and other metabolic disorders. Both animal and clinical studies have shown that co-treatment with betahistine (a histamine H1 receptor agonist/H3 receptor antagonist) is effective in controlling olanzapine-induced weight gain. In the present study, we investigate whether co-treatment with betahistine is able to prevent dyslipidemia induced by chronic olanzapine treatment and the underlying mechanisms. Female rats were orally administered with olanzapine (1 mg/kg, t.i.d.) for 3.5 consecutive weeks and then a 2.5-week drug withdrawal. Then, rats were divided into 4 groups for 5 weeks treatment: (1) vehicle, (2) olanzapine-only (1 mg/kg, t.i.d.), (3) betahistine-only (9.6 mg/kg, t.i.d.), and (4) olanzapine and betahistine (O+B) co-treatment. After completing treatment, hepatic mRNA expression was measured by qRT-PCR, while the protein levels were detected by western blot. In our study, olanzapine-only treatment significantly increased triglyceride accumulation and non-esterified fatty acids (NEFA), and upregulated mRNA expression of sterol regulatory element binding protein 1 (SREBP-1) and its target genes, while these alterations were ameliorated by O+B co-treatment. Hepatic AMP-activated protein kinase α (AMPKα) was activated in the O+B co-treatment group, with a significant reduction in nuclear SREBP-1 protein expression but an increased expression of peroxisome proliferator-activated receptor-α (PPARα) and its-responsive molecule(CPT1A), compared with olanzapine-only treatment. In addition, olanzapine significantly increased hepatic histamine H1 receptors, while O+B co-treatment significantly reversed them to normal levels. This study provided the first evidence that betahistine could act on hepatic H1 receptors via modulation of AMPKα-SREBP-1 and PPARα-dependent pathways to ameliorate olanzapine-induced dyslipidemia in rats.

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Acute effects of oral olanzapine treatment on the expression of fatty acid and cholesterol metabolism-related gene in rats

Cited by 24 publications

References 50 publications

Time-dependent changes and potential mechanisms of glucose-lipid metabolic disorders associated with chronic clozapine or olanzapine treatment in rats

Time-dependent changes and potential mechanisms of glucose-lipid metabolic disorders associated with chronic clozapine or olanzapine treatment in rats

Berberine Alleviates Olanzapine-Induced Adipogenesis via the AMPKα–SREBP Pathway in 3T3-L1 Cells

Betahistine co-treatment ameliorates dyslipidemia induced by chronic olanzapine treatment in rats through modulation of hepatic AMPKα-SREBP-1 and PPARα-dependent pathways

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