title: Betahistine co-treatment ameliorates dyslipidemia induced by chronic olanzapine treatment in rats through modulation of hepatic AMPKα-SREBP-1 and PPARα-dependent pathways.
abstract: 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.
authors.affiliation: School of Pharmaceutical Sciences, Southwest University, Chongqing 400715, PR China; Antipsychotic Research Laboratory, Illawarra Health and Medical Research Institute, Wollongong, 2522, NSW, Australia; School of Medicine, University of Wollongong, Wollongong, 2522, NSW, Australia; Engineer Research Center of Chongqing Pharmaceutical Process and Quality Control, Chongqing 400715, PR China.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Liu
authors.affiliation: Antipsychotic Research Laboratory, Illawarra Health and Medical Research Institute, Wollongong, 2522, NSW, Australia; School of Medicine, University of Wollongong, Wollongong, 2522, NSW, Australia.
authors.forename: Jiamei
authors.initials: J
authors.lastname: Lian
authors.affiliation: School of Pharmaceutical Sciences, Southwest University, Chongqing 400715, PR China; Engineer Research Center of Chongqing Pharmaceutical Process and Quality Control, Chongqing 400715, PR China.
authors.forename: Chang-Hua
authors.initials: CH
authors.lastname: Hu
authors.affiliation: Antipsychotic Research Laboratory, Illawarra Health and Medical Research Institute, Wollongong, 2522, NSW, Australia; School of Medicine, University of Wollongong, Wollongong, 2522, NSW, Australia. Electronic address: chao@uow.edu.au.
authors.forename: Chao
authors.initials: C
authors.lastname: Deng
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000494:pharmacology; D001569:Benzodiazepines / Q000009:adverse effects* / Q000494:pharmacology*; D001621:Betahistine / Q000494:pharmacology*; D050171:Dyslipidemias / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D000077152:Olanzapine; D047493:PPAR alpha / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011969:Receptors, Histamine H1 / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*; D015430:Weight Gain / Q000187:drug effects
chemical_list: D014150:Antipsychotic Agents; D047493:PPAR alpha; D011969:Receptors, Histamine H1; C497389:Srebf1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; D001569:Benzodiazepines; D055372:AMP-Activated Protein Kinases; D000077152:Olanzapine; D001621:Betahistine
keywords: AMP-activated protein kinaseα; Betahistine; Dyslipidemia; Olanzapine; Peroxisome proliferator-activated receptorα; Sterol regulatory element binding protein 1