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Aims: Chronic treatment with antipsychotics, especially most of atypical ones, leads to development of metabolic abnormalities. Olanzapine is an atypical antipsychotic widely used in the treatment of schizophrenia and bipolar disorder. The mechanisms underlying olanzapine-induced metabolic adverse effects in the liver, however, remain unclear. This study was designed to investigate olanzapine-induced insulin-desensitivity in the liver., Main Methods: Male rats were treated with olanzapine (5 mg/kg, by a gavage method, once daily for consecutive 8 weeks. Blood and liver variables were determined enzymatically or histologically. Gene/protein expression was analyzed by real-time PCR and Western blot., Key Findings: Olanzapine treatment significantly increased fasting plasma insulin concentration, the index of the homeostasis model assessment of insulin resistance (HOMA-IR), and hepatic triglyceride and fatty droplet accumulation in rats. Hepatic gene/protein expression profile revealed that olanzapine activated mRNA and protein expression of sterol regulatory element-binding protein-1c, and mRNA levels of its downstream lipogenic enzymes, acetyl-CoA carboxylase-1, fatty acid synthase and stearoyl-CoA desaturase-1. More importantly, phosphorylated protein level of both Ser 307 in insulin receptor substrate (IRS)-1 and Ser 731 in IRS-2 was increased. Furthermore, phosphorylation of Tyr 607 in phosphoinositide 3-kinase (PI3K) p85α, Ser 473 in Akt and Ser 2448 in mammalian target of rapamycin was also enhanced., Significance: Our results suggest that the IRS/PI3K/Akt signaling pathway mediates olanzapine-induced hepatic insulin resistance in male rats. Our findings may provide better understanding of the antipsychotic-induced metabolic adverse effects., (Copyright © 2018. Published by Elsevier Inc.)

Background & Aims: Liver cancer, mainly hepatocellular carcinoma, is a major malignancy and currently there are no effective treatment protocols due to insufficient understanding of hepatocarcinogenesis. As a potentially high-throughput and cost-effective experimental model, the zebrafish is increasingly recognized for disease studies. Here, we aim at using the zebrafish to generate a convenient hepatocellular carcinoma model. Methods: Using the Tet-on system for liver-specific expression of fish oncogene xmrk, a hyperactive version of epidermal growth factor receptor homolog, we have generated transgenic zebrafish with inducible development of liver cancer. Results: Liver tumors were rapidly induced with 100% penetrance in both juvenile and adult xmrk transgenic fish. Histological examination indicated that they all showed features of hepatocellular carcinoma. The induced liver tumors regressed rapidly upon inducer withdrawal. During the tumor induction stage, we detected increased cell proliferation and activation of Xmrk downstream targets Erk and Stat5, which were important for liver tumorigenesis as proved by inhibition experiments. When tumors regressed, there were decreased phosphorylated Erk and Stat5 accompanied with an increase in apoptosis. Conclusions: Our zebrafish model demonstrates the potential of a hyperactivated epidermal growth factor receptor pathway in initiating heptocarcinogenesis. It provides clear evidence for the requirement of only a single oncogene for HCC initiation and maintenance and is thus a convenient model for further investigation of oncogene addiction and future anti-cancer drug screening. [ABSTRACT FROM AUTHOR]

Abstract Ethnopharmacological relevance The modified Longdan Xiegan Tang (mLXT) has been used clinically for various neuropsychiatric disorders and liver diseases. The use of antipsychotics is associated with nonalcoholic fatty liver disease. Aim of the study To investigate the effect and underlying mechanisms of mLXT on antipsychotic-induced fatty liver. Materials and methods The representative active components in the formula were identified and quantified by a HPLC method. Fatty liver in male rats was induced by olanzapine (5 mg/kg) (p.o., × 8 weeks), and the rats were co-treated with mLXT extract (50 and 500 mg/kg). Blood and liver variables were determined enzymatically or histologically. Gene/protein expression was analyzed by real-time PCR and Western blot. Results Treatment of rats with mLXT decreased olanzapine-induced increases in hepatic triglyceride content, cell vacuolar degeneration and Oil Red O-stained area, accompanied by suppression of olanzapine-stimulated hepatic mRNA and/or protein overexpression of sterol regulatory element-binding protein (SREBP)-1c, and its downstream lipogenic enzymes for de novo lipogenesis. Besides, mLXT also activated hepatic expression of peroxisome proliferator-activated receptor-alpha and its target genes associated with fatty acid beta-oxidation, phosphorylated Thr172 in AMP-activated protein kinase (AMPK)-alpha (the upstream enzyme of SREBP-1c and PPAR-alpha), and its ratio to total AMPK-alpha. Conclusions The present results suggest that chronic treatment with mLXT ameliorates olanzapine-induced fatty liver by regulating hepatic de novo lipogenesis- and fatty acid beta-oxidation-associated gene expression mediated by SREBP-1c and PPAR-alpha, respectively, through activation of AMPK-alpha. Our findings provide the evidence that supports clinical use of the formula for antipsychotic medication-induced fatty liver. Graphical abstract fx1 [ABSTRACT FROM AUTHOR]