Acute effects of oral olanzapine treatment on the expression of fatty acid and cholesterol metabolism-related gene in rats.
OBJECTIVE
Second-generation antipsychotic drugs (SGAs) have a high risk for serious metabolic side-effects including dyslipidemia. This study aimed to investigate the acute effects of oral olanzapine treatment on the expression of genes for fatty acid and cholesterol biosynthesis in rats.


METHODS
Female Sprague-Dawley rats were treated orally with olanzapine (1mg/kg, equivalent to a human clinical dose of 10mg) via self-administration aimed to measure pharmacokinetics. Based on the pharmacokinetic analysis, the acute effects of olanzapine on sterol regulatory element binding protein (SREBP)-related fatty acid/cholesterol metabolism genes were investigated in the liver and perirenal white adipose tissue (WAT) by Real-time quantitative PCR.


RESULTS
A pharmacokinetic analysis demonstrated that the maximum concentration of olanzapine in plasma (Cmax) occurred at 6h with a peak concentration of 276.5ng/ml after a single oral treatment and with a plasma elimination half-life of 3.5h after peak. The mRNA expression of SREBP-2 and target genes for cholesterol synthesis and transport was increased 1.9 8.8 fold compared with the control at 6h after olanzapine administration but returned to basal level at 12h post-treatment, while the increased mRNA expression of SREBP-1c and its targeted fatty acid-related genes appeared at both 6h and 12h post-treatment.


CONCLUSIONS
The present study provided evidence that olanzapine at a clinically-relevant dose caused abnormal expression of genes involved in lipid metabolism in the liver and WAT. These results suggest that olanzapine may cause dyslipidemia side-effects through direct effects on lipid biosynthesis and efflux genes associated with SREBP-stimulated transcriptional changes.
Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400030, PR China; School of Pharmaceutical Sciences, Southwest University, Chongqing 400715, PR China.
Xuemei
X
Liu
Antipsychotic Research Laboratory, School of Medicine, and Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, 2522 NSW, Australia.
Chao
C
Deng
School of Pharmaceutical Sciences, Southwest University, Chongqing 400715, PR China.
Shuang
S
Cao
School of Pharmaceutical Sciences, Southwest University, Chongqing 400715, PR China.
Jingwen
J
Gong
Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400030, PR China. Electronic address: wangbc2000@126.com.
Bo-Chu
BC
Wang
School of Pharmaceutical Sciences, Southwest University, Chongqing 400715, PR China; Engineer Research Center, Chongqing Pharmaceutical Process and Quality Control, Chongqing 400715, PR China. Electronic address: chhhu@swu.edu.cn.
Chang-Hua
CH
Hu
D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001569:Benzodiazepines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D053898:Biosynthetic Pathways / Q000235:genetics*; D002784:Cholesterol / Q000096:biosynthesis*; D005227:Fatty Acids / Q000096:biosynthesis*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D000077152:Olanzapine; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley
D014150:Antipsychotic Agents; D005227:Fatty Acids; D012333:RNA, Messenger; D001569:Benzodiazepines; D002784:Cholesterol; D000077152:Olanzapine
Dyslipidemia; Olanzapine; Pharmacokinetics; SREBPs