Acute clozapine exposure in vivo induces lipid accumulation and marked sequential changes in the expression of SREBP, PPAR, and LXR target genes in rat liver

Abstract

These results demonstrate that acute clozapine exposure affects SREBP-regulated lipid biosynthesis as well as other lipid homeostasis pathways. We suggest that such drug-induced effects on lipid metabolism in peripheral tissues are relevant for the metabolic adverse effects associated with clozapine and possibly other APDs.

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

“…Although the initial upregulated expression of SREBPs target genes may be explained by the parallel peak concentration of serum drug concentration observed in these studies, the following downregulation could not be well explained by the serum drug concentration. Given the high dosages of clozapine and olanzapine used in these studies, the biphasic expression pattern is more likely a non-physiological activation followed by a compensatory rebound effect (Fernø et al 2009;Jassim et al 2012). Therefore, the gene expression patterns observed in the current study are most likely physiological responses to olanzapine treatment at a clinical equivalent dosage.…”

“…However, it is very interesting that a different (biphasic) expression pattern of lipogenic genes and cholesterol metabolism genes was reported previously in female rats: an i.p. injection of olanzapine (5mg/kg) or clozapine (25mg/kg or 50mg/kg) induced an initial upregulation of SREBP-controlled gene expression followed (at around 1 h post-treatment) by a marked downregulation of SREBPs target genes in rats (Fernø et al 2009;Jassim et al 2012). Although the initial upregulated expression of SREBPs target genes may be explained by the parallel peak concentration of serum drug concentration observed in these studies, the following downregulation could not be well explained by the serum drug concentration.…”

“…However, in contrast to the findings, acute studies in female rats found that a single intraperitoneal (i.p.) injection of clozapine (25 or 50 mg/kg) or olanzapine (5 mg/kg) causes an initial upregulation of lipogenic SREBP target genes followed by a marked and sustained downregulation of these genes in the liver and WAT (Fernø et al 2009;Jassim et al 2012).…”

Histological Study of the Effects of Olanzapine on the Liver of Adult Male Albino Rat with and without Vitamin C

“…Other hypothesis stated that lipidrelated effects have been attributed to drug-mediated blockade or antagonism of histamine H1 and serotonin 5-HT2 receptors as well as activation of hypothalamic adenosine mono phosphate activated protein kinase. This explanation pointed to a hypothalamic site of action for the metabolic deregulation of atypical antipsychotics [31][32][33] .…”

Antipsychotic drugs upregulate lipogenic gene expression by disrupting intracellular trafficking of lipoprotein-derived cholesterol

“…6 There are several reports, which show that APDs increase expression of genes involved in cholesterol and fatty acid synthesis in cultured cells derived from various tissues such as brain, liver, and adipose tissue, 4,[6][7][8][9][10] as well as in vivo. 11,12 This upregulation is mediated through increased activation of master transcriptional regulators of lipid metabolism, such as sterol regulatory element binding proteins (SREBPs). 4,6,7 There are three isoforms of SREBP.…”