Atypical antipsychotics alter cholesterol and fatty acid metabolism in vitro

Abstract

The antipsychotic actions of classic neuroleptics (typical or fi rst-generation antipsychotics, FGA) revolutionized the therapy of schizophrenia, but their extensive use has been impeded by side effects, such as extrapyramidal symptoms, and a high incidence of nonresponders. FGAs, such as haloperidol, act predominantly by blocking dopamine D 2 receptors ( 1 ). Atypical or second-generation antipsychotics (SGA) display relatively weaker antagonism of dopamine D 2 receptors but potent antagonism to serotonin 5-HT 2A receptors ( 1 ). The therapeutic use of SGAs has reduced concern on neurological side effects, but they are not free of metabolically adverse effects. An increase in body weight is fairly rapid after initiating treatment with these drugs. At long term, this may result in overt obesity, along with dyslipidemia, insulin resistance, abnormal glucose tolerance, and diabetes ( 2-4 ). Dyslipidemia is commonly manifested as an increase in total triglyceride and a decrease of high-density lipoprotein (HDL)-cholesterol plasma

Antipsychotics-induced metabolic alterations: Focus on adipose tissue and molecular mechanisms

“…Interestingly, treatment with atypical antipsychotics increases the synthesis of complex lipids (phospholipid, triacylglycerides and free fatty acids) in primary mouse and rat hepatocytes (Lauressergues et al, 2011(Lauressergues et al, , 2010 and human hepatocyte cell lines in culture (Canfran-Duque et al, 2013). Moreover, acute exposure of rats to clozapine induces a pronounced increase in the hepatic content of phospholipids and triglycerides (Ferno et al, 2009).…”

“…SREBP-2 regulates genes involved in cholesterol biosynthesis, such as the gene encoding 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR), and genes involved in cholesterol uptake, such as low-density lipoprotein receptor (LDLR) gene (Shimano, 2009). Interestingly, antipsychotics stimulate SREBP-2 activation and increase the expression of genes involved in cholesterol biosynthesis (Canfran-Duque et al, 2013;Ferno et al, 2005Ferno et al, , 2006Polymeropoulos et al, 2009). However, paradoxically, atypical antipsychotics (clozapine, risperidone, and ziprasidone) were reported to reduce cholesterol biosynthesis in several cultured human cell lines (HepG2, SH-SY5Y, and HL-60) (Canfran-Duque et al, 2013).…”

Antipsychotic-induced increase in lipid biosynthesis: activation through inhibition?

“…In this issue of Journal of Lipid Research , Canfrán-Duque et al ( 13 ) contribute new, interesting data on the effect of antipsychotic drugs on cellular cholesterol biosynthesis and transport, elaborating previous work by others and themselves ( 6 , 14 -16 ). They demonstrate that the FGA haloperidol and the SGAs clozapine, risperidone, and ziprasidone reduce de novo cholesterol biosynthesis in three different types of cultured human cells (HepG2, SH-SY5Y, and HL-60).…”

A highly sensitive method for analysis of 7-dehydrocholesterol for the study of Smith-Lemli-Opitz syndrome

“…While haploinsuffi ciency of the DHCR7 enzyme in HET carriers has not been associated with pathology, 7-DHC determination is not a generally common assay of the general population. The sensitive assay for 7-DHC in tissues and fl uids reported here provides a rapid means to identify samples having elevated levels of this reactive species, regardless of whether the cause of the increase is genetic or environmental ( 18,19,53 ).…”

“…For tissue samples, 5 ml of ice-cold Folch solution containing 0.25 mg/ml TPP, 0.005% BHT, and d 7 -7-DHC (258 ng) as the internal standard were added and homogenized with a blade that leads to increased levels of 7-DHC. Recent studies show that 7-DHC is greatly increased with the use of some psychiatric medications and it seems likely that exposure to other pharmaceutical or environmental agents will cause elevated levels of 7-DHC ( 18,19 ).…”