Omega-3 fatty acid deficiency augments risperidone-induced hepatic steatosis in rats: Positive association with stearoyl-CoA desaturase

McNamara, Robert K.; Magrisso, I. Jack; Hofacer, Rylon; Jandacek, Ronald J.; Rider, Therese; Tso, Patrick; Benoit, Stephen C.

doi:10.1016/j.phrs.2012.06.010

Cited by 12 publications

(10 citation statements)

References 69 publications

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“…n-3 PUFAs, but with comparable effects on other FAs, such as MUFAs. For instance, both TTA and OLZ increased serum levels of the delta-9-desaturase product oleic acid (C18∶1n-9) and decreased its precursor stearic acid (C18∶0), in line with previous studies demonstrating increased 18∶1/18∶0 ratio both for OLZ [22], the second-generation antipsychotic risperidone [45] and TTA [46]. The 18∶1/18∶0 ratio is an index of increased activity of stearoyl CoA (delta-9) desaturase (SCD1) [47], [48], encoded by the SREBP1 target gene Scd1 .…”

Section: Discussionsupporting

confidence: 89%

Lipid-Lowering Effects of Tetradecylthioacetic Acid in Antipsychotic-Exposed, Female Rats: Challenges with Long-Term Treatment

et al. 2012

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BackgroundPsychiatric patients often require chronic treatment with antipsychotic drugs, and while rats are frequently used to study antipsychotic-induced metabolic adverse effects, long-term exposure has only partially mimicked the appetite-stimulating and weight-inducing effects found in the clinical setting. Antipsychotic-induced effects on serum lipids are also inconsistent in rats, but in a recent study we demonstrated that subchronic treatment with the orexigenic antipsychotic olanzapine resulted in weight-independent increase in serum triglycerides and activation of lipogenic gene expression in female rats. In addition, a recent long-term study in male rats showed that chronic treatment with antipsychotic drugs induced dyslipidemic effects, despite the lack of weight gain.AimsIn the current study, we sought to examine long-term effects of antipsychotic drugs on weight gain, lipid levels and lipid composition after twice-daily administration of antipsychotics to female rats, and to investigate potential beneficial effects of the lipid-lowering agent tetradecylthioacetic acid (TTA), a modified fatty acid.MethodsFemale rats were exposed to orexigenic antipsychotics (olanzapine or clozapine), metabolically neutral antipsychotics (aripiprazole or ziprasidone), or TTA for 8 weeks. Separate groups received a combination of clozapine and TTA or olanzapine and TTA. The effects of TTA and the combination of olanzapine and TTA after 2 weeks were also investigated.ResultsThe antipsychotic-induced weight gain and serum triglyceride increase observed in the subchronic setting was not present after 8 weeks of treatment with antipsychotics, while lipid-lowering effect of TTA was much more pronounced in the chronic than in the subchronic setting, with concomitant upregulation of key oxidative enzymes in the liver. Unexpectedly, TTA potentiated weight gain in rats treated with antipsychotics.ConclusionTTA is a promising candidate for prophylactic treatment of antipsychotic-induced dyslipidemic effects, but a more valid long-term rat model for antipsychotic-induced metabolic adverse effects is required.

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Section: Discussionsupporting

confidence: 89%

Lipid-Lowering Effects of Tetradecylthioacetic Acid in Antipsychotic-Exposed, Female Rats: Challenges with Long-Term Treatment

et al. 2012

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“…For instance, Landschulz et al showed that the levels of primarily polyunsaturated (18:2 and 18:3) fat markedly suppress the expression of the hepatic SCD1 message [26]; a similar observation was replicated recently by McNamara et al [27]. …”

Section: Discussionmentioning

confidence: 76%

Fatty Liver Is Associated with Transcriptional Downregulation of Stearoyl-CoA Desaturase and Impaired Protein Dimerization

et al. 2013

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Aims and MethodsWe evaluated the modulation of liver stearoyl-CoA desaturase-1 (Scd1) by dietary factors and insulin resistance (IR) in two experimental models of high-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD). The first model included Sprague Dawley (SD) rats that developed NAFLD without IR, and the second one included a rat model of genetic IR and cardiovascular disease, the spontaneously hypertensive rats (SHR) and its normotensive, insulin-sensitive control Wistar-Kyoto (WKY). The adult rats were given standard chow diet (CD) or HFD for 10 weeks. In all the animals, we explored the hepatic Scd1 transcriptional activity and protein levels.ResultsHFD-fed rats of both strains developed severe NAFLD. Liver abundance of Scd1 mRNA was significantly decreased in HFD-fed rats regardless of the strain; SD-CD: 235±195 vs. SD-HFD 4.5±2.9, p<0.0004, and SHR-CD: 75.6±10.8 vs. SHR-HFD: 4.48±17.4, and WKY-CD: 168.7±17.4 vs. WKY-HFD: 12.9±17.4, p<0.000001 (mean±SE, ANCOVA adjusted by HOMA). Analysis of liver Scd1 protein expression showed a particular pattern in the HFD groups, characterized by the presence of high levels of a monomeric protein band (32.2–36.6 Kda, p<0.003) and decreased levels of a dimeric protein band (61.9–66.1 Kda, p<0.02) regardless of the rat strain. Pharmacologic intervention with the peroxisome proliferator-activated receptor α agonist clofibrate reverted the liver phenotype and significantly modified the hepatic Scd1 transcriptional activity and protein expression.ConclusionDiet-induced fatty liver is associated with the downregulation of hepatic Scd1 transcript and de-dimerization of the protein, and these changes were not much affected by the status of peripheral IR.

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“…Secondary analyses suggest that a larger EPA/DHA ratio has greater antidepressant efficacy [157], and a recent study found that higher EPA+DHA biostatus at baseline, which was associated with higher endpoint EPA+DHA biostatus following n -3 PUFA supplementation, was associated with increased antidepressant efficacy in depressed coronary heart disease patients [160]. Emerging evidence from controlled and open-label trials further suggests that n -3 PUFAs may augment the therapeutic efficacy of SSRI medications [83,161–164] and may be protective against adverse cardiometabolic [165–168] and hepatic [169,170] side-effects associated with second generation antipsychotic medications. Additional evidence suggests that increasing n -3 PUFA biostatus may be protective against the initial onset of depressive symptoms in hepatitis C patients during treatment with IFN-α [171], and to reduce suicidality in MDD patients [164].…”

Section: N-3 Pufa Supplementation Studiesmentioning

confidence: 99%

Polyunsaturated fatty acids and recurrent mood disorders: Phenomenology, mechanisms, and clinical application

Messamore

Almeida

Jandacek

et al. 2017

Progress in Lipid Research

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A body of evidence has implicated dietary deficiency in omega-3 polyunsaturated fatty acids (n-3 PUFA), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), in the pathophysiology and etiology of recurrent mood disorders including major depressive disorder (MDD) and bipolar disorder. Cross-national and cross-sectional evidence suggests that greater habitual intake of n-3 PUFA is associated with reduced risk for developing mood symptoms. Meta-analyses provide strong evidence that patients with mood disorders exhibit low blood n-3 PUFA levels which are associated with increased risk for the initial development of mood symptoms in response to inflammation. While the etiology of this n-3 PUFA deficit may be multifactorial, n-3 PUFA supplementation is sufficient to correct this deficit and may also have antidepressant effects. Rodent studies suggest that n-3 PUFA deficiency during perinatal development can recapitulate key neuropathological, neurochemical, and behavioral features associated with mood disorders. Clinical neuroimaging studies suggest that low n-3 PUFA biostatus is associated with abnormalities in cortical structure and function also observed in mood disorders. Collectively, these findings implicate dietary n-3 PUFA insufficiency, particularly during development, in the pathophysiology of mood dysregulation, and support implementation of routine screening for and treatment of n-3 PUFA deficiency in patients with mood disorders.

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Omega-3 fatty acid deficiency augments risperidone-induced hepatic steatosis in rats: Positive association with stearoyl-CoA desaturase

Cited by 12 publications

References 69 publications

Lipid-Lowering Effects of Tetradecylthioacetic Acid in Antipsychotic-Exposed, Female Rats: Challenges with Long-Term Treatment

Lipid-Lowering Effects of Tetradecylthioacetic Acid in Antipsychotic-Exposed, Female Rats: Challenges with Long-Term Treatment

Fatty Liver Is Associated with Transcriptional Downregulation of Stearoyl-CoA Desaturase and Impaired Protein Dimerization

Polyunsaturated fatty acids and recurrent mood disorders: Phenomenology, mechanisms, and clinical application

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