Reduced expression of fatty acid biosynthesis genes in the prefrontal cortex of patients with major depressive disorder

doi:10.1016/j.jad.2010.08.021

Journal of Affective Disorders

Volume 129, Issues 1–3, March 2011, Pages 359-363

https://doi.org/10.1016/j.jad.2010.08.021 Get rights and content

Abstract

Background

Major depressive disorder (MDD) is associated with central and peripheral deficits in long-chain polyunsaturated fatty acids (LC-PUFA), particularly those in the omega-3 fatty acid family. However, the etiology of these deficits remains poorly understood, and there is currently little known about the expression of genes that mediate fatty acid biosynthesis in MDD patients.

Methods

The expression of FADS1 (Δ5 desaturase), FADS2 (Δ6 desaturase), HELO1 [ELOVL5] (elongase), PEX19 (peroxisome), and SCD (stearoyl-CoA desaturase [Δ9 desaturase]) was determined in the postmortem prefrontal cortex of MDD patients (n = 10) and non-psychiatric controls (n = 10) by real-time reverse transcriptase polymerase chain reaction (RT-PCR).

Results

After correcting for multiple comparisons, FADS1 mRNA expression was significantly lower in MDD patients relative to controls (−27%, p = 0.009), and there were trends for lower expression of FADS2 (−30%, p = 0.07), HELO1 (−37%, p = 0.02), and SCD (−43%, p = 0.02). PEX19 mRNA expression did not differ between controls and MDD patients (−2%, p = 0.92). There were no significant gender effects, and relative reductions in FADS1, HELO1, and SCD expression were greater in patients that did not commit suicide compared with patients that did commit suicide.

Limitations

The sample size was small, and all MDD patients were receiving antidepressant medications.

Conclusions

Principal genes involved in LC-PUFA and monounsaturated fatty acid biosynthesis are down-regulated in the postmortem prefrontal cortex of MDD patients. Additional studies are needed to replicate and extend these findings in a larger sample that includes antidepressant-free MDD patients.

Introduction

A body of evidence suggests that major depressive disorder (MDD) is associated with peripheral and central deficits long-chain polyunsaturated fatty acids (LC-PUFA), particularly the omega-3 (n-3) fatty acid docosahexaenoic acid (DHA, 22:6n-3) (Conklin et al., 2010, Peet et al., 1998, McNamara et al., 2007, McNamara et al., 2010). However, the etiology of n-3 fatty acid deficits in MDD remains poorly understood, and may involve dietary insufficiency of preformed LC-PUFA (Colangelo et al., 2009, Freeman et al., 2006, Hibbeln, 1998) and/or polymorphisms in the genes that mediate LC-PUFA biosynthesis from short-chain precursors (Schaeffer et al., 2006). The n-3 fatty acid precursor alpha-linolenic acid (ALA, 18:3n-3) is converted to DHA through a series of microsomal desaturation-elongation reactions involving Δ6 desaturase (FADS2, Cho et al., 1999b), elongases (HELO1 [ELOVL5], Leonard et al., 2000), Δ5 desaturase (FADS1, Cho et al., 1999a), and conversions within peroxisomes comprised of multiple PEX gene products (Sprecher & Chen, 1999). Each of these LC-PUFA biosynthesis genes have been cloned and are highly expressed in human postmortem cerebral cortex (McNamara et al., 2008).

There is currently little known about the genes that regulate LC-PUFA biosynthesis in MDD. However, a recent microarray study found that genes involved in LC-PUFA (FADS1), and monounsaturated fatty acid (MUFA) biosynthesis (stearoyl-CoA desaturase, SCD), are down-regulated in postmortem prefrontal cortices (BA8/9,11,47) of male MDD patients that committed suicide (Lalovic et al., 2010). Moreover, antidepressant medications up-regulate sterol regulatory element-binding protein (SREBP) and SCD mRNA expression in human glioma cells (Raeder et al., 2006), and FADS1 and FADS2 promoters both possess SREBP binding sites which positively regulate their transcription (Matsuzaka et al., 2002). These findings suggest that central LC-PUFA biosynthesis is blunted in MDD and up-regulated by antidepressant medications. To extend these findings, the present study determined the expression of principal genes involved in LC-PUFA biosynthesis (FADS1, FADS2, HELO1, PEX19) and MUFA biosynthesis (SCD) in the postmortem prefrontal cortex (BA10) of MDD patients (n = 10) and age-matched non-psychiatric controls (n = 10) by real-time reverse transcriptase polymerase chain reaction (RT-PCR).

Section snippets

Postmortem brain tissue

Gene expression was determined in frozen (unfixed) postmortem prefrontal cortex (Brodmann's area [BA] 10) gray matter from non-psychiatric controls (n = 10) and patients with DSM-IV defined MDD (n = 10). Tissues were generously provided by The Stanley Medical Research Institute's Brain Collection (Torrey et al., 2000). There were no significant group differences in age at death, postmortem interval, brain weight, or brain pH (Table 1). At time of death, all MDD patients were receiving

Results

GAPDH mRNA expression did not differ between groups (p = 0.32). The two-factor ANOVA found significant main effects of Illness, F(1,98) = 10.8, p = 0.001, and Gene, F(4,98) = 3.63, p = 0.009, and the Illness × Gene Interaction was not significant, F(4,98) = 0.90, p = 0.46. After correcting of multiple comparisons, FADS1/GAPDH mRNA expression was significantly lower in MDD patients relative to controls (−27%, p = 0.009, d = 1.3), and there were trends for lower expression of FADS2 (−30%, p = 0.07, d = 1.0), HELO1

Discussion

The principal finding of the present study is that patients with MDD exhibit reduced expression of key genes involved in LC-PUFA biosynthesis, FADS1, FADS2, and HELO1, and MUFA biosynthesis, SCD, in the postmortem frontal cortex compared with controls. There were no significant gender differences, and relative reductions in FADS1, HELO1, and SCD expression were greater in patients that did not commit suicide compared with patients that committed suicide. The present results are consistent with

Role of funding source

Funding for this study was provided by NIMH Grants MH073704 and MH074858 to R.K.M.; the NIMH had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Conflict of interest statement

None of the authors have any actual or potential conflict of interest, including any financial, personal or other relationships with other people or organizations within three (3) years of beginning the work submitted that could inappropriately influence, or be perceived to influence, their work.

Acknowledgments

This work was supported in part by National Institute of Health grants MH073704 and MH074858 to R.K.M. Postmortem tissue was generously provided by The Stanley Medical Research Institute's Brain Collection courtesy of Drs. Michael B. Knable, E. Fuller Torrey, Maree J. Webster, Serge Weis, and Robert H. Yolken.

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Metabolic differences have been reported between individuals with and without major depressive disorder (MDD), but their consistency and causal relevance have been unclear.
We conducted a metabolome-wide association study of MDD with 249 metabolomic measures available in the UK Biobank (n = 29,757). We then applied two-sample bidirectional Mendelian randomization and colocalization analysis to identify potentially causal relationships between each metabolite and MDD.
A total of 191 metabolites tested were significantly associated with MDD (false discovery rate–corrected p < .05), which decreased to 129 after adjustment for likely confounders. Lower abundance of omega-3 fatty acid measures and a higher omega-6 to omega-3 ratio showed potentially causal effects on liability to MDD. There was no evidence of a causal effect of MDD on metabolite levels. Furthermore, genetic signals associated with docosahexaenoic acid colocalized with loci associated with MDD within the fatty acid desaturase gene cluster. Post hoc Mendelian randomization of gene-transcript abundance within the fatty acid desaturase cluster demonstrated a potentially causal association with MDD. In contrast, colocalization analysis did not suggest a single causal variant for both transcript abundance and MDD liability, but rather the likely existence of two variants in linkage disequilibrium with one another.
Our findings suggest that decreased docosahexaenoic acid and increased omega-6 to omega-3 fatty acids ratio may be causally related to MDD. These findings provide further support for the causal involvement of fatty acids in MDD.
Perinatal and postweaning diets high in omega-3 fatty acids have age- and sex-specific effects on the fatty acid composition of the cerebellum and brainstem of C57BL/6 mice
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The cerebellum and brainstem are highly enriched with myelin; alterations in myelin sheath formation are associated with various neuropsychiatric illnesses [18–20]. A dysregulation in SFA and MUFA homeostasis, possibly due to dysregulation in the expression of SCD1 and MBP [21], is associated with neuropsychiatric disorders [21,22]. N-3 PUFA has been shown to regulate the expression of SCD1 and MBP [23,24]; however, no study to date has investigated the effects of n-3 PUFA on SCD1 and MBP in the cerebellum and brainstem, which contain high levels of white matter and myelin, and play important roles in brain functions.
The sex- and age-specific effects of omega (n)-3 polyunsaturated fatty acids (PUFA) enriched diets on brainstem and cerebellar fatty acid composition, and the expression of stearoyl-CoA desaturase (SCD)-1 and myelin basic protein (MBP) were investigated in C57BL/6 mice. Female mice were fed diets (20% fat, w/w) high or low in n-3 PUFA before mating, during pregnancy and lactation; and offspring (both males and females) were weaned onto their mother's designated diet for 16 weeks. A diet high in n-3 PUFA caused an accretion of docosahexaenoic acid in the cerebellum. Monounsaturated fatty acids increased from weaning to 16 weeks in the cerebellum. The changes in the cerebellar fatty acids were more pronounced in females, with a significant effect of diet. A diet high in n-3 PUFA increased cerebellar SCD-1 and MBP mRNA expression. These findings are novel and demonstrate that the effects of n-3 PUFA are brain region, age- and sex-specific.
Alterations in peripheral fatty acid composition in bipolar and unipolar depression
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Lipid metabolism has been shown to play an important role in unipolar and bipolar depression. In this study, we aimed to evaluate levels of fatty acids in patients with unipolar (MDD) and bipolar depression (BDD) in comparison to patients with bipolar disorder in euthymia (BDE) and non-psychiatric controls.
Levels of saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs) were assessed in serum of (87) patients with BD (31 euthymic, 22 depressive) or MDD (34) and (31) non-psychiatric controls through GC-FID.
No significant difference in total levels of PUFAs (polyunsaturated fatty acids), SFAs (saturated fatty acids), MUFAs (monounsaturated fatty acids) and total fatty acids were found between groups. Our results demonstrated higher levels AA: EPA and AA: EPA+DHA in patients with BDD. Additionally, we observed that overall omega-6 present a positive correlation with illness duration in patients with BDD and AA: EPA ratio positively associated with illness duration in MDD group. Depression severity was positively associated with AA: EPA+DHA ratio in all participants.
Together, our results support the relevance for the balance of omega-3 and omega-6 in BDD. Also, our results suggest a potential subset of stage-related lipid biomarkers that further studies are needed to help clarify the dynamics of lipid alteration in BD and MDD.
Lipids in psychiatric disorders and preventive medicine
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Psychiatric disorders like mood disorders, schizophrenia, or drug addiction affect a sizeable proportion of the human population and severely compromise quality of life. Therefore, measures to prevent the manifestation, and treatments to ameliorate the symptoms, of these disorders are in high demand. Brain lipids determine the localization and function of proteins in the cell membrane of neurons. Lipids may also act as neurotransmitters or other signalling molecules. The lipid composition of the brain can be influenced by nutrition, environmental factors, and by behavioural activity. Thus, lipids represent a target for preventive medicine of psychiatric disorders. Here we review how brain lipids contribute to normal behaviour and to major psychiatric disorders with the focus on phospholipids/fatty acids, sphingolipids, and endocannabinoids. Accumulating evidence suggests a crucial role for membrane forming and signalling lipids in the brain in the etiopathologies of depression, bipolar disorders, schizophrenia, and drug addiction. Lipids also represent potential preventive interventions for these psychiatric disorders by either targeted dietary supplementation or pharmacological manipulation of lipid regulating enzymes.
Polyunsaturated fatty acids and recurrent mood disorders: Phenomenology, mechanisms, and clinical application
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This is also supported by a recent genotyping study which did not observe an association between common single-nucleotide polymorphisms in FADS1 or FASD2 genes and depression or suicidality in MDD patients [127]. However, DNA methylation in the Elovl5 gene was found to be associated with depression and suicidality [128], and abnormalities in FADS1 and FADS2 mRNA expression have been observed in the postmortem prefrontal cortex of patients with mood disorders [129–131]. Recent evidence further suggests that patients with mood disorders do not exhibit impaired peroxisomal function despite exhibiting robust DHA deficits [132].
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.
Polyunsaturated fatty acids and suicide risk in mood disorders: A systematic review
2017, Progress in Neuro-Psychopharmacology and Biological Psychiatry
Citation Excerpt :
The main findings revealed that both central and peripheral depletion in long-chain PUFAs, (in particular omega-3 fatty acid insufficiency) was associated with MDD. MDD subjects also exhibited a decreased expression of FADS1, FADS2, and HELO1, and SCD in the postmortem frontal cortex as compared to controls (− 27%, p = 0.009, Cohen's d = 1.3) (McNamara and Yanhong, 2011). In a subsequent postmortem observational study, McNamara and Yanhong (2011) found that there was a non-significant trend for lower DHA concentrations in depressed suicide victims compared with all controls (− 10%, p = 0.06, d = 0.5).
Deficiency of omega-3 polyunsaturated fatty acids (PUFAs) and an alteration between the ratio of omega-3 and omega-6 PUFAs may contribute to the pathogenesis of bipolar disorder and unipolar depression. Recent epidemiological studies have also demonstrated an association between the depletion of PUFAs and suicide. Our aim was to investigate the relationship between PUFAs and suicide; assess whether the depletion of PUFAs may be considered a risk factor for suicidal behavior; in addition to detailing the potential use of PUFAs in clinical practice. We performed a systematic review on PUFAs and suicide in mood disorders, searching MedLine, Excerpta Medica, PsycLit, PsycInfo, and Index Medicus for relevant epidemiological, post-mortem, and clinical studies from January 1997 to September 2016. A total of 20 articles from peer-reviewed journals were identified and selected for this review. The reviewed studies suggest that subjects with psychiatric conditions have a depletion of omega-3 PUFAs compared to control groups. This fatty acid depletion has also been found to contribute to suicidal thoughts and behavior in some cases. However, large epidemiological studies have generally not supported this finding, as the depletion of omega-3 PUFAs was not statistically different between controls and patients diagnosed with a mental illness and/or who engaged in suicidal behavior. Increasing PUFA intake may be relevant in the treatment of depression, however in respect to the prevention of suicide, the data is currently not supportive of this approach. Changes in levels of PUFAs may however be a risk factor to evaluate when assessing for suicide risk. Clinical studies should be conducted to prospectively assess whether prescriptive long-term use of PUFAs in PUFA-deficient people with depression, may have a preventative role in attenuating suicide.

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Brief reportReduced expression of fatty acid biosynthesis genes in the prefrontal cortex of patients with major depressive disorder

Abstract

Background

Methods

Results

Limitations

Conclusions

Introduction

Section snippets

Postmortem brain tissue

Results

Discussion

Role of funding source

Conflict of interest statement

Acknowledgments

Prostaglandins Leukot. Essent. Fatty Acids

J. Biol. Chem.

J. Biol. Chem.

Nutrition

Prostaglandins Leukot. Essent. Fatty Acids

Brain Res. Bull.

Prostaglandins Leukot. Essent. Fatty Acids

Lancet

J. Lipid Res.

J. Affect. Disord.

J. Lipid Res.

Schizophr. Res.

J. Lipid Res.

Biol. Psychiatry

Prostogland Leukotrienes Essential Fatty Acids

Brief report
Reduced expression of fatty acid biosynthesis genes in the prefrontal cortex of patients with major depressive disorder