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. Author manuscript; available in PMC: 2012 Mar 1.
Published in final edited form as: J Affect Disord. 2010 Sep 21;129(1-3):359–363. doi: 10.1016/j.jad.2010.08.021

Reduced Expression of Fatty Acid Biosynthesis Genes in the Prefrontal Cortex of Patients with Major Depressive Disorder

Robert K McNamara 1,*, Yanhong Liu 1
PMCID: PMC3023006  NIHMSID: NIHMS239602  PMID: 20863572

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 to 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.

Keywords: Major depressive disorder (MDD), postmortem, prefrontal cortex, delta5 desaturase (FADS1), delta6 desaturase (FADS2), elongase (HELO1), peroxisome (PEX19), stearoyl-CoA desaturase (SCD)

1. 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, 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 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 monounsaturated fatty acid 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).

2. Method

2.1. 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 antidepressant medications, including imipramine, trazodone, fluoxetine, buspirone, sertraline, nefazodone, or nortriptyline, and one patient was also receiving lithium.

Table 1.

Comparison of subject and brain tissue characteristics

Control (n=10) MDD (n=10) p-value1
Patient Characteristics:
 Age at death, mean ± S.D. (range) 47.1 ± 12.3 (29–68) 47.7 ± 9.1 (32–65) 0.90
 Gender 4M,6F 6M,4F -
 Race2 10C 10C -
 Cause of death
  Suicide 0 4
  Cardiopulmonary 8 6
  Accident 2 0
  Other 0 0
Tissue Characteristics:
 Brain hemisphere 6L/4R 5L/5R -
 Brain mass (mean grams ± S.D.) 1522 ± 191 1486 ± 152 0.65
 Postmortem interval (mean hours ± S.D.) 24.3 ± 11.3 28.9 ± 11.8 0.39
 Tissue pH (mean ± S.D.) 6.2 ± 0.3 6.2 ± 0.2 0.72
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1

Unpaired t-test (2-tail)

2

C = Caucasian

2.2. RT-PCR

The RT-PCR procedure, and primer and probe sequences, have been described in detail previously (McNamara et al., 2008). Primers and fluorogenic probes (Midland Certified Reagent Company, Midland, TX) were designed using Primer Express v.2.0 software (Applied Biosystems, Foster City, CA) based on the human mRNA sequence. Each probe was conjugated to a FAM reporter at the 5’ end and a TAMRA quencher at the 3’ end. The reverse primer for probes spanned an exon-intron junction to obviate genomic DNA contamination. Each primer pair yielded a single band on agarose gels for HELO1 (123 bp), FADS1 (80 bp), FADS2 (88 bp), PEX19 (159 bp), and SCD (150 bp). Reverse transcription was performed using the 9600 GeneAmp thermocycler (Perkin-Elmer, Norwalk, CT). All samples were processed in triplicate (and values averaged) by a technician blinded to illness state. Individual gene mRNA values were normalized to GAPDH mRNA values obtained from the same tissue sample.

2.3. Statistical analysis

The hypothesis that lipid biosynthetic gene expression (mRNA/GAPDH mRNA) differs by illness state was tested in a two-factor ANOVA, with Illness (Controls, MDD) and Gene (FADS1, FADS2, HELO1, PEX19, SCD) as main factors. Group differences in individual gene expression (mRNA/GAPDH mRNA) were evaluated with unpaired t-tests (2-tail), and Bonferroni-adjusted for five separate comparisons (α=0.05/5 = 0.01). Analysis of gender effects used a three-factor ANOVA with Illness (Controls, MDD), Gender (male, female), and Genes as main factors. Exploratory analyses were conducted using Student’s t-tests (2-tailed, α=0.05). Homogeneity of variance was confirmed using Bartlett’s test, and effect sizes were calculated using Cohen’s d. Analyses of variance (ANOVA) were performed with GB-STAT (V.10, Dynamic Microsystems, Inc., Silver Springs MD).

3. 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 x 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 (−37%, p=0.02, d = 1.3), and SCD (−43%, p=0.02, d = 1.3)(Fig. 1A). PEX19 mRNA expression did not differ between controls and MDD patients (−2%, p=0.92). The three-factor ANOVA found that the Illness x Gender interaction, F(1,80)=1.37, p=0.24, and the Illness x Gender x Gene Interaction, F(4,80)=0.22, p=0.93, were not significant. A one-factor ANOVA of controls, MDD non-suicides, and MDD suicides found a significant main effect for FADS1, F(2,19)=3.84, p=0.04, HELO1, F(2,19)=5.63, p=0.01, and SCD, F(2,19)=4.74, p=0.02. Relative to controls, reductions in FADS1, HELO1, and SCD expression were numerically greater in MDD patients that did not commit suicide (Fig. 1B). SCD expression was significantly lower in MDD non-suicides compared with MDD suicides (p=0.03), and a similar trend was observed for HELO1 (p=0.07).

Figure 1.

Figure 1

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Expression (mRNA/GAPDH mRNA) of fatty acid biosynthetic genes in the postmortem prefrontal cortex (BA 10) of non-psychiatric controls (n=10) and MDD patients (n=10) (A). Gene expression in Controls (n=10), MDD patients that did not commit suicide (n=6), and MDD patients that committed suicide (n=4)(B). Values are group mean ± S.E.M. *P≤0.05, **P≤0.01 vs. Controls, #P≤0.05 vs. MDD non-suicides.

4. 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 monounsaturated fatty acid 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 those of a recent microarray study which also found that FADS1 and SCD expression were down-regulated in postmortem prefrontal cortices (BA8/9,11,47) of male MDD patients that committed suicide (Lalovic et al., 2010), and further indicate that FADS1 and SCD expression are down-regulated in non-suicide MDD patients independent of gender. The present findings contrast, however, with prior case-control studies finding that FADS2 mRNA expression is significantly and selectively elevated in the frontal cortex of patients with schizophrenia (Liu et al., 2009) and bipolar disorder (Liu & McNamara, submitted). These distinctions may be relevant to understanding unique mechanisms underlying PUFA homeostasis dysregulation in these different disorders.

We previously reported that patients with MDD exhibit significantly lower DHA composition in the postmortem prefrontal cortex (BA10) relative to controls (−22%), and this DHA deficit was greater in female MDD patients (−32%)(McNamara et al., 2007). Moreover, another study found that male MDD patients that committed suicide did not exhibit significant DHA deficits in postmortem prefrontal cortices (BA11,47) relative to male controls (Lalovic et al., 2007), and a third study combining male and female MDD patients observed a 30 percent lower DHA concentrations (nmol/mg) in postmortem anterior cingulate cortex (BA24)(Conklin et al., 2010). It is noteworthy, therefore, that chronic dietary ALA (18:3n-3) deficiency resulting in clinically-relevant DHA deficits does not alter FADS1, FADS2, ELOVL5 [HELO1], or SCD mRNA expression in the rat prefrontal cortex (Igarashi et al., 2007). However, we found that the age-related decline in DHA and AA composition was inversely correlated with FADS1, FADS2, and HELO1 expression in postmortem prefrontal cortex (BA10) of control subjects, suggesting a compensatory up-regulation of LC-PUFA biosynthesis (McNamara et al., 2008). Therefore, the observed reductions in the expression of fatty acid biosynthetic genes in MDD patients could reflect a defect in compensatory mechanisms that up-regulate gene expression in response to LC-PUFA deficits.

Central biosynthesis of LC-PUFA (Moore et al., 1991) and monounsaturated fatty acids (Medina & Tabernero, 2002) occurs predominantly within astrocytes. It is relevant, therefore, that prior postmortem studies have found that the expression of the astrocyte-specific marker, glial fibrillary acidic protein (GFAP), and glial cell density are significantly reduced in the postmortem prefrontal cortex of younger MDD patients (Cotter et al., 2001; Si et al., 2004). The observed reduction in all major fatty acid biosynthesis genes may therefore be a consequence of reductions in astrocyte density in the prefrontal cortex of MDD patients. However, fatty acid biosynthesis is also regulated by several other factors associated with the pathophysiology of MDD, including gonadal hormones (McNamara et al., 2009), steroidal hormones (de Alaniz & Marra, 2003), and glucose/insulin (Brenner, 2003). Future studies will be required to elucidate the mechanisms mediating the down-regulation of fatty acid biosynthesis genes in MDD.

4.1. Limitations

The present study has two principal limitations. First, all MDD patients were being treated with antidepressant medications at the time of death. This is relevant because antidepressant medications up-regulate SREBP and SCD mRNA expression in human glioma cells (Raeder et al., 2006), and the promoter regions of both FADS1 and FADS2 possess SREBP binding sites which positively regulates their transcription (Matsuzaka et al., 2002). I n the present study, however, FADS1, FADS2, and SCD mRNA expression was reduced, rather than elevated, in MDD patients. This would suggest that the observed reductions in FADS1, FADS2, and SCD mRNA expression are not a consequence of antidepressant medications, and may instead indicate impaired SREBP-mediated signaling. Second, the small number of MDD patients used in the present study may not be representative of all patients with MDD. Despite the small number of patients, however, effect sizes were large (d = 1.0 – 1.3) and the results are consistent with a prior study using an independent sample of MDD patients (Lalovic et al., 2010). Nevertheless, additional studies are warranted to replicate and extend these findings in a larger sample that includes antidepressant-free MDD patients.

4.2. Conclusions and implications

In conclusion, this preliminary case-control study found reduced expression of key genes involved in LC-PUFA biosynthesis, FADS1, FADS2, and HELO1, and monounsaturated fatty acid biosynthesis, SCD, in the postmortem prefrontal cortex of MDD patients. The results are consistent with those of a recent microarray study (Lalovic et al., 2010), and a fatty acid composition study finding changes in product/precursor ratios consistent with a defect in central Δ5 desaturase activity in MDD (Conklin et al., 2010). In view of emerging data demonstrating that polymorphisms in the promoter of LC-PUFA biosynthesis genes significantly alter transcription rates and mRNA expression (Lattka et al., 2010; Nwankwo et al., 2003), as well as phospholipid LC-PUFA composition (Schaeffer et al., 2006), interrogation for polymorphisms in these genes in MDD appears warranted. Moreover, these findings would suggest that interventions with preformed LC-PUFA, thereby bypassing potentially defective biosynthetic pathways, will be required to prevent or reverse tissue LC-PUFA deficits in MDD.

Footnotes

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