Nutr Res Pract.  2019 Aug;13(4):286-294. 10.4162/nrp.2019.13.4.286.

Deficiency or activation of peroxisome proliferator-activated receptor α reduces the tissue concentrations of endogenously synthesized docosahexaenoic acid in C57BL/6J mice

• Hsiao WT
• Su HM
• Su KP
• Chen SH
• Wu HP
• You YL
• Fu RH
• Chao PM

• KMID: 2453106
• DOI: http://doi.org/10.4162/nrp.2019.13.4.286

Abstract

BACKGROUND/OBJECTIVES
Docosahexaenoic acid (DHA), an n-3 long chain polyunsaturated fatty acid (LCPUFA), is acquired by dietary intake or the in vivo conversion of α-linolenic acid. Many enzymes participating in LCPUFA synthesis are regulated by peroxisome proliferator-activated receptor alpha (PPARα). Therefore, it was hypothesized that the tissue accretion of endogenously synthesized DHA could be modified by PPARα.
MATERIALS/METHODS
The tissue DHA concentrations and mRNA levels of genes participating in DHA biosynthesis were compared among PPARα homozygous (KO), heterozygous (HZ), and wild type (WT) mice (Exp I), and between WT mice treated with clofibrate (PPARα agonist) or those not treated (Exp II). In ExpII, the expression levels of the proteins associated with DHA function in the brain cortex and retina were also measured. An n3-PUFA depleted/replenished regimen was applied to mitigate the confounding effects of maternal DHA.
RESULTS
PPARα ablation reduced the hepatic Acox, Fads1, and Fads2 mRNA levels, as well as the DHA concentration in the liver, but not in the brain cortex. In contrast, PPARα activation increased hepatic Acox, Fads1, Fads2 and Elovl5 mRNA levels, but reduced the DHA concentrations in the liver, retina, and phospholipid of brain cortex, and decreased mRNA and protein levels of the brain-derived neurotrophic factor in brain cortex.
CONCLUSIONS
LCPUFA enzyme expression was altered by PPARα. Either PPARα deficiency or activation-decreased tissue DHA concentration is a stimulus for further studies to determine the functional significance.

Keyword

PPAR alpha; clofibrate; docosahexaenoic acids; brain-derived neurotrophic factor; fatty acid desaturases

MeSH Terms

Animals
Brain
Brain-Derived Neurotrophic Factor
Clofibrate
Docosahexaenoic Acids
Fatty Acid Desaturases
Liver
Mice*
Peroxisomes*
PPAR alpha
Retina
RNA, Messenger
Brain-Derived Neurotrophic Factor
Clofibrate
Docosahexaenoic Acids
Fatty Acid Desaturases
PPAR alpha
RNA, Messenger

Figure

• 

  Fig. 1 Biosynthetic pathways of n-6 and n-3 LCPUFA with encoding genes in parentheses

• 

  Fig. 2 Hepatic mRNA levels of PPARα target genes (A) and enzymes participating in desaturation or elongation (B) of LCPUFA biosynthesis. Data are the mean ± SD, n = 8. Comparisons were based on the mRNA levels relative to WT (taken as 1). Values without a common superscript differed (P < 0.05). WT, wild-type mice; HZ, heterozygous mice; KO, knockout mice.

• 

  Fig. 3 DHA, EPA and AA percentage in the liver (A) and brain cortex (B). Data are the mean ± SD, n = 8. Values without a common superscript differed (P < 0.05). WT, wild-type mice; HZ, heterozygous mice; KO, knockout mice; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; AA, Arachidonic acid.

• 

  Fig. 4 Hepatic mRNA levels of PPARα target genes (A) and enzymes participating in the desaturation or elongation (B) of LCPUFA biosynthesis. Data are the mean ± SD, n = 16. Comparisons were based on mRNA levels relative to C group (taken as 1). **P < 0.01, ***P < 0.0001. C, control mice; CF, clofibrate-treated mice.

• 

  Fig. 5 DHA, EPA and AA percentage in the total lipid of liver (A), phospholipids of brain cortex (B) and total lipid of retina (C). Hepatic mRNA levels of Cpt1a and Ehhadh are shown in (D). Data are the mean ± SD, n = 16 (for A, B, and D) or 4 (for C). *P < 0.05, **P < 0.01, ***P < 0.0001. C, control mice; CF, clofibrate-treated mice; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; AA, Arachidonic acid.

• 

  Fig. 6 mRNA levels of gene encoding proteins associated with DHA transportation and functions in brain cortex (A) and retina (B). (C) shows BDNF protein levels in brain cortex. Data are the mean ± SD, n = 16. (A) and (B). The comparison was based on the mRNA levels relative to the C group (taken as 1). *P < 0.05, ***P < 0.0001. C, control mice; CF, clofibrate-treated mice; BDNF, brain-derived neurotrophic factor.

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