Identification of differences in human and great ape phytanic acid metabolism that could influence gene expression profiles and physiological functions

Abstract

Background: It has been proposed that anatomical differences in human and great ape guts arose in response to species-specific diets and energy demands. To investigate functional genomic consequences of these differences, we compared their physiological levels of phytanic acid, a branched chain fatty acid that can be derived from the microbial degradation of chlorophyll in ruminant guts. Humans who accumulate large stores of phytanic acid commonly develop cerebellar ataxia, peripheral polyneuropathy, and retinitis pigmentosa in addition to other medical conditions. Furthermore, phytanic acid is an activator of the PPAR-alpha transcription factor that influences the expression of genes relevant to lipid metabolism.

Results: Despite their trace dietary phytanic acid intake, all great ape species had elevated red blood cell (RBC) phytanic acid levels relative to humans on diverse diets. Unlike humans, chimpanzees showed sexual dimorphism in RBC phytanic acid levels, which were higher in males relative to females. Cultured skin fibroblasts from all species had a robust capacity to degrade phytanic acid. We provide indirect evidence that great apes, in contrast to humans, derive significant amounts of phytanic acid from the hindgut fermentation of plant materials. This would represent a novel reduction of metabolic activity in humans relative to the great apes.

Conclusion: We identified differences in the physiological levels of phytanic acid in humans and great apes and propose this is causally related to their gut anatomies and microbiomes. Phytanic acid levels could contribute to cross-species and sex-specific differences in human and great ape transcriptomes, especially those related to lipid metabolism. Based on the medical conditions caused by phytanic acid accumulation, we suggest that differences in phytanic acid metabolism could influence the functions of human and great ape nervous, cardiovascular, and skeletal systems.

Figure 1

Phytanic acid catabolism in mammals. Phytanic acid in ruminant fats is derived from phytol produced during the bacterial degradation of chlorophyll in their rumen (first stomach). After conversion to its CoA thioester, phytanic acid undergoes α-oxidation, yielding pristanic acid. This fatty acid then undergoes three subsequent rounds of β-oxidation in the peroxisome. The resulting medium chain fatty acid exits the peroxisome and translocates to the mitochondrion where the remaining carbon chain is degraded by β-oxidation. Abbreviations for the enzymes listed include: HACL1 (aka HPCL2) = 2-hydroxyphytanoyl-CoA lyase; PHYH = phytanoyl-CoA α-hydroxylase; PDH = pristanal dehydrogenase, whose gene is not yet known. We note that phytanic acid can also be degraded by β-oxidation; however, this activity of this pathway is relatively minor [40,44].

Figure 2

Phytanic acid levels in human and great ape red blood cells. Box plots representing the percentage of phytanic acid relative to total fatty acids from red blood cells are provided. Median, quartile 1, quartile 3, minimum, and maximum values are provided. In Panels A and B, the species (Hsa: human; Ptr: chimpanzee; Ppa: bonobo; Ggo: gorilla; Ppy: orangutan), human diet (V: vegan, W: western), and number of individuals successfully analyzed is provided on the X-axes. Blood donor sex (M: male, F: female) is provided in Panel B.

Figure 3

Phytanic acid catabolism in human and great ape cultured fibroblasts. Box plots representing the relative rates of (A) phytanic acid and (B) pristanic acid oxidation in cultured fibroblasts are provided. Median, quartile 1, quartile 3, minimum, and maximum values are provided. The species and number of samples successfully analyzed is provided on the X-axis of both panels.

Figure 4

Differential expression of genes related to peroxisomal lipid metabolism. We reanalyzed of Affymetrix GeneChip U133v2.0 expression profiles of human and chimpanzee tissues [51] using the masking strategy stated in the text. We used standard F-tests (FDR-adjusted using the Benjamini and Hochberg approach) to test for differences in the distributions by species for the 5 tissues. The fold change (FC) of human (Hsa) versus chimpanzee (Ptr) geometric mean gene expression scores are provided. Differentially expressed genes (≥1.2 FC in either direction with a Student's t-test, two-tailed P-value ≤0.05 after Bonferroni correction) for a given tissue are highlighted in red (higher in human) or green (higher in chimpanzee). Probe sets with (i) F-tests yielding a ≤5% FDR and (ii) differential expression in at least one tissue are shown. All data are provided in Additional File 3.