Human Urinary Metabolomic Profile of PPARα Induced Fatty Acid β-Oxidation

Abstract

Activation of the peroxisome proliferator-activated receptor α (PPARα) is associated with increased fatty acid catabolism and is commonly targeted for the treatment of hyperlipidemia. To identify latent, endogenous biomarkers of PPARα activation and hence increased fatty acid β-oxidation, healthy human volunteers were given fenofibrate orally for 2 weeks and their urine profiled by UPLC-QTOFMS. Biomarkers identified by the machine learning algorithm random forests included significant depletion by day 14 of both pantothenic acid (>5-fold) and acetylcarnitine (>20-fold), observations that are consistent with known targets of PPARα including pantothenate kinase and genes encoding proteins involved in the transport and synthesis of acylcarnitines. It was also concluded that serum cholesterol (-12.7%), triglycerides (-25.6%), uric acid (-34.7%), together with urinary propylcarnitine (>10-fold), isobutyrylcarnitine (>2.5-fold), (S)-(+)-2-methylbutyrylcarnitine (5-fold), and isovalerylcarnitine (>5-fold) were all reduced by day 14. Specificity of these biomarkers as indicators of PPARα activation was demonstrated using the Ppara-null mouse. Urinary pantothenic acid and acylcarnitines may prove useful indicators of PPARα-induced fatty acid β-oxidation in humans. This study illustrates the utility of a pharmacometabolomic approach to understand drug effects on lipid metabolism in both human populations and in inbred mouse models.

Daily physical activity, fasting glucose, uric acid, and body mass index are independent factors associated with serum fibroblast growth factor 21 levels

“…Studies in healthy volunteers have shown that PPAR-a activation increases urinary uric acid excretion (32). In accordance, fenofibrate (a PPAR-a activator) lowers serum uric acid levels (33).…”

Metabolites related to gut bacterial metabolism, peroxisome proliferator‐activated receptor‐alpha activation, and insulin sensitivity are associated with physical function in functionally‐limited older adults

“…In addition, PPAR-α activation upregulates gene expression of FA2H , CPT , and ACAD8 (Rakhshandehroo et al ., 2007; Makowski et al ., 2009; Takeda et al ., 2013), findings that may explain the associations found between 2-hydroxypalmitate, glutarylcarnitine [reductions in glutarylcarnitine are related to levels of CPT (Lee & Wolfgang, 2012)], and isobutyrylcarnitine with physical function. Separately, PPAR-α activation has been shown to reduce urinary excretion of isobutyrylcarnitine (Patterson et al ., 2009) and cinnamoylglycine (Zhen et al ., 2007), and cinnamoylglycine is increased in PPAR −/− mice (Zhen et al ., 2007). Collectively, these data suggest a role for mechanisms related to PPAR-α activation on influencing physical function in functionally-limited older adults.…”

Metabolomics reveals an essential role for peroxisome proliferator-activated receptor α in bile acid homeostasis

“…Metabolomics has revealed the downregulated tryptophan-nicotinamide pathways following Wy-14,643 treatment ( 9 ) and the decreased excretion of carnitine-conjugated metabolites by fenofi brate treatment in humans ( 13 ). Furthermore, an increase in the excretion of glycine conjugated metabolites was observed in Ppara -null mice ( 9 ), and the long-chain fatty acid carnitines, including palmitoylcaritine, myristolcarnitine, oleoylcarnitine, and palmitoleoylcarnitine, were elevated in the serum after suppression of PPAR␣ signal transduction by acetaminophen ( 14 ).…”