A phytol-enriched diet induces changes in fatty acid metabolism in mice both via PPARα-dependent and -independent pathways

Gloerich, Jolein; Vlies, Naomi van; Jansen, G. A.; Denis, Simone; Ruiter, J. P. N.; Werkhoven, M. A. Van; Durán, Marinus; Vaz, Frédéric M.; Wanders, Ronald J. A.; Ferdinandusse, Sacha

doi:10.1194/jlr.m400337-jlr200

Cited by 71 publications

(52 citation statements)

References 52 publications

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“…Other ROS generators, chaetocin and phytol, however, did not show the synergistic antitumor effect, suggesting they differ quantitatively or qualitatively from Luperox in the ROS generation mechanism in T cells (Fig. S4 A-C) (28,29).…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity

Chamoto

Chowdhury

Kumar

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

340

287

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Although immunotherapy by PD-1 blockade has dramatically improved the survival rate of cancer patients, further improvement in efficacy is required to reduce the fraction of less sensitive patients. In mouse models of PD-1 blockade therapy, we found that tumor-reactive cytotoxic T lymphocytes (CTLs) in draining lymph nodes (DLNs) carry increased mitochondrial mass and more reactive oxygen species (ROS). We show that ROS generation by ROS precursors or indirectly by mitochondrial uncouplers synergized the tumoricidal activity of PD-1 blockade by expansion of effector/ memory CTLs in DLNs and within the tumor. These CTLs carry not only the activation of mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) but also an increment of their downstream transcription factors such as PPAR-gamma coactivator 1α (PGC-1α) and T-bet. Furthermore, direct activators of mTOR, AMPK, or PGC-1α also synergized the PD-1 blockade therapy whereas none of above-mentioned chemicals alone had any effects on tumor growth. These findings will pave a way to developing novel combinatorial therapies with PD-1 blockade.PD-1 | cancer immunotherapy | mitochondria | immune metabolism | PGC-1α

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Section: Resultsmentioning

confidence: 99%

Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity

Chamoto

Chowdhury

Kumar

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

340

287

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“…This has been used as a model to study the effects of the accumulation of phytol metabolites on fatty acid metabolism, in particular via the activation of the nuclear hormone receptor peroxisome proliferator-activated receptor a (PPARa), which is an important transcription factor in the regulation of fatty acid metabolism. Both phytanic and pristanic acid have been shown to activate PPARa in vitro (14,15), and more recently, PPARa was also shown to be activated in vivo in mice fed a phytol-enriched diet (13). Figure 1 shows a schematic representation of the metabolism of phytol to phytanic acid and the enzymes involved.…”

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confidence: 99%

“…Addition of phytol to the diet results in an increase of phytol metabolites in tissues and plasma (6,(11)(12)(13). This has been used as a model to study the effects of the accumulation of phytol metabolites on fatty acid metabolism, in particular via the activation of the nuclear hormone receptor peroxisome proliferator-activated receptor a (PPARa), which is an important transcription factor in the regulation of fatty acid metabolism.…”

mentioning

confidence: 99%

Metabolism of phytol to phytanic acid in the mouse, and the role of PPARα in its regulation

Gloerich

Brink

Ruiter

et al. 2007

Journal of Lipid Research

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Phytol, a branched-chain fatty alcohol, is the naturally occurring precursor of phytanic and pristanic acid, branched-chain fatty acids that are both ligands for the nuclear hormone receptor peroxisome proliferator-activated receptor a (PPARa). To investigate the metabolism of phytol and the role of PPARa in its regulation, wild-type and PPARa knockout (PPARa 2/2 ) mice were fed a phytolenriched diet or, for comparison, a diet enriched with Wy-14,643, a synthetic PPARa agonist. After the phytolenriched diet, phytol could only be detected in small intestine, the site of uptake, and liver. Upon longer duration of the diet, the level of the (E)-isomer of phytol increased significantly in the liver of PPARa 2/2 mice compared with wildtype mice. Activity measurements of the enzymes involved in phytol metabolism showed that treatment with a PPARa agonist resulted in a PPARa-dependent induction of at least two steps of the phytol degradation pathway in liver. Furthermore, the enzymes involved showed a higher activity toward the (E)-isomer than the (Z)-isomer of their respective substrates, indicating a stereospecificity toward the metabolism of (E)-phytol. In conclusion, the results described here show that the conversion of phytol to phytanic acid is regulated via PPARa and is specific for the breakdown of (E) Phytol is a branched-chain fatty alcohol (3,7,11,15-tetramethylhexadec-2-en-1-ol) that is abundantly present in nature as part of the chlorophyll molecule. The release of phytol from chlorophyll occurs effectively in the digestive system of ruminant animals only, presumably by bacteria present in the gut (1). As a result, a relatively high amount of free phytol is present in dairy products (2). In mammals, free phytol is readily absorbed in the small intestine and is metabolized to phytanic acid, a fatty acid that accumulates in a number of metabolic disorders. Increased levels of phytanic acid in the body are toxic, so this fatty acid needs to be broken down (3-9). Because the methyl-group at the 3 position prevents b-oxidation, phytanic acid first has to undergo a round of a-oxidation. This results in the formation of pristanic acid, which is one carbon atom shorter than phytanic acid and can be normally b-oxidized (10). A deficiency in a-oxidation, such as in Refsum disease, leads to increased levels of phytanic acid in plasma and tissues of patients, and this is thought to cause the main clinical symptoms of this disorder: retinitis pigmentosa, peripheral neuropathy, and cerebellar ataxia (3, 4). Because the breakdown of phytol will contribute to the phytanic and pristanic acid levels in these patients, it is important to study its metabolism and regulation.In many animal studies, phytol is used as a precursor of phytanic acid. Addition of phytol to the diet results in an increase of phytol metabolites in tissues and plasma (6,(11)(12)(13). This has been used as a model to study the effects of the accumulation of phytol metabolites on fatty acid metabolism, in particular via the activation of the nu...

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“…The accumulation of phytol has previously been observed in the liver of rats fed with a phytol-enriched diet for 7 d. 23) Phytol is readily converted to phytanic acid in the tissue of such mammals as rats and humans. 24,25) It has been reported that phytol and phytanic acid activated the retinoid X receptor (RXR), 26) sterol carrier protein x (SCP-x), 27) and livertype fatty acid binding protein (L-FABP) in a dosedependent manner.…”

Section: )mentioning

confidence: 99%

Effect of Dietary Phytol on the Expression of α-Amino-β-carboxymuconate-ε-semialdehyde Decarboxylase, a Key Enzyme of Tryptophan-niacin Metabolism, in Rats

Matsuda¹,

Gomi²,

Hirai³

et al. 2013

Bioscience, Biotechnology, and Biochemistry

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A phytol-enriched diet induces changes in fatty acid metabolism in mice both via PPARα-dependent and -independent pathways

Cited by 71 publications

References 52 publications

Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity

Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity

Metabolism of phytol to phytanic acid in the mouse, and the role of PPARα in its regulation

Effect of Dietary Phytol on the Expression of α-Amino-β-carboxymuconate-ε-semialdehyde Decarboxylase, a Key Enzyme of Tryptophan-niacin Metabolism, in Rats

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