PPARalpha-mediated effects of dietary lipids on intestinal barrier gene
expression.
de Vogel-van den Bosch HM, Bunger M, de Groot PJ, Bosch-Vermeulen H,
Hooiveld GJ, Muller M.
Nutrition, Metabolism and Genomics group, Division of Human Nutrition,
Wageningen University, PO Box 8129, NL-6700EV, Wageningen, the
Netherlands.

BACKGROUND: The selective absorption of nutrients and other food
constituents in the small intestine is mediated by a group of transport
proteins and metabolic enzymes, often collectively called 'intestinal
barrier proteins'. An important receptor that mediates the effects of
dietary lipids on gene expression is the peroxisome
proliferator-activated receptor alpha (PPARalpha), which is abundantly
expressed in enterocytes. In this study we examined the effects of acute
nutritional activation of PPARalpha on expression of genes encoding
intestinal barrier proteins. To this end we used triacylglycerols
composed of identical fatty acids in combination with gene expression
profiling in wild-type and PPARalpha-null mice. Treatment with the
synthetic PPARalpha agonist WY14643 served as reference. RESULTS: We
identified 74 barrier genes that were PPARalpha-dependently regulated 6
hours after activation with WY14643. For eicosapentaenoic acid (EPA),
docosahexaenoic acid (DHA) and oleic acid (OA) these numbers were 46,
41, and 19, respectively. The overlap between EPA-, DHA-, and
WY14643-regulated genes was considerable, whereas OA treatment showed
limited overlap. Functional implications inferred form our data
suggested that nutrient-activated PPARalpha regulated transporters and
phase I/II metabolic enzymes were involved in a) fatty acid oxidation,
b) cholesterol, glucose, and amino acid transport and metabolism, c)
intestinal motility, and d) oxidative stress defense. CONCLUSION: We
identified intestinal barrier genes that were PPARalpha-dependently
regulated after acute activation by fatty acids. This knowledge provides
a better understanding of the impact dietary fat has on the barrier
function of the gut, identifies PPARalpha as an important factor
controlling this key function, and underscores the importance of
PPARalpha for nutrient-mediated gene regulation in intestine.

Publication Types:
*  Research Support, Non-U.S. Gov't

PMID: 18489776

Biochim Biophys Acta. 2008 Apr;1781(4):200-12. Epub 2008 Feb 12.
 
Influence of dietary fatty acids on endocannabinoid and
N-acylethanolamine levels in rat brain, liver and small intestine.
Artmann A, Petersen G, Hellgren LI, Boberg J, Skonberg C, Nellemann C,
Hansen SH, Hansen HS.
Department of Pharmacology and Pharmacotherapy, Faculty of
Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2,
DK-2100 Copenhagen, Denmark.

Endocannabinoids and N-acylethanolamines are lipid mediators regulating
a wide range of biological functions including food intake. We
investigated short-term effects of feeding rats five different dietary
fats (palm oil (PO), olive oil (OA), safflower oil (LA), fish oil (FO)
and arachidonic acid (AA)) on tissue levels of 2-arachidonoylglycerol,
anandamide, oleoylethanolamide, palmitoylethanolamide,
stearoylethanolamide, linoleoylethanolamide,
eicosapentaenoylethanolamide, docosahexaenoylethanolamide and tissue
fatty acid composition. The LA-diet increased linoleoylethanolamide and
linoleic acid in brain, jejunum and liver. The OA-diet increased brain
levels of anandamide and oleoylethanolamide (not 2-arachidonoylglycerol)
without changing tissue fatty acid composition. The same diet increased
oleoylethanolamide in liver. All five dietary fats decreased
oleoylethanolamide in jejunum without changing levels of anandamide,
suggesting that dietary fat may have an orexigenic effect. The AA-diet
increased anandamide and 2-arachidonoylglycerol in jejunum without
effect on liver. The FO-diet decreased liver levels of all
N-acylethanolamines (except eicosapentaenoylethanolamide and
docosahexaenoylethanolamide) with similar changes in precursor lipids.
The AA-diet and FO-diet had no effect on N-acylethanolamines,
endocannabinoids or precursor lipids in brain. All N-acylethanolamines
activated PPAR-alpha. In conclusion, short-term feeding of diets
resembling human diets (Mediterranean diet high in monounsaturated fat,
diet high in saturated fat, or diet high in polyunsaturated fat) can
affect tissue levels of endocannabinoids and N-acylethanolamines.

Publication Types:
*  Research Support, Non-U.S. Gov't

PMID: 18316044

Br J Pharmacol. 2007 Nov;152(5):734-43. Epub 2007 Oct 1

  
Cannabinoid activation of PPAR alpha; a novel neuroprotective mechanism.
Sun Y, Alexander SP, Garle MJ, Gibson CL, Hewitt K, Murphy SP, Kendall
DA, Bennett AJ.
School of Biomedical Sciences, University of Nottingham Medical School,
Nottingham, UK.

BACKGROUND AND PURPOSE: Although CB(1) receptor activation evokes
neuroprotection in response to cannabinoids, some cannabinoids have been
reported to be peroxisome proliferator activated receptor (PPAR)
ligands, offering an alternative protective mechanism. We have,
therefore, investigated the ability of a range of cannabinoids to
activate PPAR alpha and for N-oleoylethanolamine (OEA), an endogenous
cannabinoid-like compound (ECL), to evoke neuroprotection. EXPERIMENTAL
APPROACH: Assays of PPAR alpha occupancy and gene transactivation
potential were conducted in cell-free and transfected HeLa cell
preparations, respectively. In vivo estimates of PPAR alpha activation
through fat mobilization and gene transcription were conducted in mice.
Neuroprotection in vivo was investigated in wild-type and PPAR alpha
gene-disrupted mice. KEY RESULTS: The ECLs OEA, anandamide, noladin
ether and virodhamine were found to bind to the purified PPAR alpha
ligand binding domain and to increase PPAR alpha-driven transcriptional
activity. The high affinity synthetic CB(1/2) cannabinoid agonist WIN
55212-2 bound to PPAR alpha equipotently with the PPARalpha agonist
fenofibrate, and stimulated PPARalpha-mediated gene transcription. The
phytocannabinoid delta 9 tetrahydrocannabinol was without effect. OEA
and WIN 55212-2 induced lipolysis in vivo, while OEA pre-treatment
reduced infarct volume from middle cerebral artery occlusion in
wild-type, but not in PPAR alpha-null mice. OEA treatment also led to
increased expression of the NFkappa B-inhibitory protein, Ikappa B, in
mouse cerebral cortex, while expression of the NFkappa B-regulated
protein COX-2 was inhibited.Conclusions and implications:These data
demonstrate the potential for a range of cannabinoid compounds, of
diverse structures, to activate PPAR alpha and suggest that at least
some of the neuroprotective properties of these agents could be mediated
by nuclear receptor activation.