Immunomodulatory lipids in plants: plant fatty acid amides and the human endocannabinoid system

Since the discovery that endogenous lipid mediators show similar cannabimimetic effects as phytocannabinoids from CANNABIS SATIVA, our knowledge about the endocannabinoid system has rapidly expanded. Today, endocannabinoid action is known to be involved in various diseases, including inflammation and pain. As a consequence, the G-protein coupled cannabinoid receptors, endocannabinoid transport, as well as endocannabinoid metabolizing enzymes represent targets to block or enhance cannabinoid receptor-mediated signalling for therapeutic intervention. Based on the finding that certain endocannabinoid-like fatty acid N-alkylamides from purple coneflower ( ECHINACEA spp.) potently activate CB2 cannabinoid receptors we have focused our interest on plant fatty acid amides (FAAs) and their overall cannabinomodulatory effects. Certain FAAs are also able to partially inhibit the action of fatty acid amide hydrolase (FAAH), which controls the breakdown of endocannabinoids. Intriguingly, plants lack CB receptors and do not synthesize endocannabinoids, but express FAAH homologues capable of metabolizing plant endogenous N-acylethanolamines (NAEs). While the site of action of these NAEs in plants is unknown, endogenous NAEs and arachidonic acid glycerols in animals interact with distinct physiological lipid receptors, including cannabinoid receptors. There is increasing evidence that also plant FAAs other than NAEs can pharmacologically modulate the action of these endogenous lipid signals. The interference of plant FAAs with the animal endocannabinoid system could thus be a fortunate evolutionary cross point with yet unexplored therapeutic potential.

Lipids as targets for novel anti-inflammatory therapies

Lipids serve important functions as membrane constituents and also as energy storing molecules. Besides these functions certain lipid species have now been recognized as signalling molecules that regulate a multitude of cellular responses including cell growth and death, and also inflammatory reactions. Bioactive lipids are generated by hydrolysis from membrane lipids mainly by phospholipases giving rise to fatty acids and lysophospholipids that either directly exert their function or are further converted to active mediators. This review will summarize the present knowledge about bioactive lipids that either promote or attenuate inflammatory reactions. These lipids include polyunsaturated fatty acids (PUFA), eicosanoids including the epoxyeicosatrienoic acids (EET), peroxisome proliferation activating receptor (PPAR) activators, cannabinoids and the sphingolipids ceramide, sphingosine 1-phosphate and sphingosylphosphorylcholine.

Distribution of intramyocellular lipids in human calf muscles as determined by MR spectroscopic imaging

In this study the distribution of intramyocellular lipids (IMCL) in human calf muscles was determined by 1H-MR spectroscopic imaging (MRSI) measurements. An obstacle for MRSI measurements in the calf, including different muscles, is the inevitable inclusion of regions with high concentrations of extramyocellular lipids (EMCL). This can lead to signal bleeding and consequently to unpredictable overlaps of IMCL resonances with EMCL in voxels of interest. The results of this study show that signal bleeding from EMCL can be substantially reduced in voxels from calf muscles by the application of a lipid extrapolation (LE) procedure (Haupt et al., Magn Reson Med 1996;35:678). The spectra of all voxels located within muscle tissue were fitted, and the metabolite values were assigned to one of 10 different muscles based on image segmentation. Significant IMCL differences between some muscles were obtained, with high values in m. soleus and two to three times lower values in the tibialis anterior, tibialis posterior, and gastrocnemius muscles. In addition to gross differences between muscles, significant intersubject differences were observed in both IMCL content and distribution over different muscles. A significant correlation between fiber orientation (obtained from orientation-dependent dipolar coupling of creatine and taurine resonances) and IMCL content was found, indicating that IMCL content is directly correlated to biomechanical properties.

Changes in plasma lipids with psychosocial stress are related to hypertension status and the norepinephrine stress response

Hypertension is a known risk factor for cardiovascular disease. Hypertensive individuals show exaggerated norepinephrine (NE) reactivity to stress. Norepinephrine is a known lipolytic factor. It is unclear if, in hypertensive individuals, stress-induced increases in NE are linked with the elevations in stress-induced circulating lipid levels. Such a mechanism could have implications for atherosclerotic plaque formation. In a cross-sectional, quasi-experimentally controlled study, 22 hypertensive and 23 normotensive men (mean +/- SEM, 45 +/- 3 years) underwent an acute standardized psychosocial stress task combining public speaking and mental arithmetic in front of an audience. We measured plasma NE and the plasma lipid profile (total cholesterol [TC], low-density-lipoprotein cholesterol [LDL-C], high-density-lipoprotein cholesterol, and triglycerides) immediately before and after stress and at 20 and 60 minutes of recovery. All lipid levels were corrected for stress hemoconcentration. Compared with normotensives, hypertensives had greater TC (P = .030) and LDL-C (P = .037) stress responses. Independent of each other, mean arterial pressure (MAP) upon screening and immediate increase in NE predicted immediate stress change in TC (MAP: beta = .41, P = .003; NE: beta = .35, P = .010) and LDL-C (MAP: beta = .32, P = .024; NE: beta = .38, P = .008). Mean arterial pressure alone predicted triglycerides stress change (beta = .32, P = .043) independent of NE stress change, age, and BMI. The MAP-by-NE interaction independently predicted immediate stress change of high-density-lipoprotein cholesterol (beta = -.58, P < .001) and of LDL-C (beta = -.25, P < .08). We conclude that MAP and NE stress reactivity may elicit proatherogenic changes of plasma lipids in response to acute psychosocial stress, providing one mechanism by which stress might increase cardiovascular risk in hypertension.