Marianne Haag

Essential Fatty Acids and the Brain

Objective: To review the role of essential fatty acids in brain membrane function and in the genesis of psychiatric disease. Method: Medline databases were searched for published articles with links among the following key words: essential fatty acids, omega-3 fatty acids, docosahexanoic acid, eicosapentanoic acid, arachidonic acid, neurotransmission, phospholipase A2, depression, schizophrenia, mental performance, attention-deficit hyperactivity disorder, and Alzheimers disease. Biochemistry textbooks were consulted on the role of fatty acids in membrane function, neurotransmission, and eicosanoid formation. The 3-dimensional structures of fatty acids were obtained from the Web site of the Biochemistry Department, University of Arizona (2001). Results: The fatty acid composition of neuronal cell membrane phospholipids reflects their intake in the diet. The degree of a fatty acids desaturation determines its 3-dimensional structure and, thus, membrane fluidity and function. The ratio between omega-3 and omega-6 polyunsaturated fatty acids (PUFAs), in particular, influences various aspects of serotoninergic and catecholaminergic neurotransmission, as shown by studies in animal models. Phospholipase A2 (PLA2) hydrolyzes fatty acids from membrane phospholipids: liberated omega-6 PUFAs are metabolized to prostaglandins with a higher inflammatory potential, compared with those generated from the omega-3 family. Thus the activity of PLA2 coupled with membrane fatty acid composition may play a central role in the development of neuronal dysfunction. Intervention trials in human subjects show that omega-3 fatty acids have possible positive effects in the treatment of various psychiatric disorders, but more data are needed to make conclusive directives in this regard. Conclusion: The ratio of membrane omega-3 to omega-6 PUFAs can be modulated by dietary intake. This ratio influences neurotransmission and prostaglandin formation, processes that are vital in the maintenance of normal brain function.

Long chain polyunsaturated fatty acids : selected mechanisms of action on bone

Evidence presented over the past 20 years has shown that long-chain polyunsaturated fatty acids (LCPUFAs), especially the n-3 fatty acids such as eicospentaenoic acid (EPA) and docosahexaenoic acid (DHA) are beneficial for bone health. Some studies in humans indicate that LCPUFAs can increase bone formation, affect peak bone mass in adolescents and reduce bone loss as measured using bone mineral densitometry. The cellular mechanisms of action of the LCPUFAs, however, are complex and involve modulation of fatty acid metabolites such as prostaglandins, resolvins and protectins, several signalling pathways, cytokines and growth factors. LCPUFAs affect receptor activator of nuclear factor κβ (RANK), a receptor found on the osteoclast, the cell causing bone resorption, which controls osteoclast formation. Lipoxygenase (LOX) generated lipid mediators (resolvins, lipoxins, protectins and docosanoids) have both anti-inflammatory and pro-resolving activities. Both resolvins and lipoxins inhibit inflammation-induced bone resorption. Arachidonic acid significantly upregulates inducible NO synthase (iNOS) mRNA expression in human osteoblast-like cells, thereby possibly enhancing osteoclastic activity. The protective effect of EPA on osteoblastogenesis could be mediated by the biphasic cross-talk between PGE(2) and NO production involving COX-2 and iNOS pathways. Other mediators of osteoblast maturation include PPARα ligands such as linoleic acid and possibly DHA in association with bone morphogenic proteins. Since DHA is a weaker ligand for PPARγ, more uncommitted mesenchymal stem cells are thought to differentiate into osteoblasts rather than adipocytes. This review addresses selected cellular mechanisms that may explain the beneficial effects of the LCPUFAs on bone.

Omega-3 fatty acids modulate ATPases involved in duodenal Ca absorption

Dietary supplementation with fish oil that contains omega-3 polyunsaturated fatty acids has been shown to enhance bone density as well as duodenal calcium uptake in rats. The latter process is supported by membrane ATPases. The present in vitro study was undertaken to test the effect of omega-3 fatty acids on ATPase activity in isolated basolateral membranes from rat duodenal enterocytes. Ca-ATPase in calmodulin-stripped membranes was activated in a biphasic manner by docosahexanoic acid (DHA) (10-30 microg/ml) but not by eicosapentanoic acid (EPA). This effect was blocked partially by 0.5 microM calphostin (a protein kinase C blocker). DHA inhibited Na,K-ATPase (-49% of basal activity, [DHA]=30 microg/ml, P <0.01). This effect could be reversed partially by 50 microM genistein, a tyrosine kinase blocker. EPA also inhibited Na,K-ATPase: (-47% of basal activity, [EPA]=30 microg/ml, P <0.01), this effect was partially reversed by 100 microM indomethacin, a cyclo-oxygenase blocker. Omega-3 fatty acids are thus involved in multiple signalling effects that effect ATPases in BLM.

Effects of arachidonic acid and docosahexaenoic acid on differentiation and mineralization of MC3T3-E1 osteoblast-like cells

Osteoblasts in culture can differentiate into mature mineralizing osteoblasts when stimulated with osteogenic agents. Clinical trials and in vivo animal studies suggest that specific polyunsaturated fatty acids (PUFAs) may benefit bone health. The aim of this study was to investigate whether arachidonic acid (AA) and docosahexaenoic acid (DHA) affect osteogenesis in osteoblasts and the transdifferentiation into adipocytes. Results from this study show that long‐term exposure to AA inhibited alkaline phosphatase (ALP) activity in these cells, which might be prostaglandin E2 (PGE2)‐mediated. DHA exposure also inhibited ALP activity which was evident after both short‐ and long‐term exposures. The mechanism whereby DHA inhibits ALP activity is not clear and needs to be investigated. Although long‐term exposure to PUFAs inhibited ALP activity, the mineralizing properties of these cells were not compromised. Furthermore, PUFA exposure did not induce adipocyte‐like features in these cells as evidenced by the lack of cytoplasmic triacylglycerol accummulation. More research is required to elucidate the cellular mechanisms of action of PUFAs on bone. Copyright

Effect of arachidonic acid on duodenal enterocyte ATPases.

Duodenal ion transport processes are supported by ATPase enzymes in basolateral membranes of the enterocyte. In vivo studies have shown that long term n-6 poly-unsaturated fatty acid (PUFA) supplementation in rats causes increases in intestinal Ca absorption, coupled with a higher total calcium balance and bone calcium content. The present in vitro study was undertaken to test the effect of arachidonic acid (AA), a highly unsaturated (and thus physiologically potent) member of the n-6 PUFA family, on ATPases in enterocyte basolateral membranes isolated with a sorbitol density gradient procedure. This paper presents results which show that AA inhibits Na+,K+-ATPase in a dose-dependent manner (-67% of basal activity at a concentration of 30 microg/ml, P < 0.005) but that this effect is not mediated by protein kinase C, as shown by the use of the protein kinase C blocker calphostin (0.5 microM). Indomethacin (IDM) at 0.1 mM, a cyclo-oxygenase blocker, could also not reverse the inhibitory effect of AA on Na+,K+-ATPase. Ca2+-ATPase, on the other hand, is not affected significantly (-10%, P > 0.05) by arachidonic acid at 30 microg/ml.

Short-term fatty acid effects on adipocyte glucose uptake: mechanistic insights.

The modulation of insulin sensitivity in visceral fat tissue could be important in the treatment of Type 2 diabetes mellitus. Selected fatty acids may impact on insulin-stimulated and basal glucose uptake in adipocytes, thus isolated rat epididymal adipocytes were exposed to 100 microM oleic, arachidonic, eicosapentaenoic, docosahexaenoic or stearic acids and insulin (15 nM) or vehicle for 30 min. Glucose uptake was quantified by measuring uptake of 3H-deoxyglucose/mg adipocyte protein/min. Where appropriate, inhibitors were included to elucidate the mechanisms involved. In this model, insulin stimulated glucose uptake with 62+/-7%. All fatty acids tested, except for stearic acid, depressed insulin-stimulated glucose uptake by an average of 33+/-4.2%. On the other hand, all fatty acids tested except stearic and arachidonic acids, stimulated basal glucose uptake with an average of 34+/-8.1%. Inhibitor studies showed the involvement of prostaglandins, lipoxins, protein kinase C and tyrosine kinase in these processes.