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Fats for Life

July 2001

By Karin Granstrom Jordan, M.D.

Recently it has been discovered that elevated levels of the mineralocorticoid hormone aldosterone plays a much larger role in hypertension and cardiac disease than previously believed. Aldosterone-reducing drugs are used in the treatment of hypertension and have recently been discovered to be effective also for treatment of heart failure (Weber, 1999).

In addition to many other mechanisms of action, both GLA and DHA have now been found to inhibit aldosterone production, which may be a discovery of great importance in the prevention of cardiovascular disease.

One of the key mechanisms in the regulation of blood pressure is the renin-angiotensin-aldosterone system. Renin is released from the kidneys in response to low blood pressure and stimulates the production of aldosterone via several intermediate steps, including angi-otensin I and II. Aldosterone controls sodium and water uptake in the kidneys, and elevated levels increase the blood pressure.

Not all cases of hypertension, however, are triggered through the renin-angiotensin system. So-called primary aldosteronism has traditionally been regarded as a rare cause of hypertension (1%) but has recently been discovered to be more frequent than earlier believed (10% to 15% of patients with essential hypertension) (Fardella et al., 1999). This condition is characterized by excess production of aldosterone in the adrenal gland, without involvement of the renin-angiotensin-aldosterone system. Characteristic features of primary aldosteronism are high aldosterone levels, low renin levels and a high aldosterone/renin ratio.

Since elevated aldosterone levels have been found to play such a major role in hypertension, a research team under Marguerite Engler investigated the relationship between GLA, DHA and aldosterone in animals. In several previous experimental studies Engler et al. had demonstrated that borage oil and DHA have blood pressure lowering effects in hypertensive, normotensive, old and young rats (Engler et al., 1992, 1993). When the scientists studied the effects of GLA and DHA on the renin-angiotensin-aldosterone system in rats, genetically programmed for hypertension (Engler et al., 1998 and 1999), it became clear that both these EFAs affect the renin-angiotensin-aldosterone system. Although in slightly different ways, both GLA and DHA decreased the production of aldosterone. In the GLA study the aldosterone/renin ratio was significantly lower in the borage oil group than in the control group given sesame oil. In the DHA study aldosterone was significantly lowered (33%) compared to the control group fed a diet containing corn/soybean oil. A remarkable reduction of the systolic blood pressure was also seen in both studies. In the borage oil group the decrease was 12 mmHg after three weeks, and in the DHA study the blood pressure was 34 mmHg lower on an average after six weeks.

The observations in these studies suggested that borage oil (GLA) inhibits the adrenal responsiveness to angiotensin II through diminished angiotensin receptor activity in aldosterone producing cells. Decreased aldosterone levels stimulate renin secretion and the net effect is a desirable reduction in the aldosterone/renin ratio. DHA on the other hand, appears to affect the aldosterone production without involving angiotensin receptors.

Kimura et al. (1995) found that DHA supplementation could to a large extent prevent an increase in blood pressure in rats genetically programmed to develop hypertension and stroke (spontaneously hypertensive rats). While the average blood pressure in the control group of young rats on “normal” diet increased form 120.2 to 202.9 mmHg during the test period, blood pressure in the DHA supplemented group only increased to 149.8 mmHg. Serum creatinine levels and blood urea nitrogen were significantly lower in the DHA group, which indicates beneficial changes in renal function.

These experimental blood pressure lowering effects on rats have been confirmed in clinical trials on humans. Mori et al. (1999) conducted an interesting, double-blind, placebo-controlled trial with 59 overweight, hyperlipidemic men to compare the effects of purified EPA, DHA and olive oil supplementation (4g/d in capsules). Only DHA had significant blood pressure and heart rate lowering effects. Systolic and diastolic blood pressure fell on average 5.8 and 3.3 mmHg respectively, and daytime heart rate fell 3.7 bpm. These results also show that DHA, rather than EPA, is the principal omega-3 fatty acid in fish and fish oils responsible for their beneficial effects on the cardiovascular system.

The beneficial effects of the omega-3 fatty acids EPA and DHA had previously been attributed mainly to EPA because of its predominance in fish oil. However, it has recently become clear that DHA is the more important of the two. For example, in comparison to EPA, DHA has consistently proven to be more effective in lowering plasma triglycerides, increasing HDL cholesterol levels and lowering blood pressure and heart rate, while also being unique in its effect on the central nervous system.

In another randomized clinical trial a combination of highly purified DHA and EPA significantly reduced blood pressure in mildly hypertensive men (Prisco et al, 1998). Daily supplementation with 1.4 g DHA and 2.04 g EPA resulted in a decrease in both systolic (6 mmHg) and diastolic (5 mmHg) blood pressure after two months. No further effect was observed at four months and there was a return to baseline levels after two months without supplementation.

Basic Fat Chemistry

Fatty acids are distinguished by length (number of carbon atoms) and location of double bonds. Fatty acids with no double bonds are called saturated, while unsaturated fatty acids come with one or more double bonds. The double bonds change the biological function of the fatty acid.

Each molecule of fat, whether solid fat or liquid oil, is made up of three fatty acids attached to a glycerol molecule. Saturated fatty acids make saturated fats, which are typically animal fats, semisolid to solid at room temperature. Unsaturated fats are typically vegetable oils, liquid at room temperature.

Generally speaking the saturated fats are the bad ones that are involved in the development of diseases such as atherosclerosis, heart disease and cancer. The unsaturated fats, in unprocessed form and moderate amounts, are generally beneficial for health.

Plants and animals can make unsaturated fatty acids from saturated fats to an extent that the human body is incapable of. This ability enables plants to produce the essential omega-6 and omega-3 fatty acids linoleic and alpha-linolenic acid, which are vital to human health.

The “parent” of EFAs in the omega-6 family is linoleic acid (18:2w6). It has a chain of 18 carbon atoms, two double bonds, the first of which on the 6th carbon from the end, hence the name omega-6. This polyunsaturated fatty acid is abundant in safflower and sunflower oil, and is found to a lesser extent in sesame, corn and soybean oil. Its derivative gamma-linolenic acid (GLA, 18:3w6) is found in borage oil, hemp oil and evening primrose oil and has been the focus of research for a couple of decades.

The omega-3 family parent is alpha-linolenic acid (18:3w3), which has three double bonds with the first one in the 3-position. This family is sometimes called superunsaturated to distinguish it from the polyunsaturated omega-6 family. Alpha-linolenic acid is found in flax, perilla, hemp and pumpkin seed oils as well as in canola and walnut oil. It is also found in green plants and micro-algae. Derivatives of this essential fatty acid include eicosapentaenoic acid (EPA, 20:5w3) and docosahexaenoic acid (DHA, 22:6w3). Both are found in cold-water fish, such as salmon, mackerel, herring and tuna that feed on DHA-rich micro-algae.

EFAs must be metabolized in several steps to express their full biological activity. Derivatives of linoleic acid are gamma-linolenic acid (GLA), dihomo-gamma-linolenic acid (DGLA) and arachidonic acid (AA), while alpha-linolenic acid converts to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).

Important enzymes are necessary for the conversion of the EFAs in a process of elongation and desaturation (removal of hydrogen atoms, creating additional double bonds). The first step in both these families requires the enzyme delta-6-desaturase (D6D). The metabolites will in turn with the help of the enzymes cyclo-oxygenase and lipoxygenase convert to eicosanoids: prostaglandins, thromboxanes and leukotrienes. These are substances that have a big impact on body function in general and on inflammatory activity in particular. We get bad or good effects depending on the kind of fat ingested and its related eicosanoid production (Leaf et al., 1988).

Serum lipids (Cholesterol and triglycerides)

GLA and DHA have repeatedly shown a remarkable effect on the reduction of cholesterol and triglyceride levels in both animal and human studies.

In a clinical trial involving 12 hyperlipidemic men GLA supplementation of 240 mg/day was given for four months. The results demonstrated a significant average reduction of triglyceride levels (48%), most of which was achieved as early as four weeks after the start. Total cholesterol and LDL-cholesterol levels were significantly decreased, whereas the good HDL cholesterol was significantly increased (22%). (Guivernau et al., 1994).

While most studies of omega-3 supplementation have been done on men, an interesting study on the effects of omega-3 fatty acids on serum lipids in post-menopausal women was recently published (Stark et al., 2000). In this placebo-controlled, double-blind trial, 36 women received either omega-3 fatty acids (2.4 g/d EPA and 1.6 g/d DHA) or placebo oil. After 28 days of supplementation there was a marked reduction in serum triglycerides (26%) and a 28% lower ratio of triglycerides to HDL-cholesterol. Women with and without hormone replacement had the same results.

The long-term prevention of atherosclerosis does not, as we now know, depend entirely on lowering cholesterol and triglyceride levels, but rather on increasing the good HDL-cholesterol. Reduced incidence of cardiovascular disease has been observed in the presence of high HDL levels. Specific subfractions of HDL appear to be involved in this process.

A study on 350 men and women with normal blood pressure demonstrated an increase of HDL2, a particularly beneficial subgroup of HDL-cholesterol, particularly in women, when given omega-3 fatty acids for six months (Sacks et al., 1994).

The effects of GLA on subfractions of HDL were studied in rabbits due to their similarity of plasma lipoprotein to humans (Fragoso et al., 1992). After four weeks of GLA supplementation there were no changes in the total cholesterol and triglyceride levels, but large changes in the distribution of HDL subfractions. A relative increase in the proportion of HDL2b and HDL3c was observed, an alteration that returned to basal levels 12 weeks after GLA withdrawal. This is especially noteworthy since the HDL2b subfraction is increased in centenarians as compared to both ‘middle-aged’ and ‘elderly’ subjects according to a study on long-lived individuals conducted by Barbagallo et al. (1998). In the same study HDL2b was also found to be inversely correlated with coronary heart disease and therefore likely to favor healthy aging.

Cutting Edge Research on PPAR-RXR

“The discovery that some fatty acids can act as hormones, by binding to and activating nuclear factors, and thus regulate cellular and physiological pathways at the transcriptional level, emphasizes that fatty acids are not just passive energy-providing molecules, but are active participants in metabolic regulation.” (Wahli et al., 1999)

It would be only logical that fatty acids, being such essential molecules in our physiology, were closely regulated; that the body had sensors that could respond to changes in the available levels of fatty acid metabolites.

Very recently a regulatory system for the metabolism of fats was discovered. Perixosome Proliferator-Activated Receptors (PPARs) were identified as nuclear hormone receptors, linking metabolism and gene expression. PPARs are transcription factors that regulate the expression of genes involved in fatty acid metabolism (Wahli et al., 1999). Not surprisingly, EFAs have been proven to play a key role in this regulatory system.

Polyunsaturated fatty acids, particularly EFAs and their metabolites have been found to be PPAR ligands, binding to and activating these nuclear receptors. The antidiabetic drugs, called glitzones or thiazolidinediones, act similarly as PPAR ligands (see text). It was originally demonstrated that PPAR is activated by fibrates, a group of lipid-lowering agents. Because fibrates and polyunsaturated fatty acids were known to possess similar activities, the attention of researchers turned to fatty acids. Forman et al. (1997) discovered that GLA, DHA and other EFAs are efficient activators of PPARa.

To activate gene transcription, PPAR must combine with the retinoic X receptor (RXR) to form the heterodimer PPAR-RXR. RXR is the receptor for a vitamin A metabolite (9-cis-retinoic acid), and has recently been identified as a cofactor for efficient gene expression activated by many other members of the steroid and thyroid hormone receptor superfamily, including the PPAR, vitamin D, and thyroid hormone receptors. A research team investigating brain tissue from mice last year identified an RXR-activating factor that turned out to be DHA (Mata de Urquiza et al., 2000). DHA binds directly to RXR, and like the other EFAs known to bind to PPAR, it is likely to express many of its beneficial effects through the PPAR-RXR heterodimer. This discovery suggests that DHA influences neural function through activation of an RXR-signaling pathway.

The new awareness of the PPAR-RXR system and its ligands makes the powerful influence of EFAs on the organism more understandable, and encourages further research on the details of how to use EFAs in prevention and treatment of our most feared diseases.