Atherosclerosis and conjugated linoleic acid

Atherosclerosis can be defined as the development of abnormal fat deposits in the artery wall. Atherosclerotic lesions are believed to progress through a focal, lipid-filled foam cell stage (fatty streak) into an advanced, complicated lesion that contains abundant extracellular cholesterol ester in the atheromatous gruel within the arterial intima. Weakening of the arterial wall and/or rupture of complicated lesions may presage clinical complications. Atherosclerosis is known to occur in many arteries throughout the body, although the association between atherosclerosis extent in different arteries is variable (Wolfet al. 1994; Rudel et al. 1995a,b). In human subjects, atherosclerosis in the coronary arteries is the underlying cause of CHD with its associated mortality from myocardial infarction. The literature contains many references to effects of specific fatty acids on the development of atherosclerosis or CHD. The strongest case can be made when clinical and epidemiological data in human subjects is supported by data in appropriate animal models. Study in relevant animal models facilitates assignment of molecular mechanisms. A classic example is that of linoleic acid. Diets enriched in this fatty acid have long been shown to be beneficial in reducing CHD risk in human subjects (Morris et al. 1977; Shekelle et al. 1981), and have been shown to protect against the development of coronary artery atherosclerosis in monkeys (Rudelet al. 1995a,b) and aortic atherosclerosis in transgenic mice (Rudel t al. 1998). Efforts to reduce LDL-cholesterol concentration and modify LDL particle composition both appear related to the beneficial effects. Work done in hamsters (Spady & Dietschy, 1988; Spadyet al. 1993) has suggested a potential mechanism for the beneficial effect of dietary linoleic acid in lowering LDL-cholesterol concentrations. Diets containing enrichments of this polyunsaturated fatty acid (PUFA) appear to limit down-regulation of hepatic LDL receptors by dietary cholesterol, perhaps by limiting the availability of hepatic cholesterol to a putative regulatory pool. Resulting plasma LDL clearance rates may be higher and LDL-cholesterol concentrations lower. LDL composition may also be important in the linoleic acid effect (Rudelt al. 1997). In his original prediction that essential PUFA would protect against atherosclerosis, Sinclair (1956) suggested that moresaturated cholesterol esters may be less readily disposed of and be more atherogenic. Subsequent clinical studies have shown inverse associations between the proportion of plasma cholesterol ester as cholesteryl linoleate and adverse CHD outcome (Lawrieet al. 1961; Kingsburyet al. 1969; Kirkeby et al. 1972). While this information about positive effects on atherosclerosis of diets containing linoleic acid is available, a potential down-side also exists. A popular theory of atherosclerosis postulates that increased oxidation of low density lipoproteins (LDL) predisposes to increased CHD (Steinberget al. 1989). The enrichment of LDL with lipids rich in linoleic acid demonstrably predisposes LDL particles to oxidative modificationin vitro (Reavenet al. 1993; Thomaset al. 1994), and yet less atherosclerosis has been demonstrated in this setting as mentioned above. While this apparent paradox does not invalidate the hypothesis that LDL oxidation is important in atherosclerosis, it does suggest that the phenomenon of LDL oxidation, by itself, is not sufficient to explain atherogenesis. Linoleic acid apparently has benefits to atherosclerosis that override any increase in susceptibility to oxidation. An isomer of linoleic acid that also may have important consequences for atherosclerosis, as well as cancer, is conjugated linoleic acid (CLA). Actually, CLA represents several positional isomers of linoleic acid, including what may be the most common isomer, K9-cis, K11-trans octadecadienoic acid (Banni & Martin, 1998). While CLA is not a major constituent of any fat source as linoleic acid is, it appears to be present in small amounts (typically , 2 %) in many fat sources. This fatty acid appears to be a product of a biohydrogenation reaction catalysed by an enzyme, linoleate isomerase ( EC 5.2.1.5), present in the bacteria of ruminant animals (Keplert al. 1966, 1970). While some CLA may also be formed during chemical hydrogenation reactions, it appears that it is present in higher proportions in dairy products than in vegetable fats (Chinet al. 1992). Availability of CLA in milk fat may be a function of the diet, with higher proportions being present when the animals’ diets contain more PUFA. The CLA present in human tissue and blood plasma is apparently derived from the diet, although this is not yet established with certainty. Rats have an enzyme in liver that can convert theK11-trans octadecenoic acid, itself one of the common positional isomers of trans fatty acids, to the K9-cis, K11-trans octadecadienoic acid (Banni & Martin, 1998). It is unknown if this pathway is present in human liver, but if it were present, at least some of the body’s CLA could be formed from some of the trans fatty acids in partially hydrogenated fats, for example. In any case, it is important to understand if CLA is indeed beneficial and not harmful. Numerous studies have documented an anticarcinogenic activity for CLA in animal models (reviewed by Banni & Martin, 1998). However, a potential role for CLA in British Journal of Nutrition(1999),81, 177–179 177