Literature Review:Conjugated Linoleic Acid: Prospects and Problems for Human Health Promotion

Abstract

Conjugated linoleic acids are a class of 18-carbon polyunsaturated fatty acids found primarily in the meat of ruminant animals and dairy products. Since being shown to inhibit skin neoplasia in mice by Ha, et. Al. (1987), CLA has been demonstrated to have antiatherosclerotic, antidiabetic, antiadipogenic, and anticarcinogenic effects in cell lines and animal models. Attention to these findings has led to the availability of CLA as a dietary supplement. The safety and efficacy of CLA in this capacity is not well established, however, since relatively few studies of CLA's effects have been conducted in humans. Among these, most have produced ambiguous results, while a few have shown deleterious effects of CLA supplementation in high-risk populations, including insulin resistance and lowered HDL:LDL cholesterol ratios. This review surveys the experimental and clinical effects of CLA on the development and maintenance of Atherosclerosis, diabetes, obesity, and cancer. It is concluded that, pending a fuller characterization of its molecular mechanisms and human efficacy, CLA may prove to be an effective natural supplement for the purposes of general health promotion.

Introduction

The term conjugated linoleic acid (CLA) refers to a group of constitutional and stereoisomers of linoleic acid (LA, cis-9,cis-12 octadecadienoic acid). The two double bonds of CLA may be in the 7,9; 8,10; 9,11; 10,12; or 11,13 positions (Belury 2002). These double bonds may occur in every geometric isomeric configuration. Naturally occurring dietary CLA is composed primarily of the cis-9,trans-11 isomer (Parodi 1997), also known as rumenic acid (Kramer et al. 1998), with trans-10,cis-12 CLA comprising a smaller portion and other isomers present in trace amounts. The two primary isomers of CLA, along with LA, are illustrated in Figure 1.

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The majority of CLA in the human diet comes from the meat and milk products of ruminant animals, especially beef and products from cow's milk such as cheese and butter. Most CLA is produced in the rumen by hydrogenation of LA to cis-9,trans-11-CLA (Kepler et al. 1966). A small portion of cis-9,trans-11-CLA is then directly absorbed into surrounding tissue (Chin et al. 1994), while most is hydrogenated at the 9-position, to yield vaccenic (trans-11-octadecenoic) acid (Harfoot and Hazlewood 1988). Vaccenic acid is then absorbed into tissues, where it can be turned back into cis-9,trans-11-CLA by the delta-9-desaturase enzyme. One study found that this conversion also occurs in human tissues, with an average of 19% of dietary vaccenic acid being converted to cis-9,trans-11-CLA (Turpeinen et al. 2002). The CLA used in laboratory research most commonly consists of roughly equal portions (~40-45% each) of cis-9,trans-11- and trans-10,cis-12-CLA, with trace amounts of other isomers. The findings of many recent, isomer-specific experiments strongly suggest that some effects of CLA are isomer-specific or may result from synergistic action of multiple, independent isomer-specific mechanisms (Pariza et al. 2001).

The human health effects of CLA became the subject of widespread inquiry following a study in which Ha and colleagues (Carcinogenesis 8, 1881-7) first reported its inhibitory effects on mouse epidermal neoplasia. Since that time, a large body of in vitro and animal research has accumulated to suggest that CLA promotes various aspects of human health (Wahle et al. 2004). An extensive, regularly updated bibliography of CLA research since 1987 can be found online at . Popular attention to these findings has led to the marketing of CLA as a dietary supplement, despite the scarcity of research involving human subjects. The wide availability of CLA is particularly questionable in light of the inconclusive or negative results of some of the human studies, which will be discussed later in this review.

This article will review the observed effects of CLA on chronic disease states including Atherosclerosis, diabetes, obesity, and cancer, and evaluate the potential risks and benefits of CLA as a general dietary supplement.

CLA shows beneficial effects in animal models of Atherosclerosis, but its effects on cholesterol ratios appear to vary by isomer

As early as 1994, CLA supplementation was shown to lower blood low-density lipoprotein (LDL) and triglyceride levels in rabbits (Lee et al. 1994). Since then, both rabbit and mouse models have usually shown CLA to be an effective inhibitor of Atherosclerosis, although the effects of specific isomers remain unclear. The results of investigations into the role of CLA on processes related to Atherosclerosis are summarized in Table 1.

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A recent study in the apoE(-/-) mouse model of Atherosclerosis found that dietary supplementation with cis-9,trans-11-CLA not only retarded the development of atherosclerotic lesions, but actually effected a regression in aortic lesions. Analysis of cells in the aortic root found that CLA-supplemented animals had increased expression of the nuclear transcription factor peroxisome proliferator activated receptor γ (PPARγ), particularly in vascular smooth muscle cells (Toomey et al. 2003). Application of known PPARγ ligands has been shown to inhibit Atherosclerosis in mouse models (Kersten et al. 2000), suggesting that CLA may elicit its antiatherosclerotic effects through a PPARγ-mediated pathway.

Work in rabbits with pre-established atheromatous lesions has had similarly promising results: CLA inhibited the establishment of new lesions by 50% when fed as part of a 0.2% cholesterol (atherogenic) diet, and reduced established lesions by 26% as part of a cholesterol-free (regression) diet. CLA was also found to have the same degree of antiatherosclerotic effects whether fed as cis-9,trans-11 isomer, trans-10,cis-12 isomer, or a mixture of isomers, suggesting a non-isomer specific mechanism of action in this case (Kritchevsky et al. 2004). Thus, the mechanism responsible for inhibition of atheromatous lesions appears to be non-isomer specific.

In contrast, an in vivo hamster study found a significant improvement in HDL-cholesterol : LDL-cholesterol ratio elicited by cis-9,trans-11-CLA only, while the effect of a mixed-isomer preparation was barely significant (p=0.06) (Valeille et al. 2004). A human study found that while cis-9,trans-11-CLA lowers LDL-cholesterol : high-density lipoprotein (HDL)-cholesterol ratios, trans-10,cis-12-CLA has the opposite effect (Tricon et al. 2004).

Coen and colleagues (2004) have shown that CLA treatment in vitro decreases production of 6-keto-prostaglandin-F1α, a breakdown product of prostaglandin I2, in bovine aortic endothelial cell. Prostaglandin I2 levels are significantly elevated in human patients with Atherosclerosis (Belton et al. 2000), so its downregulation by CLA may be one means by which CLA elicits its anti-atherosclerotic effects.

Research has shown that CLA has a significant inhibitory effect on the establishment and progression of Atherosclerosis in animal models, but differences between isomers need to be clarified. Further work needs to be done to investigate promising putative mechanisms, such as downregulation of prostaglandin I2 and ligand-activation of PPARγ, as well as to identify other potential mechanisms capable of explaining the isomer-specific effects of CLA on cholesterol ratios.

CLA may reduce markers of diabetes through a PPARγ-dependent pathway in animals, but some animal and human studies have shown deleterious effects

Some evidence suggests that CLA may also be useful in the treatment and prevention of diabetes. However, the molecular mechanisms involved are not well characterized, and the results of human studies in certain populations furnish some cause for concern. Several important observations of the impact of CLA on parameters of diabetes are summarized in Table 2.

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Two studies in Zucker Diabetic Fatty fa/fa (ZDF) rats found that CLA favorably modulated various markers of diabetes, including hyperinsulinemia and impaired glucose tolerance (Houseknecht et al. 1998; Ryder et al. 2001). In both cases, analysis suggested that the effect was due in part to increased activation of PPARγ, a transcription factor known to mediate the expression of several genes important to the uptake and metabolism of glucose and Lipids.

Subsequent work in human preadipocytes found differential effects of trans-10,cis-12-CLA and cis-9,trans-11-CLA on both activation and expression of PPARγ. Chronic treatment with trans-10,cis-12-CLA reduced expression of PPARγ target genes as well as PPARγ itself. This indicates that trans-10,cis-12-CLA acts as an antagonist to ligand-activation of existing PPARγ, a downregulator of the gene for PPARγ itself, or as both an antagonist and downregulator of PPARγ (Brown and McIntosh 2003). In contrast, cis-9,trans-11-CLA increased expression of PPARγ relative to trans-10,cis-12-CLA and vehicle controls (Brown et al. 2003).

Whatever the specific relationship may be between PPARγ and CLA intake with respect to diabetes, some animal and clinical trials suggest that caution should be exercised in the use of CLA as a potential dietary supplement. A study by Tsuboyama-Kasaoka et al. (2000) found that CLA supplementation may actually have undesirable effects on insulin sensitivity, with 1% dietary CLA (mixed isomers) causing lipodystrophy and insulin resistance in mice. Later work by that laboratory found that reducing the percentage of CLA relative to total dietary fat avoided these adverse effects (Tsuboyama-Kasaoka et al. 2003). Clement and colleagues (2002) also observed hyperinsulinemia, as well as fatty liver, in mice fed 0.4% trans-10, cis-12-CLA diets.

Recent human studies by Riserus and colleagues have lent some support to the unfavorable mouse data. One study in abdominally obese men with metabolic syndrome found that trans-10,cis-12-CLA supplementation increased insulin resistance by 19%. The effect on insulin resistance was not seen in subjects receiving a CLA isomeric mixture (Riserus et al. 2002). Metabolic syndrome denotes a cluster of conditions including abdominal obesity, insulin resistance, dislipidemia (high blood Lipids), and hypertension. It is considered a key risk factor for the development of Atherosclerosis and type II diabetes (Grundy 2004). A follow-up analysis of the data set from Riserus et al. (2002) found that the trans-10,cis-12-CLA-induced insulin resistance was closely related to an increase in plasma levels of proinsulin, the precursor molecule to insulin (Riserus et al. 2004 (1)). Elevated levels of proinsulin have been linked to increased incidence of heart disease and type II diabetes. The same group later found that cis-9,trans-11-CLA supplementation in a similarly at-risk group of obese men decreased insulin sensitivity by 15%, and the decreases were closely linked to increases in lipid peroxidation (Riserus et al. 2004 (2)).

It seems, then, that although CLA shows promise as a preventive agent with regards to diabetes, further research is needed to determine the mechanisms underlying the divergent effects of cis-9,trans-11- and trans-10,cis-12-CLA in animals. Further clinical studies are also needed to determine how proinsulin and lipid peroxidation levels may relate to CLA-dependent insulin resistance in humans with symptoms of metabolic syndrome.

CLA usually reduces fat depot mass in various animal models, possibly by inhibiting lipoprotein lipase-mediated lipid uptake into adipocytes

Research has found that dietary CLA reduces fat deposition in a variety of animals including mice (Ohnuki et al. 2001), rats (Azain et al. 2000), hamsters (de Deckere et al. 1999), and pigs (Ostrowska et al. 1999). The findings of these and other studies of the effects of CLA on obesity are presented in Table 3. Although some of these studies observed a small but significant reduction in overall energy intake among CLA-fed treatments (West et al. 1998; Takahashi et al. 2002), other investigators have reported similar fat reduction effects of CLA in the absence of decreased intake (DeLany et al. 1999; Azain et al. 2000).

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West and coworkers (1998) observed an increase in energy expenditure in mice fed a CLA isomeric mixture. Increased energy expenditure is not a universal feature of dietary CLA supplementation, however. One study, for instance, observed no significant changes in oxygen consumption or carbon dioxide or heat production among CLA-fed female Sprague-Dawley rats (Azain et al. 2000).

A range of underlying processes have been proposed and evaluated as potentially contributing to the consistent anti-adipogenic effects of dietary CLA supplementation. Ohnuki et al. (2001) observed a significant increase in oxygen consumption and decrease in fat depot weight among male mice fed a 0.25% CLA diet. A higher level (1.0%) of CLA did not augment the fat-lowering effect, and caused marked increases in liver weight, as well as fatty liver, in some mice. A previous study demonstrated that CLA inhibits activity of lipoprotein lipase in adipocytes, possibly due to difficulty in incorporating CLA into cellular Lipids (Park et al. 1997).

Since the increased oxygen consumption among CLA-fed groups could indicate that unincorporated CLA may be oxidized more readily than other fatty acids, Ohnuki and colleagues (2001) hypothesize that the increase in liver weight, which has been observed repeatedly by others (Clement et al. 2002; West et al. 1998), may be the result of unused fatty acids or triglycerides accumulating in the liver.

What is most consistent among animal studies is a substantial decrease in the mass of various adipose tissue depots. Poulos et al. (2001) found a reduction in larger adipocytes and an increase in smaller adipocytes among Sprague-Dawley rats fed CLA. Reduced adipocyte size agrees well with the previously mentioned finding that CLA reduces activity of lipoprotein lipase (Park et al. 1997), a key factor in lipid uptake. Similarly, Azain and colleagues (2000) demonstrated that the overall fat mass reduction was primarily a result of reduced adipocyte volume, as opposed to a reduced quantity, of adipocytes, in their experiments.

This conception appears in notable contrast to observations of increased apoptosis in adipocytes of CLA-fed animals, as inferred from levels of apoptotic factors such as tumor necrosis factor alpha (TNF-alpha) and uncoupling protein-2 (UCP-2) (Tsuboyama-Kasaoka et al. 2000).

Work in human subjects has been inconclusive as to CLA's potential for use in the treatment or prevention of obesity. One trial of 60 overweight or obese human subjects produced a significant reduction in body fat mass with CLA levels of 3.4 g/day (Blankson et al. 2000). Despite this apparent promise, neutral and negative results strongly urge caution in the dietary use of CLA among abdominally obese individuals, who may be at elevated risk for diabetes or Atherosclerosis. Serious side effects, including insulin resistance and increases in lipid peroxidation, have been observed in subsequent studies involving subjects showing signs of metabolic syndrome (Riserus et al. 2002; 2004).

CLA inhibits initiation and growth of breast, colorectal, prostate, and skin cancers in animal models, but findings from studies of human CLA intake and cancer incidence are inconclusive

The most extensive research on CLA has investigated its role in the prevention and inhibition of breast, colorectal, prostate, and skin cancers. Table 4 summarizes results of various studies on CLA and cancer. CLA has been shown conclusively to have significant inhibitory effects in cell lines and animal models of these cancers; however, the molecular mechanisms that produce these effects, and whether they may be translated to humans, are largely unknown.

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As mentioned previously, the first study to draw significant attention to CLA found that these "heat-altered derivatives of linoleic acid" decreased the yield of chemically induced papillomas in a rat model of skin cancer (Ha et al. 1987). Findings of this kind have been reproduced in animal models of mammary (Ip et al. 1994), colorectal (Kim and Park 2003), and prostate (Cesano et al. 1998) cancers.

CLA also appears to reduce tumor metastasis in certain animal models. A rat xenograft experiment using human prostatic carcinoma cells found that 1% dietary CLA was able to significantly reduce lung metastases (Cesano et al. 1998). A later study examined the effects of CLA on metastasis of mammary tumor cells to the lungs in mice. Two sets of experiments were conducted, one assessing metastasis to the lungs from existing mammary tumors, the other assessing direct invasion of the lungs by injected human mammary tumor cells. These parallel experimental designs showed similar levels of reduction across designs. This fact suggests that CLA may exert its inhibitory effects during the later stages of the metastatic cascade, such as invasion, vascularization, and survival, since the earlier stages (release from primary tumor, survival in bloodstream) were bypassed in the injection experiments (Hubbard et al. 2003). A similar, later study by Hubbard and colleagues (2006) found that substituting beef tallow (BT) into CLA-enriched diets in place of half of the standard fat source, a vegetable fat blend (VFB), lowered by 50% the amount of CLA needed to maximally inhibit metastasis. The VFB was rich in linoleic acid, a compound shown as part of this study to reduce CLA-modulated tumor cell toxicity in culture, suggesting that linoleic acid may also be involved in modulating the effect of CLA on metastasis. Another recent metastasis study found that CLA reduced invasiveness of MKN28 human gastric and Colo320 colon cancer cell lines (Kuniyasu et al. 2006). This effect was negated by addition of an antisense deoxynucleotide for the PPARγ gene, indicating that CLA acts at least partially through this transcription factor to reduce invasiveness in these cell lines. The same study found that peritoneal metastases were significantly reduced in mice injected with the MKN28 and Colo320 cell lines (Kuniyasu et al. 2006).

One tissue-specific finding has emerged regarding the effects of CLA on the development of tissues relevant to mammary cancer. Work by Ip and colleagues (1995) has shown that feeding CLA to female rats during a specific pubertal period (21-42 days of age) conferred protection against later (day 56) mammary cancer induction by methylnitrosurea (MNU). When CLA supplementation was begun after administration of MNU, protection was only conferred as long as supplementation continued (Ip et al. 1995). Morphological analysis from a later study revealed that CLA supplementation during the pubertal period caused a decrease in epithelial branching and terminal end buds (TEBs), the structures most susceptible to tumor initiation in the rat mammary gland. Increasing dietary CLA above 1% caused both tumor yield and TEB density to plateau in parallel fashion, supporting the hypothesis that CLA can exert a lasting effect on mammary cancer risk in this model by reducing the population of potentially neoplastic TEBs (Ip et al. 1999).

The only data available on the effects of CLA on cancer in humans come from epidemiological studies, and these generally have been inconclusive. One case-control study that supports an anticarcinogenic role for CLA in the human population measured serum CLA levels in pre- and post-menopausal women with breast cancer and population-matched controls. Among postmenopausal but not premenopausal women, lower serum CLA was associated with a higher risk of breast cancer. Specifically, among the postmenopausal subjects, comparison of the highest quintile versus the lowest quintile of serum CLA produced an odds ratio for development of breast cancer of 0.4 (Aro et al. 2000). Work by Chajes and others (2002) in women presenting either malignant breast cancer (cases) or benign breast disease (controls) sought a correlation between CLA in breast adipose tissue samples and the presence of malignant cancer. No significant link was found between CLA and malignancy. A similar, later study by the same lab also found a null association between CLA in breast biopsy samples and risk of subsequent metastasis (Chajes et al. 2003). It should be noted, however, that both of the previous two studies were conducted using adipose samples with a mean CLA percentage (of total fatty acids) of only 0.44%, which is below the level of efficacy observed in most animal studies. An epidemiological study using dietary data from the Netherlands Cohort Study on Diet and Cancer found a slightly significant positive correlation between CLA intake and breast cancer incidence (Voorrips et al. 2002). A recent epidemiological study of women from the Swedish mammography cohort looked for an association between CLA intake, as inferred from dietary records, and colorectal cancer incidence. It found an odds ratio of 0.71 between the highest and lowest quartiles of intake (Larsson et al. 2005). The necessarily statistical nature of these studies makes data generation and interpretation inherently susceptible to confounding factors. Of particular concern when attempting to isolate the effects of CLA through dietary surveys are the wide array of other compounds, such as linoleic acid, other trans-fatty acids, and saturated fatty acids, that are found in the same food sources as CLA and may also have roles in the development of cancer. Thus, the data to date prevent any solid conclusions from being drawn as to whether reasonable increases in human intake of CLA could confer a significant protection against cancer.

Conclusions

CLA elicits a wide range of beneficial effects in various cell culture and animal models of disease. Still, a minority of studies have reported ambiguous or deleterious effects of CLA supplementation. These observations must be carefully considered and warrant further investigation before the widespread use of CLA for general purposes, such as weight loss, should be promoted. One important objective for researchers is the clear characterization of the molecular mechanisms by which the isomers of CLA elicit their effects. While much research has been conducted to date towards this end (reviewed in Belury 2002; Pariza et al. 2000), the emergence of differences between CLA isomers, cell and tissue types, and animal models have led to difficulty in clearly accounting for the observed effects.

The use of CLA as a weight loss supplement presents a particularly complex safety concern, since overweight or obese individuals may be predisposed to develop other conditions, such as Atherosclerosis and diabetes, in which CLA appears to play a modulatory role. Thus, special attention should be paid to explaining the observations of negative health effects such as insulin resistance and increased LDL:HDL cholesterol ratios in the continuing evaluation of CLA as a dietary supplement. In addition to in vitro and animal mechanistic studies, further clinical and epidemiological studies are needed to identify which, if any, of the experimental effects of CLA apply to humans.

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