Biological Effects of Conjugated Linoleic Acid

34

Biological Effects of Conjugated Linoleic Acid Yung-Sheng Huang, Teruyoshi Yanagita, Koji Nagao, and Kazunori Koba

CONTENTS I. Introduction r....... II. CLA and Human Health A. CLA and Cancer B. CLA and Weight Management C. CLA and Heart Health and Arteriosclerosis D. CLA and Diabetes E. CLA and Immune Function and Inflammatory Response F. CLA and Bone Health III. Possible Mechanisms of CLA Effects A. Effect of CLA on Fatty Acid Oxidation Related Enzymes B. Effect of CLA on Fatty Acid and Eicosanoid Synthesis C. CLA as Antioxidant D. Effect of CLA on Gene Expression IV. Other Conjugated Fatty Acids A. Anticarcinogenic Effect ..: B. Antiobese Effect V. Safety and Dosage of CLA VI. Conclusion References

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825 826 826 826 827 827 827 828 828 828 828 829 829 830 830 830 830 830 831

I. INTRODUCTION Conjugated linoleic acid (CLA) is a group of positional and geometric isomers of linoleic acid with conjugated double bonds located at positions 8 and 10,9 and 11, 10 and 12, or 11 and 13, and these double bonds may be of cis and trans configuration (Eulitz et aI., 1999) (Figure 34.1). This group of isomers is synthesized by microbial fermentation (bacteria, Butyrinvibrio jibrisolvens) occurring in the gut of ruminant animals (such as sheep and cattle) (Kepler et aI., 1966). Thus, CLAs are predominantly found in dairy products and meat from ruminants (Chin et aI., 1992). The concentration of CLA in these foods can be as high as 30 mg/g depending on the diet of the ruminant animal, and are generally higher if the animal is grazing on fresh, green pasture than feeding a grain (Dhiman et aI., 1999). Interestingly, the highest concentration of CLA when compared with other foods is found in Kangaroo meat (Engelke et aI., 2004). Kangaroos are not true ruminant animals, but like ruminants, they ferment feed in their foregut. Other foods including vegetable oils, eggs, seafood, poultry, and pork may also contain CLA but at very low levels. The most abundant isomer in food is cis 9, trans 11-18:2 (c9,tll-18:2), followed by t10, c12-18:2. Evidence indicates that different CLA isomers exert different health effects (Ip et aI., 1999; Pariza et aI., 2001; Li et aI., 2006). 825

Fatty Acids in Foods and Their Health Implications

826

12

9

GOOH

cis-9,cis-12-18:2 (linoleic acid) 9

~

GOOH

11

cis-9,trans-11-18:2 (c9,t11-GLA)

GOOH

trans-10,cis-12-18:2 (t1 O,c12-GLA)

FIGURE 34.1

Chemical structure of conjugated linoleic acids.

II. CLA AND HUMAN HEALTH Interest in the beneficial effects of CLA on human health started from the original findings by Pariza and his coworkers that red meat contains a component exhibiting the cancer-fighting properties (Ha et aI., 1987). Since then, CLA has been the subject of a variety of research, and findings also suggest that CLA possesses other benefits such as increased metabolic rate, decreased abdominal fat, enhanced muscle growth, lowered cholesterol and triglycerides, lowered insulin resistance, reduced food-induced allergic reactions, and enhanced immune system.

A. CLA AND CANCER Early research with animal models demonstrated that CLA found in red meat could interfere with the growth of breast and prostate tumors (Ip et aI., 1991, 1994). Since then, more studies have further shown the cancer-fighting potential of CLA. However, most of the evidence on breast as well as skin, liver, and colon cancers has come from animal and human cancer cell lines in vitro. Clinical studies were scarce. Nevertheless, recent results from a large French study have indicated that dietary CLA could protect against breast cancer in humans (Chajes et aI., 2003). Evidence indicates that CLA inhibits the initiation and incidence of mammary tumors in rodents. It also had a significant effect on the latency, metastasis, and pulmonary tumor burden of transplantable murine mammary tumors grown in mice (Hubbard et aI., 2000). Recently, Ohtsua et aI. (2005) demonstrated that CLA decreases cellular proliferation and inhibits NF-KB and activator protein-1 activation in PC3 cancerous prostate epithelial cells.

B. CLA AND WEIGHT MANAGEMENT Obesity has become a major health issue in the affluent societies. In the United States, over 30% of the adult population is obese. During the past decade, the percent of obese people has doubled (Flegal et aI., 2002). CLA is one of nutrients that has been shown to be able to reduce body fat and to increase lean body mass (LBM) in pigs (Dugan et aI., 1997), mice ( Park et aI., 1997; DeLany et aI., 1999; Pariza et aI., 2000), and rats and chicks (Martin et aI., 2000; Pariza et aI., 2000; Wang et aI., 2003). In humans, CLA shows a tendency to reduce body fat, particularly abdominal fat, change serum total lipids, and decrease whole body glucose uptake (Blankson et aI., 2000; Smedman and Vessby, 2001; Thorn et aI., 2001).

Biological Effects of Conjugated Linoleic Acid

827

On the other hand, there are studies failed to confirm this benefit (West et aI., 1998; Blankson et aI., 2000; Riserus et aI., 2001; Smedman and Vessby, 2001; Thorn et aI., 2001; Kreider et aI., 2002; Kamphuis et aI., 2003; Larsen et aI., 2003; Gaullier et aI., 2004; Malpuech-Brugere et aI., 2004; Wang and Jones, 2004). Atkinson (1999) did not find any differences between the CLA group (2.7 g/day) and the placebo group in a 6 months placebo-controlled, randomized, double-lind study in obese volunteers. Zambell et al. (2000) have found that CLA supplementation (3 g/day) had no effect on body composition and energy expenditure in 17 healthy, adult women for 64 days following a baseline period of 30 days. C. CLA AND HEART HEALTH AND ARTERIOSCLEROSIS

One of the major risk factors for coronary heart disease is high levels of cholesterol, particularly lowdensity lipoproteins (LDL) cholesterol (or "bad" cholesterol); because cholesterol over time can form plaque in arteries, narrowing them, reducing heart's blood supply. Animals fed a CLA-containing diet had a significantly reduced LDL and total cholesterol and triglyceride levels in blood (Kritchevsky et al., 2000), and reduced cholesterol concentration in liver (Sakono et al., 1999). Results from studies with rabbits and hamsters have indicated that CLA can lower plasma lipoproteins and early aortic atherosclerosis in rabbits and hamsters (Lee et al., 1994; Nicolosi et al., 1997). In human, a small double-blind trial has also found that CLA could reduce blood cholesterol levels in healthy human subjects (Noone et al., 2002). Among different CLA isomers, the t 1O,c 12-CLA as compared to linoleic acid has been shown to be more effective in lowering the concentration of total cholesterol and triglyceride, whereas raising the concentration of serum HDL-cholesterol (Akahoshi et al., 2(03). The hypotensive properties of CLA have also been reported. Feeding of CLA mixture and the tl0,c12-CLA isomer has been shown to prevent the development of obesity-induced hypertension in obese, diabetic Zucker rats and obese OLETF rats (Nagao et aI., 2003a,b), and prevent the development of essential hypertension in nonobese spontaneously hypertensive rats (Inoue et aI., 2004). In addition, CLAs (both c9,tll- and tlO,c12-isomers) have been shown to inhibit the arachidonic acid- and collagen-induced platelet aggregation, and the formation of proaggregatory cyclooxygenase product, TXA2 (Truitt et aI., 1999). D. CLA AND DIABETES

The incidence of type II diabetes in the affluent societies is increasing dramatically. There is evidence that CLA may have the ability to normalize glucose metabolism. In studies with obese, diabetic rats, feeding of CLA diet normalized impaired glucose tolerance, and the effect of CLA was similar to that of the pharmaceutical agent troglitazone (Houseknecht et aI., 1998; Belury et aI., 2003). In another study, dietary supplementation with CLA also lowered body mass, levels of blood sugar, triglycerides, and insulin, and improved glucose utilization in diabetes (Belury et aI., 2003). The beneficial effect of CLA are attributable to the specific action of the tl0,c12-isomer (Ryder et aI., 2001). In vitro studies showed that the tlO,c12-isomer but not the c9,tll-isomer lowered body weight but stimulated peroxisome proliferator-activated receptor-y (PPAR-y)-mediated reporter gene activity. The activation of PPAR-y may play some role in the putative antidiabetic activity of CLA (Houseknecht et aI., 1998). However, there is also growing evidence that CLA may worsen blood sugar control. In overweight people without diabetes, CLA might promote insulin resistance and thus decrease insulin sensitivity, creating a prediabetic state (Riserus et aI., 2002; Larsen et aI., 2003; Moloney et aI., 2004; Riserus et aI., 2004).

E.

CLA AND IMMUNE FUNCTION AND INFLAMMATORY RESPONSE

The immune system protects the body by fighting disease. CLA can enhance the immune system. Feeding CLA to chicks provided partial protection against the catabolic effects of endotoxin

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(Cook et aI., 1993). CLA also supports the production of key immune system cells and the inflammation response system. When the immune system is challenged by antigen or polyclonal T cell mitogens, such as concanavalin A and phytohemagglutinin, and their production of interleukin-2, feeding CLA could improve the age-related decrease in the ability of T cells to proliferation in mouse (Hayek et aI., 1999). More, feeding CLA could significantly increase the splenic levels of immunoglobulin A (IgA), IgG, and IgM in mice (Sugano et aI., 1997; Yamasaki et aI., 2000).

F. CLA AND BONE HEALTH Recently, effects of CLA on bone have been investigated (Cook et aI., 1997; Watkins and Seifert, 2000; Thiel-Cooper et aI., 2001; Doyle et aI., 2005; Banu et aI., 2006). In vitro studies using MC3T3E 1 osteoblast-like cells showed that CLA increased levels of osteocalcin, alkaline phosphatase activity' and calcium absorption (Fernandes et a!., 1986). In vivo studies using young chicken, mice, and pigs have shown that in the presence of CLA there is an increase in bone mass. However, in young rats, CLA decreased bone formation rates (Ammann et aI., 1992; Griffin et aI., 1993), but when CLA was given along with n-6 PUFA, bone formation rates increased (Lu et aI., 1994). In humans, a study that tested the effects of CLA supplementation on the biochemical markers of bone metabolism has reported that in adult men CLA supplementation did not affect markers of bone metabolism (Rahman et aI., 2003). A recent study on the effects of CLA on postmenopausal women has concluded that dietary intake of CLA may benefit bone mineral density (Brownbill et aI., 2005). The mechanism by which CLA exerts its effect on bone is still not very clear, although a few theories have been reported recently. CLA has been shown to enhance bone mineralization (Kelly et aI., 2003; Kelly and Cashman, 2004). In the presence of PUFA, CLA has been shown to modulate the action and expression of COX-2 enzyme, thereby alter the prostaglandin-dependent bone resorption (Li and Watkins, 1998; Li et aI., 1999). Dietary CLA is also known to reduce both proinflammatory IL-1 (Thomas and Burguera, 2002) and IL-6 production (Burguera et aI., 2001). Studies have reported that IL-1 and IL-6 induce bone resorption by stimulating the recruitment and formation of osteoclasts, and thereby releasing calcium from bone (Kang and Pariza, 2001; Reseland and Gordeladze, 2002).

III. POSSIBLE MECHANISMS OF CLA EFFECTS A. EFFECT OF CLA ON FATTY ACID OXIDATION RELATED ENZYMES The mechanism that underlines the CLA-induced changes on body fat content has been related to two aspects: (1) expedite the body's fat metabolism by increasing lipolysis in adipocyte and (2) enhance fatty acid oxidation in both adipocytes and skeletal muscle cells (Park et aI., 1999; Pariza et aI., 2000). In mice, dietary CLA significantly increased total camitine palmitoyl transferase activity in both fat pad and skeletal muscle (Park et aI., 1999), and the hormone sensitive lipase activity in adipocytes (Park et aI.,' 1997). In 3T3-L1 adipocytes, CLA inhibited the heparin-releasable lipoprotein lipase (LPL) activity and intracellular concentration on triacylglycerol and glycerol (Park et a!., 1997).

B. EFFECT OF CLA ON FATTY ACID AND EICOSANOID SYNTHESIS CLA is known to affect fatty acid and eicosanoid metabolism (Figure 34.2). As CLA can be readily incorporated into membrane phospholipids, the effect can be exerted through replacing arachidonic acid by CLA in cell membrane and reducing the availability of arachidonic acid for eicosanoid synthesis (Liu and Belury, 1998; Sugano et aI., 1998; Banni et aI., 1999). Belury and Kempa-Steczko (1997) have demonstrated decreased arachidonic acid levels in hepatic neutral lipids of rats fed CLA. CLA can also compete with fatty acid metabolic enzymes and thus affect the synthesis of arachidonic acid (Sebedo et aI., 1997; Sugano et aI., 1999). Feeding CLA has been shown to increase

829


CLA

~

X

c6,c9-18:2

J

A.6-Desaturase

!

CLA

\onga~

c6,c9,c12-18:3 CLA)

Elongase

CEDA

CEDA

cB,c11

~-Desaturase

/-~

cB,c11,c14-20:3

CLA )

A.8-Desaturase

J

5-18:3

c5,c8,c11,c14-20:4

FIGURE 34.2 Effect of CLA on n-6 fatty acid metabolism. CLA: conjugated linoleic acid; CEDA: conjugated eicosadienoic acid; ~5-18:3: c5,c9,c12-18:3.

the proportions of stearic, docosatetraenoic, and docosapentaenoic acids in serum lipids and thrombocytes, while proportions of palmitic, oleic, and dihomo-gamma-linolenic acids decreased, suggesting a decrease in the estimated L\-6 and L\-9 and an increase in the L\-5 desaturase activities (Smedman and Vessby, 2001). Recently in a transformed yeast system, Chuang et ai. (2001a,b, 2004) have demonstrated that CLA inhibited essential fatty acid metabolic enzymes such as L\-6desaturase, L\-5-desaturase, and elongase. Eder et ai. (2002) have demonstrated that t10,c12-CLA suppressed the L\6-desaturase in HepG2 cell. C. CLA AS ANTIOXIDANT

It has been shown in in vitro and in vivo studies that CLA is an effective antioxidant (Ra et aI., 1987; Ip et aI., 1991). Indeed, comparative studies have shown that CLA is as effective as butylated hydroxytoluene (BHT), more potent than a-tocopherol, and approximately two times more powerful an antioxidant than beta-carotene (Ra et aI., 1990; MacDonald, 2000). In the body CLA can be taken up by phospholipids, where CLA serves as one of the structural components of cell membranes and protect cell from the detrimental effect of peroxides. Because numerous studies have demonstrated that oxidative reactions are associated with the development of cancer and atherosclerosis, the ability of CLA to reduce the harmful effects of these oxidative reactions could be attributed to its health beneficial effect.

D.

EFFECT OF eLA ON GENE EXPRESSION

CLA interacts with dozens of genes, but not all consequences are known. The ability of CLA to modulate lipid metabolism appears to be a pivotal mechanism of CLA's beneficial effects in mice and rats. The effect of CLA on body composition changes observed in animals seems to be associated mainly with the t10,c12-CLA isomer (Park et aI., 1999). The t10,c12-isomer decreased the expression of stearoyl-CoA desaturase mRNA in mouse liver and adipocytes (Lee et aI., 1998; Choi et aI., 2000). Stearoyl-CoA desaturase activity is a key enzyme in lipogenesis, and inhibition of this enzyme activity depresses fat synthesis. Dietary CLA induces the expression of genes dependent in part on the transcription factor, peroxisome proliferator-activated receptor (PPAR). Several CLA isomers are high-affinity ligands and activators for PPAR (Moya-Camarena and Belury, 1999).

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IV. OTHER CONJUGATED FATTY ACIDS There are also other types of conjugated fatty acids in some plant seed oils. Punicic acid (c9,tll, c13-conjugated linolenic acid, CLN) in pomegranate seed oil, a-eleostearic acid (c9,t 11 ,t13-CLN) in bitter gourd oil and tung seed oil, catalpic acid (t8,tl0,cI2-CLN) in pot marigold seed oil (Suzuki et al., 2001; Kohno et al., 2002). It has been reported that several seaweeds contain conjugated trienoic and tetraenoic fatty acids. Ptilotafilicna contains t5,t7,t9,cI4,cI7-conjugated eicosapentaenoic acid (CEPA) and c5,t7,t9,c14,c 17-CEPA (Lopez and Gerwick, 1987). Bossiella orbigniana contains c5,c8,t 1O,t12,c14CEPA (Burgess et al., 1991). Green seaweed Anadyomene stellata contains stella-heptaenoic acid, c4,c7,t9,tll,cI3,cI6,cI9-conjugated docosaheptaenoic acid (Mikhailoba et al., 1995).

A.

ANTICARCINOGENIC EFFECT

Results from the in vivo study indicate that dietary CLN inhibits azoxymethane-induced colonic aberrant crypt foci in rats (Kohno et aI., 2002). There are also several reports indicating the cytotoxic effects of CLN on various human cancer cell lines suggesting that conjugated trienes are stronger anticarcinogens than conjugated dienes (Igarashi and Miyazawa, 2000a; Suzuki et aI., 2001). The cytotoxic actions of conjugated EPA and conjugated DHA were demonstrated in several cancer cell lines including colorectal, hepatoma, lung, breast, and stomach (Igarashi and Miyagawa, 2000b; Tsujita-Kyutoku etaI., 2004; Tsuzuki et aI., 2004).

B.

ANTIOBESE EFFECT

The antiobese effects of CLN have also been demonstrated. Dietary supplementation of CLN reduced perirenal adipose tissue weight by increasing triglyceride lipolysis, enhancing hepatic fatty acid beta-oxidation and reducing hepatic fatty acid synthesis in rats (Koba et aI., 2002, 2006), in chickens, obese rats, and human liver-derived cells (Lee et aI., 2002; Arao et aI., 2004a,b).

V. SAFETY AND DOSAGE OF CLA Evidence shows that for an individual with a body weight of 70 kg to reduce body fat mass is about 3.4 g (Blankson et aI., 2000). Results from a randomized, double-blind, placebo-controlled trial shows that CLA supplementation (3.4 g/day in triglyceride form) for 24 months in healthy, overweight adults was well tolerated, and that CLA decreases body fat mass in overweight humans, and may help maintain initial reductions in body fat mass and weight in the long term (Gaullier et aI., 2004). Thus, all evidence indicates that dietary supplementation of CLA at this dosage does not have any adverse effects. There are concerns regarding the use of CLA by nursing mothers. Results from a double-blind, placebo-controlled study indicates that use of CLA by the lactating women reduces the fat content of breast milk (Masters et aI., 2002). Since infants require the fat in breast milk for energy and proper growth and development, one should be prudent to recommend CLA supplement to the nursing mothers (Bee, 2000). CLA occurs naturally in foods such as milk, cheese, beef, and lamb as well as many processed foods (Chin et al., 1992), and whole milk usually contains less than 2 mg/g of CLA in milk fat, most people consume less than 1 g/day from these food sources (Ip et al., 1994; Parodi, 1994; Herbal et aI., 1998). In order to get enough CLA from the diet one would require considerable intake of these types of foods. This approach is not only impractical, but also having a seriously negative impact on one's metabolism due to the high intake of calories. Supplemental CLA is usually derived from synthesis.

VI. CONCLUSION CLA appears to be a generally safe nutritional substance (Whigham et aI., 2004). CLA exerts many beneficial effects, such as anticarcinogenic, antiobese, antiatherogenic, anti-inflammatory, and so forth.


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However, not all CLA isomers are equal; since specific CLA isomers exhibit different functions (Yotsumoto et aI., 1999; Evans et aI., 2002; Hargrave et aI., 2002; Rodriguez et aI., 2002; Nagao et aI., 2003c; Yanagita et aI., 2003; Jaudszus et aI., 2005). The availability of different isomerspecific CLA products may provide a more efficient approach to the CLA supplementation.

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