Lipid metabolism dysregulation in rheumatoid arthritis: from multi-omics discovery to adjunctive therapy with conjugated linoleic acid.

The effects of dietary conjugated linoleic acid alone or incombination with linoleic acid and oleic acid on fatty acid composition of egg yolk, embryo mortality and chick yolk sac content retention in chickens

Fats in the new millennium: more complexity but a better understanding?

Conjugated linoleic acid (CLA) is able to reduce adiposity by affecting lipid metabolism. In particular, CLA administration to mice reduces body fat mass with a concomitant lipid accumulation in the liver. We investigated the effects of CLA on the activity of the mitochondrial citrate carrier (CIC), which is implicated in hepatic lipogenesis. The transport activity of the CIC, measured both in intact mitochondria and in the proteoliposomes, progressively increased with the duration of CLA feeding. An increase in the CIC activity of approximately 1.7-fold was found in 16 week CLA-treated mice with respect to control animals. A kinetic analysis showed a 1.6-fold increase in the V(max) of citrate transport but no change in the K(m) value. Western blot experiments revealed an increase of approximately 1.7-fold in the expression of CIC after CLA treatment. A strict correlation between the increase in CIC activity and the stimulation of the cytosolic lipogenic enzymes was also found. These data indicate that the CIC may play a role in the onset of hepatic steatosis in CLA-fed mice by supplying the carbon source for de novo fatty acid synthesis.

Effect of Dietary Supplementation with Conjugated Linoleic Acid, with Oleic, Linoleic, or Linolenic Acid, on Egg Quality Characteristics and Fat Accumulation in the Egg Yolk

We determined the effects of conjugated linoleic acid (CLA) supplementation during resistance training. Seventy-six subjects were randomized to receive CLA (5 g.d(-1)) or placebo (PLA) for 7 wk while resistance training 3 d.wk(-1). Seventeen subjects crossed over to the opposite group for an additional 7 wk. Measurements at baseline, 7 wk, and 14 wk (for subjects in the crossover study) included body composition, muscle thickness of the elbow flexors and knee extensors, resting metabolic rate (RMR), bench and leg press strength, knee extension torque, and urinary markers of myofibrillar degradation (3-methylhistidine (3MH) and bone resorption (cross-linked N-telopeptides (Ntx)). After 7 wk the CLA group had greater increases in lean tissue mass (LTM) (+1.4 vs +0.2 kg; P < 0.05), greater losses of fat mass (-0.8 vs +0.4 kg; P < 0.05), and a smaller increase in 3MH (-0.1 vs + 1.3 micromol.kg LTM.d(-1); P < 0.05) compared with PLA. Changes between groups were similar for all other measurements, except for a greater increase in bench press strength for males on CLA (P < 0.05). In the crossover study subjects had minimal changes in body composition, but smaller increases in 3MH (-1.2 vs +2.2 micromol.kg LTM.d(-1); P < 0.01) and NTx (-4.8 vs +7.3 nmol.kg(-1) LTM.d(-1); P < 0.01) while on CLA versus PLA. Supplementation with CLA during resistance training results in relatively small changes in body composition accompanied by a lessening of the catabolic effect of training on muscle protein.

In this study, we evaluated the relationship between ferritin levels and disease activation in rheumatoid arthritis (RA) patients. We included 44 patients with RA, 20 patients with systemic lupus erythematosus (SLE), 25 patients with infection, 22 patients with malignancy, and 20 healthy control subjects. Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), whole blood count, and serum iron parameters were determined in all cases. The joint findings in RA patients were recorded, and disease activity score (DAS) was calculated. In SLE patients, antinuclear antibody (ANA) and anti-dsDNA titers and C3 and C4 complement levels were determined. SLE disease activity index (SLEDAI) score was calculated. Serum ferritin levels in the RA, SLE, and control groups were lower than those in the infection and malignancy groups (p<0.05). The ferritin levels in the RA group did not differ significantly from the SLE and control groups. In RA patients, serum ferritin level had a positive correlation with ESR, CRP, RF, platelet count, and DAS score and had a negative correlation with hematocrit (all p values <0.05). In SLE patients, on the other hand, serum ferritin had a positive correlation with ANA, anti-dsDNA, and SLEDAI (all p values <0.05). According to DAS, ferritin level in inactive RA patients was lower than that in active RA patients. When transferrin saturation was considered, iron deficiency anemia was a quite frequent finding in both active and inactive RA patients. Interestingly, we observed that ferritin level in RA patients was similar to the control group; however, it was a good parameter of disease activation. This is because a reduction in storage iron and resultant iron deficiency anemia are very common in RA patients.

Conjugated linoleic acid (CLA) causes insulin resistance and hepatic steatosis in conjunction with depletion of adipokines in some rodent models. Our objective was to determine whether the maintenance of adipokines, mainly leptin and adiponectin, by either removing CLA from diets or using an adiponectin enhancer, rosiglitazone (ROSI), could attenuate CLA-induced insulin resistance. Male C57BL/6 mice were consecutively fed two experimental diets containing 1.5% CLA mixed isomer for 4 weeks followed by a diet without CLA for 4 weeks. CLA significantly depleted adiponectin but not leptin and was accompanied by hepatic steatosis and insulin resistance. These effects were attenuated after switching mice to the diet without CLA along with restoration of adiponectin. To further elucidate the role of adiponectin in CLA-mediated insulin resistance, ROSI was used in a subsequent study in male ob/ob mice fed either control (CON) or CLA diet. ROSI maintained significantly higher adiponectin levels in CON- and CLA-fed mice and prevented the depletion of epididymal adipose tissue and the development of insulin resistance. In conclusion, we show that insulin resistance induced by CLA may be related more to adiponectin depletion than to leptin and that maintaining adiponectin levels alone either by removing CLA or using ROSI can attenuate these effects.

The purpose of this study was to examine the effects of conjugated linoleic acid (CLA) supplementation in conjunction with 6 weeks of aerobic exercise training on the physical working capacity at the fatigue threshold (PWCFT), timed sit-ups, and the standing long jump. Thirty-three untrained to moderately trained men (mean ± SD; age = 21.6 ± 2.8 years) participated in this double-blind, placebo-controlled study and were randomly assigned to either a CLA (Clarinol A-80; n = 17) or placebo (PLA; sunflower oil; n = 16) group. Before and after 6 weeks of aerobic training (50% VO2peak for 30 minutes, twice per week) and supplementation (8 ml CLA or PLA per day), each subject completed an incremental cycle ergometer test to exhaustion to determine the PWCFT, maximal number of sit-ups in 1 minute, and the standing long jump. There were no differences (all p ≥ 0.23) between the CLA and PLA groups for the analysis of covariance-adjusted posttest mean values for PWCFT, sit-ups, or standing long jump. The PWCFT increased from pre- to posttraining in the CLA (p = 0.003) and PLA (p = 0.003) groups. There were no differences (p > 0.05) from pre- to posttraining for sit-ups and standing long jump in either the CLA or PLA groups. There was no effect of CLA on the training-induced increases in PWCFT, nor were there any effects of CLA or aerobic training on the maximum number of sit-ups or standing long jump. Thus, CLA had no ergogenic benefits on this model of aerobic training-induced improvements in neuromuscular fatigue, or on field tests of muscle endurance and power.

1.1 Chemical structure of CLA CLA is a term given to a group of positional and geometric isomers of linoleic acid (cis-9, cis-12, C 18:2 LA) in which double bonds are conjugated, instead of being in the typical methylene interrupted configuration.Each double bond can be cis or trans configuration giving rise to possible CLA isomers (Kelly et al., 1998).Although conjugation of double bonds occurs as part of free radical mediated oxidation of linoleic acid.CLA is a true isomer of LA, in that it does not possess additional oxygen (Vandenberg et al., 1995). Isomers of CLACLA therefore, includes 28 positional and geometrical isomers of which only cis-9, trans-11 and trans-10, cis-12 have thus far been proven to have biological activities (Park et al., 2003).Of the two physically important isomers cis -9, trans -11 (rumenic acid) is the most prevalent comprising 80-90% of the total CLA in food products from ruminants where as trans-10, cis-12 is present in small amounts at 3-5% of total CLA (Parodi, 2003).Analysis of cheese using silver ion-high performance chromatography and G-C electron ionization mass spectrometry showed that isomers of CLA present (in fat percent) total CLA were cis-9, trans-11 (78-84%); trans-7, cis-9 plus trans -8, cis -10 (8-13%); trans-11,cis-13 (1-2%); cis-12,trans-14 (<1%) and the total trans/trans isomers (5-9%) (Parodi, 2003) 1.3 Sources of CLA CLA occurs in many foods, however, the principal dietary sources are dairy products and other foods derived from ruminants.The CLA content of some common foods is shown in (Table 1).www.intechopen.comConjugated Linoleic Acid: A Milk Fatty Acid with Unique Health Benefit Properties 113 CH 3 (CH 2 ) 5 (CH 2 ) 7 COOH C H C C C H H H CH 3 (CH 2 ) 4 (CH 2 ) 8 COOH C H

Conjugated linoleic acid (CLA) is a complex mixture of positional and geometric conjugated isomersof linoleic acid. Dairy products are the major dietary source of CLA and cis-9, trans-11 CLA (9,11CLA) is the predominant isomer resulting from the specific metabolism of feed derived fatty acids inthe rumen. Recent studies suggest endogenous synthesis of CLA by action of Δ-9 desaturase on trans-11 18:1 fatty acid (vaccenic acid, VA) is more important than ruminal production. In view of potentialhuman health benefits, several studies have attempted to enrich eggs with CLA by supplementing thediets of laying hen with mixtures of CLA. This has resulted in marked enrichment but also negativeeffects on egg quality and loss of hatchability of the eggs with concurrent increase in saturated fattyacid content in egg yolk. Such changes are consistent with Δ-9 desaturase inhibition especially associatedwith the presence of the trans-10, cis-12 CLA isomer (10,12 CLA) in the CLA mixtures. It istherefore worthwhile to determine which of the major CLA isomers present in the CLA mixtures, 9,11CLA or 10,12 CLA, is associated with the negative effects on egg quality. This was done by supplementingthe diets of laying hen with relatively pure forms of 9,11 CLA and 10,12 CLA. Furthermore,using relatively pure forms of 9,11 CLA and 10,12 CLA allowed us to determine the transfer efficiencyof 9,11 CLA and 10,12 CLA into egg yolk. In addition, endogenous conversion of VA to 9,11CLA in hens and deposition in egg yolk was examined.Experimental treatments consisted of diets supplemented with 0, 0.5, 1.0 and 1.5 g/d of CLA orVA. CLA isomer content (% of total fatty acids) of the materials was 83 and 7% (9,11 CLA), 9 and85% (10,12 CLA), 35 and 35% (Mix CLA) of 9,11 CLA and 10, 12 CLA, respectively. VA was suppliedin the form of dehydrated hydroxy stearic acid with trans-11 C18:1 content of 28%. The othermajor isomers in this product were cis-11, trans-12 and cis-12 C18:1 (28, 11 and 11%, respectively).There were three hens in each treatment and experimental diets were fed for 21 days. When dietswere supplemented with 9,11 CLA, 10,12 CLA and Mix CLA the transfer efficiencies (percentageof dietary CLA recovered in the egg) of 9,11 CLA and 10,12 CLA in egg yolk total lipids were 21 and&lt;1%, 24 and 12%, 20 and 9%, respectively. Dietary VA was efficiently converted to 9,11 CLA anddeposited in the yolk. The slope of linear regression of VA plus 9,11 CLA versus 9,11 CLA in the eggyolk total lipids represents an estimate of the average conversion over the range of VA intakes studied.In this study 74% of VA available for desaturation was converted to 9,11 CLA. The transfer efficiencyof VA (percentage of dietary VA recovered as VA plus 9,11 CLA in the egg) was 14%. Dietary vaccenicacid in hens is efficiently converted to 9,11 CLA, but the overall efficiency of dietary VA use forCLA enrichment is quite low. Further studies examining the limitations of VA transfer to the liver andavailability for conversion by Δ-9 desaturase should be examined.

In hypoxic conditions, miRNA-210 plays an important role in regulating the expression of hypoxia-inducing factor-1α (HIF-1α) and the differentiation of T helper 17 (Th17) cells, and this may be involved in the development and function of the immune system. This study was to investigate the miR-210 expression levels in peripheral blood mononuclear cells (PBMCs) from patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) and its association with the clinical and laboratory features of both diseases. Real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) was used to detect miR-210 expression levels in PBMCs from 35 patients with SLE, 38 patients with RA, and 35 healthy controls. Compared with the healthy controls, the miR-210 expression levels were significantly increased in patients with SLE (P=0.001) and there was increased significantly expression of miR-210 in SLE with pleuritis (Z=-2.345, P=0.019) and anti-SSB/La-positive group (Z=-2.076, P=0.038). However, we have not found the significant correlation between the miR-210 levels and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score (r s=0.091, P=0.602). Although, no significant difference between miR-210 levels in RA patients and those in healthy controls was found (Z=-1.226, P=0. 220). There was a significant decreased expression of miR-210 in active RA patients than inactive RA patients (Z=-4.011, P<0.001). The dysregulation of miR-210 levels in SLE and RA patients suggests that miR-210 might play an important role in the pathogenesis of these diseases.

Production of conjugated linoleic acid (CLA) by the potential probiotic bacterium Lactobacillus plantarum WU-P19 was investigated with the aim of enhancing production. CLA produced using this bacterium may be used to supplement dietary intake. Cultures were fed linoleic acid for conversion to CLA and the CLA produced was measured. In some cases, chitosan was added to cultures to improve cellular uptake of linoleic acid. Under static conditions at 37 °C, the bacterium grew and produced CLA in the pH range of 5.5–6.5. At pH 6.0, a 36-h incubation period maximized the concentration of the dry biomass (0.82 g/L), the CLA content in the biomass (4.1 mg/g), and linoleic acid in the biomass (1.2 mg/g). In comparison with cultures grown without linoleic acid in the medium, supplementing the medium with linoleic acid at 600 μg/mL slowed the production of CLA, but the CLA content in the dry biomass increased to 12–14 mg/g and the linoleic acid content increased to 8–11 mg/g. Supplementing the culture medium with chitosan and linoleic acid enhanced production of CLA in the dry biomass to 21 mg/g within 36 h. Nearly 50% of the CLA was cis-9, trans-11-CLA, and the remainder was trans-10, cis-12-CLA. Linoleic acid content of the dry biomass was increased to 37 mg/g. Accumulation of CLA in the cells was enhanced by feeding linoleic acid. Supplementing the culture with linoleic acid and chitosan further increased accumulation of CLA.

The effect of pH and polyunsaturated C18 fatty acid source on the production of vaccenic acid and conjugated linoleic acids in ruminal cultures incubated with docosahexaenoic acid

Previous work by Ip and co‐workers showed that mammary cancer prevention by conjugated linoleic acid (CLA) is independent of the level of fat in the diet. Because CLA is an isomer of linoleic acid, there is the question regarding whether the effect of CLA is due to a displacement of linoleic acid in cells. To further evaluate whether there might be an interaction between linoleic acid and CLA, the present study was designed to examine the dose response to CLA (at 0.5%, 1 %, 1.5%, and 2%) in rats fed a 2% or a 12% linoleate diet (both basal diets contained 20% total fat by weight). The end points of investigation included the bio‐assay of mammary tumorigenesis in the rat dimethyl‐benzl[a]Janthracene model as well as the incorporation of CLA, linoleic acid, and arachidonic acid in mammary glands. The mammary carcinogenesis results showed that the efficacy of tumor suppression by CLA was not affected by linoleate intake. With either linoleate diet, no further protection was evident with levels of CLA >1%. Analysis of neutral lipids and phospholipids of the mammary tissue indicated that 1) the accumulation of CLA in mammary tissue was dose dependent from 0.5% to 2%, 2) CLA concentration was 10 times higher in neutral lipids than in phospholipids, 3) the incorporation of CLA in either fraction was not affected by the availability of linoleic acid, and 4) CLA did not appear to displace linoleic acid or arachidonic acid in the mammary tissue. The above findings suggest that there may be distinctive mechanisms in the modulation of tumor development by linoleic acid and CLA.

Human γδ T cells recognize conserved endogenous and stress-induced antigens typically associated with autoimmune diseases. However, the role of γδ T cells in autoimmune diseases is not clear. Few autoimmune disease-related antigens recognized by T cell receptor (TCR) γδ have been defined. In this study, we compared Vδ2 TCR complementarity-determining region 3 (CDR3) between systemic lupus erythematosus (SLE) patients and healthy donors. Results show that CDR3 length distribution differed significantly and displayed oligoclonal characteristics in SLE patients when compared with healthy donors. We found no difference in the frequency of Jδ gene fragment usage between these two groups. According to the dominant CDR3δ sequences in SLE patients, synthesized SL2 peptides specifically bound to human renal proximal tubular epithelial cell line HK-2; SL2-Vm, a mutant V sequence of SL2, did not bind. We identified the putative protein ligand chaperonin-containing T-complex protein 1 subunit ζ (CCT6A) using SL2 as a probe in HK-2 cell protein extracts by affinity chromatography and liquid chromatography-electrospray ionization-tandem mass spectrometry analysis. We found CCT6A expression on the surface of HK-2 cells. Cytotoxicity of only Vδ2 γδ T cells to HK-2 cells was blocked by anti-CCT6A antibody. Finally, we note that CCT6A concentration was significantly increased in plasma of SLE and rheumatoid arthritis patients. These data suggest that CCT6A is a novel autoantigen recognized by Vδ2 γδ T cells, which deepens our understanding of mechanisms in autoimmune diseases.