Patricia L. Mitchell

Conjugated linoleic acids, atherosclerosis, and hepatic very-low-density lipoprotein metabolism

Conjugated linoleic acids (CLAs) are isomeric forms of the 18:2 fatty acid that contain conjugated sites of unsaturation. Although CLAs are minor components of the diet, they have many reported biological activities. For nearly a decade, the potential for CLA to modify the atherosclerotic process has been examined in animal models, and studies of supplementation of the human diet with CLA were started with the anticipation that such an intervention could also reduce the risk of cardiovascular disease. Central to the hypothesis is the expectation that dietary modification could alter plasma lipid and lipoprotein metabolism toward a more cardioprotective profile. This review examines the evidence in support of the hypothesis and the mechanistic studies that lend support for a role of CLA in hepatic lipid and lipoprotein metabolism. Although there are still limited studies in strong support of a role for CLA in the reduction of early atherosclerotic lesions, there has been considerable progress in defining the mechanisms of CLA action. CLA could primarily modulate the metabolism of fatty acids in the liver. The tools are now available to examine isomer-specific effects of CLA on hepatic lipid and lipoprotein metabolism and the potential of CLA to modify hepatic gene expression patterns. Additional animal and cell culture studies will increase our understanding of these unusual fatty acids and their potential for health benefits in humans.

Conjugated Linoleic Acid Supplementation for 8 Weeks Does Not Affect Body Composition, Lipid Profile, or Safety Biomarkers in Overweight, Hyperlipidemic Men

The usefulness of conjugated linoleic acid (CLA) as a nutraceutical remains ambiguous. Our objective was, therefore, to investigate the effect of CLA on body composition, blood lipids, and safety biomarkers in overweight, hyperlipidemic men. A double-blinded, 3-phase crossover trial was conducted in overweight (BMI ≥ 25 kg/m(2)), borderline hypercholesterolemic [LDL-cholesterol (C) ≥ 2.5 mmol/L] men aged 18-60 y. During three 8-wk phases, each separated by a 4-wk washout period, 27 participants consumed under supervision in random order 3.5 g/d of safflower oil (control), a 50:50 mixture of trans 10, cis 12 and cis 9, trans 11 (c9, t11) CLA:Clarinol G-80, and c9, t11 isomer:c9, t11 CLA. At baseline and endpoint of each phase, body weight, body fat mass, and lean body mass were measured by DXA. Blood lipid profiles and safety biomarkers, including insulin sensitivity, blood concentrations of adiponectin, and inflammatory (high sensitive-C-reactive protein, TNFα, and IL-6) and oxidative (oxidized-LDL) molecules, were measured. The effect of CLA consumption on fatty acid oxidation was also assessed. Compared with the control treatment, the CLA treatments did not affect changes in body weight, body composition, or blood lipids. In addition, CLA did not affect the β-oxidation rate of fatty acids or induce significant alterations in the safety markers tested. In conclusion, although no detrimental effects were caused by supplementation, these results do not confirm a role for CLA in either body weight or blood lipid regulation in humans.

Conjugated linoleic acid isomers have no effect on atherosclerosis and adverse effects on lipoprotein and liver lipid metabolism in apoE −/− mice fed a high-cholesterol diet

Dietary supplementation with conjugated linoleic acid (CLA) has been shown, in several animal models, to decrease the development of atherosclerosis. The mechanism behind the anti-atherogenic properties of CLA is not clear. The objectives of this study were to determine the effect of CLA on atherosclerosis, lipoprotein and liver lipid metabolism, and plasma adiponectin and insulin in apoE(-/-) mice fed an atherogenic (16%, w/w fat; 1.25%, w/w cholesterol) diet. Mice were fed the diet with or without supplementation of linoleic acid (LA), c-9,t-11 CLA, t-10,c-12 CLA, or a 1:1 mixture of the two CLA isomers, at a concentration of 0.5% (w/w), for 12 weeks. Relative to the LA group, CLA supplementation had no significant effect on the lesion area in either en face preparations of the aorta or in aortic root cross-sections. Plasma triacylglycerol and cholesterol concentrations were higher in the t-10,c-12 CLA group than all other treatment groups and liver weight was also increased in this group due to a three-fold increase in liver triacylglycerol. Supplementation with t-10,c-12 CLA or mixed CLA reduced plasma adiponectin levels, whereas t-10,c-12 CLA increased plasma insulin levels. Liver triglycerides correlated directly with blood glucose and plasma insulin and inversely with plasma adiponectin. We conclude that dietary supplementation with CLA does not affect atherosclerosis of the apoE(-/-) mouse on a high-cholesterol diet. Furthermore, t-10,c-12 CLA causes adverse changes in adipocyte function and plasma and liver lipid metabolism, which are partially ameliorated by the inclusion of the c-9,t-11 CLA isomer.

Adipocyte Enhancer‐Binding Protein 1 Modulates Adiposity and Energy Homeostasis

Objective: To determine whether adipocyte enhancer binding protein (AEBP) 1, a transcriptional repressor that is down‐regulated during adipogenesis, functions as a critical regulator of adipose tissue homeostasis through modulation of phosphatase and tensin homolog deleted on chromosome ten (PTEN) tumor suppressor activity and mitogen‐activated protein kinase (MAPK) activation.

Low-Molecular-Weight Peptides from Salmon Protein Prevent Obesity-Linked Glucose Intolerance, Inflammation and Dyslipidemia in LDLR−/−/ApoB100/100 Mice

BACKGROUNDnWe previously reported that fish proteins can alleviate metabolic syndrome (MetS) in obese animals and human subjects.nnnOBJECTIVESnWe tested whether a salmon peptide fraction (SPF) could improve MetS in mice and explored potential mechanisms of action.nnnMETHODSnApoB(100) only, LDL receptor knockout male mice (LDLR(-/-)/ApoB(100/100)) were fed a high-fat and -sucrose (HFS) diet (25 g/kg sucrose). Two groups were fed 10 g/kg casein hydrolysate (HFS), and 1 group was additionally fed 4.35 g/kg fish oil (FO; HFS+FO). Two other groups were fed 10 g SPF/kg (HFS+SPF), and 1 group was additionally fed 4.35 g FO/kg (HFS+SPF+FO). A fifth (reference) group was fed a standard feed pellet diet. We assessed the impact of dietary treatments on glucose tolerance, adipose tissue inflammation, lipid homeostasis, and hepatic insulin signaling. The effects of SPF on glucose uptake, hepatic glucose production, and inducible nitric oxide synthase activity were further studied in vitro with the use of L6 myocytes, FAO hepatocytes, and J774 macrophages.nnnRESULTSnMice fed HFS+SPF or HFS+SPF+FO diets had lower body weight (protein effect, P = 0.024), feed efficiency (protein effect, P = 0.018), and liver weight (protein effect, P = 0.003) as well as lower concentrations of adipose tissue cytokines and chemokines (protein effect, P ≤ 0.003) compared with HFS and HFS+FO groups. They also had greater glucose tolerance (protein effect, P < 0.001), lower activation of the mammalian target of rapamycin complex 1/S6 kinase 1/insulin receptor substrate 1 (mTORC1/S6K1/IRS1) pathway, and increased insulin signaling in liver compared with the HFS and HFS+FO groups. The HFS+FO, HFS+SPF, and HFS+SPF+FO groups had lower plasma triglycerides (protein effect, P = 0.003; lipid effect, P = 0.002) than did the HFS group. SPF increased glucose uptake and decreased HGP and iNOS activation in vitro.nnnCONCLUSIONSnSPF reduces obesity-linked MetS features in LDLR(-/-)/ApoB(100/100) mice. The anti-inflammatory and glucoregulatory properties of SPF were confirmed in L6 myocytes, FAO hepatocytes, and J774 macrophages.

t-10, c-12 CLA Dietary Supplementation Inhibits Atherosclerotic Lesion Development Despite Adverse Cardiovascular and Hepatic Metabolic Marker Profiles

Animal and human studies have indicated that fatty acids such as the conjugated linoleic acids (CLA) found in milk could potentially alter the risk of developing metabolic disorders including diabetes and cardiovascular disease (CVD). Using susceptible rodent models (apoE−/− and LDLr−/− mice) we investigated the interrelationship between mouse strain, dietary conjugated linoleic acids and metabolic markers of CVD. Despite an adverse metabolic risk profile, atherosclerosis (measured directly by lesion area), was significantly reduced with t-10, c-12 CLA and mixed isomer CLA (Mix) supplementation in both apoE−/− (p<0.05, nu200a=u200a11) and LDLr−/− mice (p<0.01, nu200a=u200a10). Principal component analysis was utilized to delineate the influence of multiple plasma and tissue metabolites on the development of atherosclerosis. Group clustering by dietary supplementation was evident, with the t-10, c-12 CLA supplemented animals having distinct patterns, suggestive of hepatic insulin resistance, regardless of mouse strain. The effect of CLA supplementation on hepatic lipid and fatty acid composition was explored in the LDLr−/− strain. Dietary supplementation with t-10, c-12 CLA significantly increased liver weight (p<0.05, nu200a=u200a10), triglyceride (p<0.01, nu200a=u200a10) and cholesterol ester content (p<0.01, nu200a=u200a10). Furthermore, t-10, c-12 CLA also increased the ratio of 18∶1 to 18∶0 fatty acid in the liver suggesting an increase in the activity of stearoyl-CoA desaturase. Changes in plasma adiponectin and liver weight with t-10, c-12 CLA supplementation were evident within 3 weeks of initiation of the diet. These observations provide evidence that the individual CLA isomers have divergent mechanisms of action and that t-10, c-12 CLA rapidly changes plasma and liver markers of metabolic syndrome, despite evidence of reduction in atherosclerosis.

Treatment with a novel agent combining docosahexaenoate and metformin increases protectin DX and IL-6 production in skeletal muscle and reduces insulin resistance in obese diabetic db/db mice

To compare the therapeutic potential of TP‐113, a unique molecular entity linking DHA with metformin, for alleviating insulin resistance in obese diabetic mice through the PDX/IL‐6 pathway.