Geraldine F. Keogh

The mitochondria-targeted anti-oxidant mitoquinone decreases liver damage in a phase II study of hepatitis C patients.

Background: Increased oxidative stress and subsequent mitochondrial damage are important pathways for liver damage in chronic hepatitis C virus (HCV) infection; consequently, therapies that decrease mitochondrial oxidative damage may improve outcome. The mitochondria‐targeted anti‐oxidant mitoquinone combines a potent anti‐oxidant with a lipophilic cation that causes it to accumulate several‐hundred fold within mitochondria in vivo.

Regeneration of the Heart in Diabetes by Selective Copper Chelation

Heart disease is the major cause of death in diabetes, a disorder characterized by chronic hyperglycemia and cardiovascular complications. Although altered systemic regulation of transition metals in diabetes has been the subject of previous investigation, it is not known whether changed transition metal metabolism results in heart disease in common forms of diabetes and whether metal chelation can reverse the condition. We found that administration of the Cu-selective transition metal chelator trientine to rats with streptozotocin-induced diabetes caused increased urinary Cu excretion compared with matched controls. A Cu(II)-trientine complex was demonstrated in the urine of treated rats. In diabetic animals with established heart failure, we show here for the first time that 7 weeks of oral trientine therapy significantly alleviated heart failure without lowering blood glucose, substantially improved cardiomyocyte structure, and reversed elevations in left ventricular collagen and beta(1) integrin. Oral trientine treatment also caused elevated Cu excretion in humans with type 2 diabetes, in whom 6 months of treatment caused elevated left ventricular mass to decline significantly toward normal. These data implicate accumulation of elevated loosely bound Cu in the mechanism of cardiac damage in diabetes and support the use of selective Cu chelation in the treatment of this condition.

Postprandial response of adiponectin, interleukin-6, tumor necrosis factor-α, and C-reactive protein to a high-fat dietary load

OBJECTIVE Circulating levels of adiponectin are low in obesity and metabolic disorders associated with increasing fat mass including insulin resistance and dyslipidemia. Body fat stores may be positively related to intake of dietary fat, but little is known of mechanisms by which serum adiponectin may be regulated through diet. We investigated acute effects of a high-fat load and changes in fatty acid saturation on circulating adiponectin and associated mediators of inflammation including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and C-reactive protein (CRP). METHODS A high-fat test meal (59 +/- 4 g fat; 71% of energy as fat) containing a high ( approximately 71:29) or low ( approximately 55:45) ratio of saturated:unsaturated fatty acids was given at breakfast on two occasions. Blood samples were collected at 0 (baseline), 1, 3, and 6 h for measurement of adiponectin, IL-6, TNF-alpha, and high-sensitivity CRP. A fat-exclusion lunch, snack, and dinner were also given and blood samples collected at 10 and 24 h. RESULTS Eighteen healthy, lean men completed the trial. There was no evidence of acute change in circulating adiponectin in response to the lipid bolus or a differential effect of fatty acid saturation on adiponectin, high-sensitivity CRP, or IL-6 (P > 0.05). IL-6 increased over 6 h on both treatments (time, P < 0.05). TNF-alpha decreased on the high saturated:unsaturated fatty acid treatment (treatment by time, P < 0.05). There were no significant correlations between circulating adiponectin and insulin on either dietary treatment in these normoglycemic subjects. CONCLUSION Acute changes in the content of saturated and unsaturated fatty acids had no adverse effect on postprandial circulation of the adipose-related factors adiponectin, IL-6, TNF-alpha, or high-sensitivity CRP.

Lipid-lowering effects of a modified butter-fat: a controlled intervention trial in healthy men

Objective: To investigate the lipid-lowering potential of a butter-fat modified through manipulations in bovine feeding to increase the unsaturated:saturated fatty acid ratio.Design: Double-blind, randomised, cross-over intervention trial.Setting: University of Auckland Human Nutrition Unit, New Zealand.Subjects: Twenty healthy, male subjects.Intervention: A residential trial in which all foods and beverages were provided during two intervention periods, comprising 3 weeks of high unsaturated ‘modified’ vs 3 weeks of saturated ‘control’ butter feeding separated by a 4 week washout. Diets were of typical composition of 39 percentage energy (en%) fat (20 en% butter-fat), 48 en% CHO, 13 en% protein.Results: There was a significant decrease in both total (P<0.05, −7.9%) and LDL-cholesterol (P<0.01, −9.5%) during modified butter feeding. There was no significant effect of treatment on a range of other risk factors including HDL-cholesterol, triglyceride, apolipoprotein A or B, nonesterified fatty acids (NEFA), haemostatic clotting factor VII and fibrinogen or glucose (P>0.05). Subjects were maintained in energy balance and there was no significant change in body weight during intervention. Butter-fat composition alone differed between treatments.Conclusions: A significant improvement in cardiovascular risk can be achieved by moderate changes in dietary fatty acid profile, achieved through a common and well accepted food source, butter-fat.Sponsorship: New Zealand Dairy Board, Wellington; Auckland Uniservices Ltd, Auckland; Maurice & Phyllis Paykel Trust, Auckland, New Zealand.

Assessment of erythrocyte phospholipid fatty acid composition as a biomarker for dietary MUFA, PUFA or saturated fatty acid intake in a controlled cross-over intervention trial

BackgroundDietary intervention trials rely on self-reported measures of intake for assessment of energy and macronutrient composition. Dietary fat intake is of particular interest due to strong associations with pathophysiology. In epidemiological trials phospholipid fatty acid composition may reflect composition of habitual diet, although strong correlations have been identified only for essential polyunsaturated fatty acids (PUFAs). Preliminary evidence shows that saturated fatty acids (SFA) C15:0 and C17:0 may be acceptable biomarkers. This study measured changes in erythrocyte membrane fatty acids during a period of strictly controlled fat feeding to investigate their use as a short-term marker of compliance, particularly for intake of SFAs.ResultsThis was a randomised cross-over trial in which diet was provided and strictly controlled. 20 healthy, male subjects were given a 40 energy % (en%) fat diet, high in saturated (high-SFA, 20 en%) or unsaturated (high-USFA, 24 en%) fatty acids for 2 periods of 3 weeks. Subjects were residential during intervention with all food and beverages provided. Dietary composition was verified by direct chemical analysis. Blood samples were collected on days 1,7,14, 21 and analysed for red blood cell (RBC) membrane fatty acid composition. Pearson correlation showed RBC fatty acid composition to mimic dietary composition by 3 weeks, but the relationships were weak. Of the SFAs only RBC C16:0 decreased in response to decreased dietary content on high-USFA treatment (ANOVA, diet, P < 0.05). Of the USFAs, higher levels of C18:1 MUFA, C20:4 and C22:6 long chain PUFA on high-USFA diet lead to higher C18:1, C20:4 and C22:6 within RBCs (ANOVA, time*diet, P < 0.05). Pearsons correlation was significant between dietary and RBC fatty acids during the 21d dietary manipulation for C18:1, and C20:5, C22:6 only (P < 0.05).ConclusionRBC membrane fatty acids cannot reliably be used as an independent measure of compliance for dietary SFA intake in short-term studies. The MUFA oleic acid and PUFAs EPA and DHA may be more useful as markers of compliance during short term intervention trials.

Effect of high-fat meals and fatty acid saturation on postprandial levels of the hormones ghrelin and leptin in healthy men

Objective:Ghrelin and leptin play a role in control of food intake and adiposity but mechanisms regulating these hormones in man are poorly defined and evidence that dietary fats may have adverse effects is inconclusive. We investigated whether high-fat meals, which differed in saturated fatty acid (SFA) content acutely modified these hormones.Design:Randomised, double-blind, crossover trial. A high-fat (HF) test meal (59±4 g fat; 71% of energy as fat) was given for breakfast on two occasions. Meals comprised either high (∼70:30) or low (∼55:45) saturated:unsaturated fatty acid (SFA:USFA) ratio. Fasting and postprandial measurements of serum total ghrelin (RIA), leptin (enzyme-linked immunosorbent assay (ELISA)) and insulin (RIA) were made over 6 h. Postprandial measurements were also made at 10 and 24 h following a fat-exclusion lunch, snack and dinner.Subjects:A total of 18 lean, healthy men.Results:There was no significant effect of the fatty meal (time, P>0.05), nor a differential effect of SFA:USFA ratio (treatment*time, P>0.05) on ghrelin over 6 h. Leptin decreased in response to both HF treatments (time, P<0.001) but increased SFA content did not further inhibit hormone secretion (treatment*time, P>0.05). There was no significant correlation between ghrelin or leptin and circulating insulin (P>0.05).Conclusion:We conclude that HF diets may adversely effect serum leptin, although the circadian decrease may account in part for this response. Increasing dietary SFAs had no deleterious effects on leptin or total ghrelin.

No evidence of an effect of alterations in dietary fatty acids on fasting adiponectin over 3 weeks.

Objective: Little is known about the effects of alterations in fatty acid classes on adiponectin, a hormone secreted by the adipocyte known to be important in the development of diabetes and cardiovascular disease (CVD). Any factor, including diet, that may positively influence adiponectin gene expression or increase circulating levels might be useful for improving such metabolic abnormalities. We investigated the effects of alterations in dietary fatty acid saturation on fasting serum adiponectin and associated peptides.

Effect of moderate changes in dietary fatty acid profile on postprandial lipaemia, haemostatic and related CVD risk factors in healthy men

Objective: To investigate the effect of moderate changes in dietary fatty acid profile on postprandial risk factors for cardiovascular disease (CVD).Design: Double-blind, randomised, crossover, intervention trial.Setting: University of Auckland Human Nutrition Unit, New Zealand.Subjects: A total of 18 lean healthy men.Interventions: A dairy butter fat modified to reduce the saturated:unsaturated fatty acid ratio and a conventional high saturated butter fat were given on two separate occasions as a high-fat test meal (59±4 g fat; 71 en% fat) at breakfast. A fat exclusion lunch, dinner and snacks were also given. Blood samples were collected at 0 (baseline), 1, 3, 6, 10 and 24 h.Results: Maximum peak in total triacylglycerol (TAG) occurred 3 h postprandially and was highest on modified treatment (diet, P<0.05) due predominantly to increased TAG within the chylomicron-rich fraction. Transient peaks in total-, LDL- and HDL-cholesterol occurred postprandially, but did not differ between dietary treatments (P>0.05). There were no differential effects of diet on postprandial free fatty acids, apo A, apo B, glucose, insulin, amylin or haemostatic clotting factors (P>0.05).Conclusions: In a group of healthy young men, replacement of 16% of total saturated fatty acids by mono- and polyunsaturated fats within a dairy lipid did not induce postprandial changes in CVD risk that may be considered beneficial for health.Sponsorship: Fonterra, Wellington; New Zealand.