Thesis (Ph.D.)-- University of Wisconsin--Madison, 2007. / Includes bibliographical references.

Thesis (M.Phys.Ed.)--Memorial University of Newfoundland, 2004. / Includes bibliographical references.

Doctor of Philosophy / Department of Human Nutrition / Sara Rosenkranz / The aims of this dissertation were to provide innovative, applicable insights regarding the impact of single-meal consumption on metabolic and inflammatory responses in the acute post-meal (“postprandial”) period. In Chapter 2, the connection between large postprandial glucose and triglyceride (TG) fluxes and cardiovascular disease (CVD) risk were reviewed. A new marker of metabolic status, Metabolic Load Index (MLI), calculated by adding glucose and TG, was proposed based on several considerations: 1) independent associations between postprandial glucose and TG with CVD risk, although the substrates are considered to increase risk through similar mechanisms; 2) postprandial glucose and TG responses are interrelated; and 3) meals consumed in daily life typically contain both carbohydrate and fat. MLI may be useful in characterizing metabolic status/risk in both clinical and research settings. Chapter 3 was a systematic review with the purpose of objectively describing postprandial responses (i.e. magnitude and timing) to a high-fat meal (HFM) in five commonly assessed inflammatory markers: interleukin (IL)-6, C-reactive protein (CRP), tumor necrosis factor (TNF)-α, IL-1β, and IL-8. IL-6 increased in >70% of studies, starting at ~1.4 pg/mL pre-meal and peaking at ~2.9 pg/mL ~6 hours post-HFM. Other markers (CRP, TNF-α, IL-1β, and IL-8) did not change after the HFM in the majority of studies. These findings suggest that IL-6 is an inflammatory marker that routinely increases following HFM consumption. Future postprandial studies should further investigate IL-6, as well as explore novel markers of inflammation. In Chapter 4, we compared the metabolic and inflammatory responses to a HFM (17 kcal/kg, 60% fat), representative of meals used in previous postprandial studies, to two meal trials that were more reflective of typical eating patterns: a moderate-fat meal (MFM; 8.5 kcal/kg, 30% fat), and a biphasic meal (BPM), in which the MFM was consumed twice, three hours apart. The HFM elicited a greater total area-under-the-curve (tAUC) TG response (1348.8 ± 783.7 mg/dL x 6 hrs) compared to the MFM (765.8 ± 486.8 mg/dL x 6 hrs; p = 0.0005) and the BPM (951.8 ± 787.7 mg/dL x 6 hrs; p = 0.03), but the MFM and BPM were not different (p = 0.72). It appears that the large postprandial TG response observed in previous studies may not be representative of the daily metabolic challenge for many individuals. Chapter 5 assessed the impact of both aging and chronic physical activity level on postprandial metabolic responses by comparing three groups: younger active (YA), older active (OA), and older inactive (OI) adults. The TG tAUC response was lower in YA (407.9 ± 115.1 mg/dL x 6 hr) compared to OA (625.6 ± 169.0 mg/dL x 6 hr; p = 0.02) and OI (961.2 ± 363.6 mg/dL x 6 hr; p = 0.0002), while the OA group TG tAUC was lower than OI (p = 0.02). Thus, it is likely that both aging and chronic physical activity level impact the postprandial metabolic response. This series of projects provides needed clarification regarding the postprandial metabolic and inflammatory responses to single-meal intake, particularly in the context of real-life application.

No description available.

An experiment was designed to study in the same animal any preferential absorption of a free fatty acid in the presence of a triglyceride of the same fatty acid. Rats were administered a mixture of free fatty acid and its triglyceride labeled with carbon-13 and carbon-14 respectively. Each isotope in the fed lipid and in the lipid recovered from the gastrointestinal tract was measured. The isotope effect, if any, was studied by administering a mixture of palmitic acid-1-C13 and palmitic acid-1-C14.

In recent years elevated levels of serum triglycerides have become of increasing importance in the field of medical technology. Abnormally high triglycerides have been claimed to be a major cause of numerous diseases and illnesses. Fredrickson and his associates (7, 15) have introduced a system for classifying hyperlipidemia and in all classes elevated triglycerides is a major laboratory finding. Disorders include obesity, diabetes, pancreatitis, xanthomatosis, hypothyroidism, and liver and kidney diseases; but most important is atherosclerosis Some work has been done in the development of new methods of serum triglyceride analyses. The most advanced work makes use of an "automated analyzer" of the type produced by Technicon Corporation under the trademark AutoAnalyzer. This instrument determines the serum levels by the same method as above but at a faster rate, but the equipment is costly. A second method makes use of light scattering indices (nephelometry) to assess serum triglycerides. Work in this area has been done by Helman, Blevins, and Gleason (12). Their results were consistent, in most cases, with those of the colorimetric method. Of the thirty Fredrickson classifications they made by nephelometry twenty-one were in agreement with manual methods. However, Baty and Batsakis (1) have concluded that nephelometry provides too indirect an assay to give consistent results for serum triglycerides. A third method employs chromatography and infrared spectrophotometry. Freeman, Lindgren, Ng, and Nichols (8) showed that first, the lipids could be separated by chromatographic techniques, and then the extraction could be analyzed by infrared measurements. However, it is found that fractionating the lipid leads to error and is quite time consuming. Still other methods use phenylhydrazine (13, 16), mercaptoacetic acid (5), or oxidation to yield aldehydes, which are then thin-layer chromatographed (18). In light of the numerous above methods and the error and time involved in analysis, the development of a new improved method with the time factor in mind was attempted. The use of infrared spectrophotometry was employed, but without the use of any prior extractions. It is hoped that this technique can give accurate and consistent values for triglyceride levels with a minimum amount of time expended. The new method should also be easy to install with a simplified procedure which would minimize error.

Objectives Hypertriglyceridemia-induced pancreatitis is an important cause of acute pancreatitis (AP) in children, which lacks established guidelines. The aim of this study was to review management approaches at a single pediatric center. Methods This retrospective study included all inpatients younger than 21 years with AP and triglycerides (TG) of 1000 mg/dL or greater. A linear mixed effect model was used to calculate drop in TGs. The patient's diet, intravenous fluid (IVF) rate, insulin, and plasmapheresis were included in the model. Results Seventeen admissions were identified among 8 patients, average age 15 years (range, 6-19 years). Fifty percent had recurrent AP and 29% of admissions had complications including 1 death. The population was primarily female (75%), white (75%), and overweight, and 63% had diabetes. The median stay was 5.4 days. There were 14 approaches used with variations in IVF rates, insulin, plasmapheresis, and nill per os (NPO) versus feeds. Variables that reduced TG's were NPO, higher IVF rates, plasmapheresis, and insulin (P < 0.05). Importantly, NPO reduced TGs faster than those who started early nutrition. Conclusions Hypertriglyceridemia is an important cause of pancreatitis in children. This study shares a management algorithm from a single institution. Larger studies are needed for more evidence-based guidelines.

Twenty-four male university students were fed vegetarian diets containing 100 grams of protein. Seventy-five grams of protein came either from soy, non-fat dairy products or egg white. Diets were adjusted so that differences in total caloric intake, protein, carbohydrate, fat and fatty acid composition were minimal between the dietary treatments. Plasma total triglyceride and very low density lipoprotein-triglycerides were measured at the beginning, weekly throughout the experimental period, and two weeks after completion of the study. No significant differences existed in serum lipid values between treatment diets nor was any interaction between diet and week observed. A significant week effect was observed indicating that subjects fed soy, non-fat dairy products or egg whites responded in the same fashion to the diet from week to week. This relationship was true for both variables: serum triglycerides and VLDL-triglycerides. Serum triglyceride concentrations for all treatment groups combined at baseline were 79 mg/ 100 ml, increasing to 82 mg/100 ml at week 1 and decreasing to 64 mg/100 ml at week two. An increase of 84 mg/100 ml was noted at week three. Decreases were observed at week four, with serum concentrations of 65 mg/100 ml. From week four to follow-up serum triglyceride concentration rose to 83 mg/100 ml. Similar trends were noted in serum VLDL-triglyceride levels when mean concentration were combined for all treatment groups. Serum VLDL-triglyceride concentrations at baseline were 48 mg/100 ml. At week one serum VLDL-triglyceride concentrations remained unchanged with values of 40 mg/100 ml in both instances. Decreases were observed at week 4 with serum VLDL-triglyceride concentrations increased to 38 mg/100 ml. The results indicate that plasma triglycerides and VLDL-triglycerides are influenced by other dietary factors rather than by the protein source. / Master of Science

The apoC-III proteoform containing two sialic acid residues (apoC-III2) has different in vitro effects on lipid metabolism compared with asialylated (apoC-III0) or the most abundant monosialylated (apoC-III1) proteoforms. Cross-sectional and longitudinal associations between plasma apoC-III proteoforms (by mass spectrometric immunoassay) and plasma lipids were tested in two randomized clinical trials: ACT NOW, a study of pioglitazone in subjects with impaired glucose tolerance (n = 531), and RACED (n = 296), a study of intensive glycemic control and atherosclerosis in type 2 diabetes patients. At baseline, higher relative apoC-(I)II2 and apoC-III2/apoC-III1 ratios were associated with lower triglycerides and total cholesterol in both cohorts, and with lower small dense LDL in the RACED. Longitudinally, changes in apoC-III2/apoC-III1 were inversely associated with changes in triglycerides in both cohorts, and with total and small dense LDL in the RACED. apoC-III2/apoC-III1 was also higher in patients treated with PPAR-gamma agonists and was associated with reduced cardiovascular events in the RACED control group. Ex vivo studies of apoC-III complexes with higher apoC-III2/apoC-III1 showed attenuated inhibition of VLDL uptake by HepG2 cells and LPL-mediated lipolysis, providing possible functional explanations for the inverse association between a higher apoC-III2/apoC-III1 and hypertriglyceridemia, proatherogenic plasma lipid profiles, and cardiovascular risk.

Dyslipidemia often accompanies metabolic diseases such as obesity and type II diabetes mellitus and represents a risk factor for cardiovascular disease. Clearance of triglycerides from the plasma is mediated by lipoprotein lipase (LPL), which hydrolyzes the triglycerides in chylomicrons and VLDL, liberating fatty acids for tissue uptake. LPL functions in the capillaries of the heart, adipose tissue, and skeletal muscle where LPL is anchored to the capillary wall by its endothelial cell transporter GPIHBP1. LPL activity is regulated by several factors including three members of the angiopoietin-like (ANGPTL) family–ANGPTL3, ANGPTL4, and ANGPTL8. How these proteins interact with LPL, especially in the physiological context of LPL anchored to endothelial cells by GPIHBP1, has not been well characterized. In my studies of ANGPTL4, I found when LPL is bound to GPIHBP1, it is partially, but not completely, protected from inactivation by ANGPTL4. Inactivation of LPL by ANGPTL4 leads to the dissociation of active LPL dimers into inactive monomers and I found that these monomers have a greatly reduced affinity for GPIHBP1. ANGPTL4 can be cleaved in vivo, separating the N-terminal coiled-coil domain from the C-terminal fibrinogen like-domain. I found the N-terminal domain alone is a much more potent LPL inhibitor than the full-length protein, even though both appear to have similar binding affinities for LPL-GPIHBP1 complexes. When I investigated ANGPTL3, I found ANGPTL3 itself is not a potent inhibitor of LPL at physiological concentrations, and unlike ANGPTL4, cleavage of ANGPTL3 does not improve its ability to inhibit LPL. Instead I found that ANGPTL3 forms a complex with ANGPTL8, a complex that only forms efficiently when the two proteins are co-expressed, and that this complex allows ANGPTL3 to bind and inhibit LPL. My data provide new insights into how ANGPTL proteins regulate LPL activity and the delivery of fat to tissues.