Thesis (Ph. D.)--University of Texas at Austin, 2001. / Vita. Includes bibliographical references. Available also from UMI/Dissertation Abstracts International.

Thesis (M.S.)--University of Michigan, 1978.

The integration of biological and genetic data has established that diverse biological processes, involving multiple effectors, influence circulating levels of triglyceride and cholesterol. This diversity may underlie the genetic complexity of human dyslipidemias, including the common and highly atherogenic condition, Familial Combined Hyperlipidemia (FCHL). The aetiologies of FCHL are currently undetermined. In this thesis, a multi-pronged approach was employed to identify genes/variants contributing to the linkage observed between the chromosome 21q22.2-22.3 interval and lipid traits, in white-British FCHL families. Additionally GPIHBP1, which encodes glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1, was studied. GPIHBP1 represents a strong FCHL candidate gene due to its role in the lipolytic processing of triglyceride-rich lipoproteins. Combined genetic and gene expression analyses, focussed upon a refined 3.8Mb interval on chromosome 21q22.3 that was linked to lipid abnormalities in subsets of FCHL families, identified two genes (COL18A1 and PKNOX1 ) that warrant further investigation with regard to their contribution to FCHL. Promising results were also obtained for C21orf57, which resides just outside the 3.8Mb interval. Genetic association analyses in 1725 members of 239 FCHL families identified nominal association (P=0.0009) between a TSPEAR variant, rs34163868, and plasma triglyceride levels. Furthermore, transcript levels of CBS and TRPM2 were significantly altered by treatment with the PPAR-agonist bezafibrate in a rat hepatoma cell line, thus implicating these genes in triglyceride/fatty acid metabolism. In combined analysis of five independent cohorts, the minor allele of the GPIHBP1 variant, rs11538388 was protective against hypertriglyceridemia (P=2.98x10-4). The same allele was associated with decreased risk of coronary heart disease in the prospective Northwick Park Heart Study II (hazard ratio for carriers=0.76, P=0.0480) and delayed age of onset in the Southampton Atherosclerosis Study (odds ratio=0.76, P=0.0146). Collectively, these data demonstrate that the rs11538388 minor allele, or variant in linkage disequilibrium, is associated with more favourable processing of atherogenic lipoproteins.

published_or_final_version / Pharmacology and Pharmacy / Master / Master of Medical Sciences

Not available / text

Hyperlipidemia is prevalent following heart transplantation, and may play a role in the development of late graft atherosclerosis. The charts of 35 heart transplant recipients (n = 32 males and 3 females) were reviewed retrospectively up until three years post transplantation, to describe a time-course of hypercholesterolemia after transplantation, and to determine the mechanisms involved in its pathogenesis. All patients received prednisone, cyclosporine, and azathioprine for immunosuppression. A progressive rise in both serum cholesterol (2.4 $ pm$ 0.4 mmol/l, p $<$ 0.01), and body weight (8.4 $ pm$ 1.6 kg, p $<$ 0.01) were observed during the first 8 and 10 months respectively. Levels stabilized thereafter, remaining above pretransplant levels. Triglyceride, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol concentrations were all above normal limits following transplantation. Tapering of prednisone dose had a significant effect on serum cholesterol levels, whereas diet had a beneficial effect on body weight. A randomized, controlled, dietary intervention study then followed to further assess the effect of dietary intervention on minimizing or preventing post transplantation hyperlipidemia and weight gain. Five patients were counselled the Step One Lipid-Lowering diet, two patients were controls. All study patients demonstrated a lower overall increase in serum cholesterol levels than other transplant recipients. Reported nutritional intakes were similar between both groups. Increases in body weight were related to increases in body fat. Patients in the diet group demonstrated improvements in their level of nutrition knowledge, which correlated with lower serum cholesterol levels. Changes in serum cholesterol were also associated with appetite, hunger, perceived interest, perceived benefits, perceived barriers, and attitudes toward food. Changes in body weight were associated with appetite, hunger, perceived barriers, and stress. As

Thesis (M.D.)--Boston University

No description available.

Background: The pathogenesis of gallbladder mucocele is unknown in the dog. It has been proposed that hyperlipidemia could impair gallbladder motility and contribute to gallbladder mucocele formation. Objectives: The objective of this study was to compare gallbladder motility in dogs with hyperlipidemia to healthy, control dogs using ultrasonography. We hypothesized that hyperlipidemic dogs have decreased gallbladder motility, defined by increased fasting gallbladder volume (GBV) and decreased gallbladder ejection fractions at 60 (EF60) and 120 minutes (EF120) compared to controls. Animals: 26 hyperlipidemic dogs, 28 healthy control dogs Methods: Twenty-six hyperlipidemic and 28 healthy, age-matched control dogs were prospectively enrolled. Hyperlipidemia was defined as hypercholesterolemia (>332 mg/dL) and/or hypertriglyceridemia (>143 mg/dL). Dogs with both primary and secondary causes of hyperlipidemia were included. All dogs were fasted for at least 12 hours prior to collection of plasma biochemistry and pre-prandial ultrasound. Ultrasound was performed on dogs in the fasted state as well as at 60 and 120 minutes after being fed 10g/kg of a high fat diet (Hill's a/d diet; Hill's Pet Nutrition, Topeka, Kansas, USA). GBVs and EFs were calculated using the following formulas: GBV = (0.52 x L x W x H)/kg and EF = ((GBV0- GBV60,120)/GBV0) x 100, respectively. GBV0, GBV60, GBV120, EF60 and EF120 were compared between dogs with hyperlipidemia and controls using the Wilcoxon rank sum test. Statistical significance was set to p<0.05. Results: Hypercholesterolemia and hypertriglyceridemia were present in 15/26 (58%) and 21/26 (81%) hyperlipidemic dogs, respectively and 10/26 (38%) had elevations in both parameters. The median age in both groups was 10 years. Median (range) cholesterol concentration was 346 mg/dL (181-1372 mg/dL) and 238 mg/dL (153-324) in hyperlipidemic and control dogs, respectively. Median triglyceride concentration was 330 mg/dL (52-2213) and 65.5 mg/dL (32-142) in hyperlipidemic and control dogs, respectively. Eleven (42%) hyperlipidemic dogs were considered severely hyperlipidemic based on the triglyceride and/or cholesterol concentrations above 500 mg/dL. There were significant differences in GBV0 and GBV60 between hyperlipidemic and control dogs. Dogs with severe hyperlipidemia had significantly larger GBVs at all time points. Dogs with hypercholesterolemia also had significantly greater GBVs at all times compared to dogs without hypercholesterolemia. Median EF60 and EF120 were not significantly different between hyperlipidemic and control dogs nor severely hyperlipidemic and mildly hyperlipidemic dogs. Conclusions: Hyperlipidemic dogs have significantly greater fasting and postprandial GBVs but similar ejection fractions when compared to control dogs. Gallbladder emptying is unaltered in hyperlipidemic dogs, but gallbladder volume is higher in hyperlipidemic dogs after feeding. This distention could contribute to bile retention of bile and potentially gallbladder disease. / Master of Science / The gallbladder (GB) is a reservoir for bile. The GB contracts to deliver bile to the intestines after a meal to help with digestion of nutrients and fats, and to rid the body of harmful waste. When the GB becomes diseased, abnormal bile flow can become toxic to the liver and endanger the patient's health. One of the most common GB diseases in dogs is GB mucocele (buildup of mucus in the GB). The cause of GB mucocele formation is not well understood. One proposed cause is decreased contractions of the GB related to increased cholesterol and/or elevated triglycerides (hyperlipidemia). Our study investigated whether hyperlipidemia leads to poor gallbladder contraction, possibly explaining GB mucocele formation. We used ultrasound scans before and after eating to compare gallbladder motility in dogs with hyperlipidemia to healthy, control dogs. We hypothesized that hyperlipidemic dogs would have decreased gallbladder motility compared to controls. Twenty-six dogs with elevated cholesterol and/or elevated triglycerides and 28 healthy, age-matched control dogs were enrolled. Ultrasound was performed on dogs in the fasted state as well as 60 and 120 minutes after being fed. There were significant differences in findings between affected dogs and control dogs. Dogs with very high blood lipid levels had significantly larger gall bladder volumes (GBVs). Dogs with high cholesterol also had significantly greater GBVs at all times compared to normal dogs. This finding indicates that excessive bile may be retained in the gall bladders of dogs with hyperlipidemia, possibly affecting the function of the organ. Our study also looked at difference between the two groups in measures of ejection fraction, which can gage how efficiently the gall bladder releases bile. No differences were noted between the healthy group and the affected group. Conclusions and Outcomes: Hyperlipidemic dogs have significantly greater GBVs than control dogs both before and after eating, but similar ejection fractions. This study provides a clearer understanding of the mechanisms of gall bladder disfunction in dogs.

Obese individuals are at greater risk of various comorbidities including cancer, diabetes, and cardiovascular disease (CVD). Endocrine imbalances and dyslipidemia are likely contributors to the etiology of these diseases in obese individuals. / The objectives of this research project were: (1) to determine the effectiveness of a self-selected diet and exercise weight loss (WtL) protocol in overweight and obese women; (2) to investigate the effects of moderate WtL on hormones associated with the regulation of energy balance, blood lipid levels, and low density lipoprotein (LDL) particle size; (3) to characterize changes in cholesterol metabolism as a result of moderate WtL through an examination of factors that likely play a role in its modulation, specifically body composition and single nucleotide polymorphisms (SNP) in ATP binding cassette (ABC)G5 and ABCG8 transporter. / In carrying out these objectives, 35 women were included in a 24-week WtL trial. Hormone, lipids, and cholesterol metabolism were assessed at the end of two stabilization periods. During these periods, body composition was also measured via magnetic resonance imaging (MRI). WtL was achieved through a 20% decrease in energy intake using diet combined with a 10% increase in energy expenditure through physical activity. / Overall, participants lost an average of 11.7+/-2.5 kg. WtL resulted in improvements in blood lipid risk factors of CVD with minimal effect on LDL particle size. No associations were found between leptin, ghrelin, adiponectin, and insulin. Cholesterol synthesis decreased as a result of WtL, while cholesterol absorption and turnover did not change. Despite an absence of change in turnover, increases were predicted by decreases in visceral adipose tissue, and decreases in cholesterol absorption were associated with losses in total and upper body skeletal muscle. This study also showed that changes in cholesterol concentrations and metabolism after WtL are associated with SNPs in ABCG5 and ABCG8 genes. / These findings suggest that hormones important in the regulation of energy homeostasis may exert their effects independently. Moderate WtL results in cardioprotective changes in blood cholesterol levels primarily due to changes in cholesterol synthesis. These findings also indicate that the responsiveness of blood cholesterol levels and metabolism to weight loss is modulated by changes in body composition and SNPs in ABCG5 and ABCG8.