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Title: Investigation into the effects of end stage renal failure and renal replacement therapy on adipose tissue metabolism
Author: Alouffi, Sultan Mohammed R.
ISNI:       0000 0004 2734 1550
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2012
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Background and aims: End stage renal disease (ESRD), an increasing global major public health problem, has greatly increased cardiovascular disease risk (CVD) than the general population for unknown reasons. Preliminary data suggest that adipose tissue, shown to contribute to CVD risk in non-ESRD populations, may also play a part in ESRD. Adipose tissue is a complex organ which not only functions as a fat storing depot, but also plays an essential role in lipid metabolism. Recently, researchers have recognized that adipose tissue is also an endocrine organ since it secretes several cytokines and adipokines including leptin, adiponectin and interlukin-6 (IL-6). Alteration in circulating adipokines has been shown in ESRD patients. The objective of the study was to clarify the role that adipose tissue and lipoproteins may have in ESRD. The work presented in this thesis has focused on the role of adipose tissue in ESRD patients undergoing haemodialysis and peritoneal dialysis. Both the nutrient and endocrine functions of adipose tissue were addressed in this thesis. Materials and methods: Most studies were carried out on novel in vitro adipocyte assay system developed for these experiments. Novel approaches to investigate ESRD included isolating lipoprotein fractions (VLDL, LDL and HDL) by ultracentrifugation from ESRD and matched human controls followed by incubation with the normal adipocytes in the novel assay system developed for these experiments. One experiment involved collection of human adipose tissue samples. Given the scope of the thesis mainly gene expression data was collected on candidate genes analysed by quantitative real-time PCR in these novel pilot studies. Results: An atherogenic lipoprotein profile was seen in ESRD patients. Haemodialysis patients had increased serum triglycerides and decreased HDL- cholesterol compared to the control subjects. Both haemodialysis and peritoneal dialysis groups had increased VLDL. The lipoprotein pattern in the present study also indicated the peritoneal dialysis group had more atherogenic lipoproteins, IDL and small dense LDL. Expression of lipoprotein lipase, hormone-sensitive lipase and regulatory proteins of lipid metabolism complement protein 3 and low density lipoprotein receptor were downregulated when treated with uraemic lipoproteins in vitro. Serum concentrations of total adiponectin, high molecular weight adiponectin and leptin were significantly higher in the ESRD. Gene expression of adiponectin, IL-6 and leptin was lower in ESRD patients. The results showed a tendency towards an increased accumulation of macro phages in adipose tissue in ESRD patients. Discussion: These findings are strongly suggestive of a defective storage function as well as impaired ability to release fatty acids consistent with dysfunctional adipose tissue in ESRD. These data strongly suggest that normal adipocyte function is altered when exposed to a uraemic environment in vitro. Macrophage infiltration into adipose tissue has been suggested to play role in insulin resistance and systemic inflammation. The results from the modulation of this in vitro adipocyte assay system not only serves as a convenient and unique model to study mechanisms of disease such as ESRD and its treatments but has so far also provided an initial insight that strongly suggests several mechanisms that could contribute to the CVD risk associated with ESRD. Conclusion: An in vitro system to study the effect of uraemic lipoproteins and serum on adipose tissue nutrient and endocrine function through adipocyte gene expression was conducted and compared where available with the corresponding circulating protein measurements. Further studies in ESRD, both by broadening the number of adipocyte genes (and proteins) and undertaking a mechanistic approach to clarifying the reasons for the changes observed would be necessary and informative.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral