Epidemiological studies suggest that obesity is associated with increased risk of colorectal cancer (CRC) development. Cytosolic Malic Enzyme (ME1) is a lipogenic enzyme that generates NADPH required for fatty acid synthesis. ME1 expression is subject to dietary and hormonal regulation, and its expression in the liver and adipose tissue has been correlated with obesity and diabetes. However, the role of intestinal ME1 in the development of these conditions has not been investigated. In Chapter 2 of this dissertation, I examined the effects of absence of ME1 (in MOD-1 mice) and consumption of soy protein isolate (SPI) diet on adiposity, endocrine status, and expression of pre-malignancy biomarkers in the colon and small intestine of mice when challenged with high-fat diet (HF). The MOD-1 genotype and SPI-HF diet resulted in decreased body and retroperitoneal fat weights, serum insulin and leptin levels, serum leptin/adiponectin ratio, and colon Mtor and Cyclin D1 mRNA levels. MOD-1 mice had reductions in liver weight, hepatosteatosis, and colon crypt depth, compared to WT mice. SPI-HF diet lowered Me1 gene expression only in retroperitoneal fat. To evaluate the effect of intestinal ME1 expression on obesity, hepatosteatosis and CRC development, we generated transgenic (Tg) mice over-expressing ME1 in the gastrointestinal epithelium (Chapter 3). Male ME1-Tg mice fed a HF diet had significantly more body and liver weight than WT littermates. ME1-Tg mice had deeper intestinal crypts, a higher intestinal BrdU labeling index, elevated serum glucose, and increased expression of intestinal and liver lipogenic and cholesterol synthesis genes. ME1-Tg mice were crossed with an initiated mouse model of colon cancer, the Apcmin/+ mouse, to generate progeny with intestinal ME1 over-expression in the background of APCmin/+ mutation (Chapter 4). Apcmin/+/ME1-Tg mice showed a significant increase in the intestinal tumor burden compared to Apcmin/+/WT counterparts. The increase in the tumor burden was manifested by increased numbers of small-sized tumors (diameter < 1 mm), suggesting increased initiation of tumorigenesis induced by ME1 over-expression. The collective results from these studies support an important functional role of intestinal ME1 expression in obesity, hepatosteatosis, and CRC development. Dietary or therapeutic targeting of ME1 may therefore provide the means to reduce risk of both obesity and CRC.
|Advisor:||Simmen, Frank A.|
|Commitee:||Hakkak, Reza, Simmen, Rosalia C.M., Ware, Jerry, Wight, Patricia A.|
|School:||University of Arkansas for Medical Sciences|
|Department:||Physiology and Biophysics|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 75/05(E), Dissertation Abstracts International|
|Subjects:||Health sciences, Oncology|
|Keywords:||Adiposity, Colon cancer, Malic enzyme, Me1, Obesity, Soy|
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