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Philip Howles, PhDAssistant Professor Department Pathology and Laboratory Medicine
Dr. Howles investigates the role of diet-gene interactions on lipid and cholesterol absorption and metabolism using genetically engineered mice, with particular focus on diseases related to lipoprotein metabolism and obesity. He studies the role of carboxyl ester lipase (CEL), made by pancreas and liver, in HDL metabolism and reverse cholesterol transport. Data show that this enzyme plays a significant role in hydrolysis of HDL-cholesteryl esters during their selective uptake by the liver. Surprisingly, absence of CEL results in more rapid transport of HDL-derived sterols to the bile. The overall physiological effect is a 30-40% increase in reverse cholesterol transport, the removal of excess cholesterol from the body via biliary transport and fecal excretion. In a humanized mouse model, absence of CEL raises HDL in addition to enhancing reverse cholesterol transport. Drug discovery projects are underway based on the results of this research. Dr. Howles also investigates the role of the intestinal cholesterol transporter, NPC1L1, on fat absorption and metabolism. Studies show modestly reduced fat absorption in addition to dramatically reduced cholesterol absorption by mice lacking this gene and mice treated with the drug ezetimibe (Zetia), which blocks its function. Knockout and drug treated mice have altered hepatic lipid and glucose metabolism and are resistant to diet-induced obesity. Current studies are aimed at discovering how changing cholesterol absorption influences metabolism of dietary fat and glucose, with particular focus on changes to the composition of chylomicrons and consequent changes in dietary nutrient partitioning during the postprandial period.
Dr. Howles collaborates with Drs. Hui and Tso on how changes in cholesterol absorption influences metabolism. Anticipated Core Use: Gene and Protein Expression, Bioinformatics, and Integrative Morphology Cores.
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Dietary fat and cholesterol absorption is decreased in ezetimibe-treated and Npc1l1-/- mice. Cholesterol absorption (left) was measured by the dual-isotope method and fat absorption (right) was measured by the sucrose polybehenate method. Mice were fed basal chow. *P <0.001; **P = 0.033, ***P = 0.025 compared with controls. Figure from Am J Physiol Gastrointest Liver Physiol, 2008;295:G776-83.
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