Cardiovascular & Lipid Disorders

Philip Howles

Philip Howles , PhD

Pathology & Lab Med-North

Research Assistant Professor

Research Summary

Research in my lab is aimed at understanding the processes of lipid absorption and metabolism. These studies are especially relevant because of the rapid increase in obesity in developed countries and the consequent rise in Type II diabetes. In addition, hyperlipidemia is a major risk factor for cardiovascular diseases which remain a major couse of morbidity and mortality in "Western" cultures.

One project is focused on elucidating the intracellular steps and cellular machinery that are involved in lipid absorption and chylomicron production by the intestinal epithelium. The second project is focused on the selective uptake of cholesterol esters from HDL by hepatocytes and the subsequent processing of that cholesterol for bile acid synthesis, lipoprotein production or secretion as biliary cholesterol.

Both projects utilize knockout mice in which the gene for carboxyl ester lipase (CEL, cholesterol esterase, bile salt stimulated lipase) has been ablated. During active lipid absorption, these mice produce intestinal lipoproteins that are dramaticlly different in size and protein composition, suggesting that enzyme plays an important role in chylomicron synthesis and/or secretion - most likely by affecting Golgi function. Absence of a functional CEL gene also appears to alter the processing of HDL-cholesterol by hepatocytes, resulting in changes in bile acid production and biliary cholesterol secretion.
All studies involve a combination of physiological, biochemical, and molecular techniques as well as both in vivo and in vitro (cell culture)systems.

Recent Publications

Labonte E., L. Camarota, J. Roja, R. Jandacek, D. Gilham, J. Davies, Y. Ioannou, D. Hui, P. Tso and P. Howles (2008)Reduced absorption of saturated fatty acids and resistance to diet-induced obesity and diabetes by ezetimibe-treated and Npc1l1-/- mice.American Journal of Physiology – Gastrointestinal and Liver Physiology 295: (in press)

Hui, D., E. Labonte and P. Howles (2008)Development and Physiological Regulation of Intestinal Lipid Absorption. III. Intestinal Transporters and Cholesterol Absorption.American Journal of Physiology – Gastrointestinal and Liver Physiology 294:G839-843.

Nogueiras, R., P. Wiedmer, D. Perez-Tilve, C. Veyrat-durebex, J. Keogh, G. Sutton, P. Pfluger, T. Castaneda, S. Neschen, S. Hofmann, P. Howles, D. Morgan, S. Benoit, I. Szanto, B. Schrott, A. Schurmann, H. Joost, C. Hammond, D. Hui, S. Woods, K. Rahmouni, A. Butler, I. Farooqi, S. O’Rahilly, F. Rohner-Jeanrenaud and M. Tschop, (2007)The central melanocortin system directly controls peripheral lipid metabolism.Journal of Clinical Investigation 117:3475-88.

Gilham,D., E. Labonte, J. Rojas, R. Jandacek, P. Howles and D. Hui (2007)Carboxyl ester lipase deficiency exacerbates dietary lipid absorption abnormalities and resistance to diet-induced obesity in pancreatic triglyceride lipase knockout mice.Journal of Biological Chemistry 282:24642-24649.

Labonte, E., P. Howles, N. Granholm, J. Rojas, J. Davies, Y. Ioannou and D. Hui (2007)Class B type I scavenger redeptor is responsible for the high affinity cholesterol binding affinity of intestinal brush border membrane vesicles.Biochimica et Biophysica Acta [epub ahead of print March 16, 2007]

Book Chapters

Howles, P. and D. Hui (2001). Cholesterol Esterase. In Intestinal Lipid Metabolism (C. Mansbach, A Kuksis and P. Tso, editors), p.119-134, Kluwer Academic/Plenum Publishers, New York.

Nikiforov, Y and P. Howles (2001). Polymerase Chain Reaction. In Morphology Methods: Cell and Molecular Biology Techniques (R. Lloyd, editor), p.181-207. Humana Press, Totowa, New Jersey.

 

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