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Research

Research in the Howles lab is aimed at understanding the processes of cholesterol and fat absorption and metabolism. These studies are especially relevant because hyperlipidemia (e.g. high cholesterol) is a major risk factor for cardiovascular disease which remains the major cause of morbidity and mortality in the United States. Furthermore, the alarming increase of obesity and the consequent rise in Type II diabetes will present a major challenge to health care institutions in the coming decades. A complete understanding of the interplay between lipid metabolism and glucose metabolism will be critical for the development of effective therapeutic measures to both treat and prevent these diseases.

Our main project is focused on understanding the intracellular steps and cellular machinery involved in the selective uptake of cholesterol from HDL by hepatocytes and the subsequent processing of that cholesterol for secretion as biliary cholesterol, coversion to bile salts, or lipoprotein (VLDL) production. Another project is focused on the process of lipid absorption and chylomicron production by the intestinal epithelium, and the subsequent delivery of dietary fat to various tissues such as heart, muscles, fat depots, and the liver.

The first project utilizes knockout mice in which the gene for carboxyl ester lipase (CEL, cholesterol esterase, bile salt stimulated lipase) has been ablated. Absence of a functional CEL gene alters the processing of HDL-cholesterol by hepatocytes, resulting in changes in bile acid production, biliary sterol secretion, and reverse cholesterol tranport. The second project utilizes the drug ezetimibe (Zetia) and NPC1L1 knockout mice to study dietary fat and cholesterol absorption. Drug-treated and knockout mice produce intestinal lipoproteins that are dramaticlly different in size and composition, suggesting that bot the drug and the NPC1L1 protein plays an important role in chylomicron synthesis and/or secretion - most likely by affecting trafficking of cholesterol or fat to the endoplasmic reticulum or Golgi bodies. More importantly, fat carried by these chylomicrons has a different metabolic fate in drug-treated and knockout mice with subsequent effects on glucose metabolism and insulin sensitivity.


CLAS

Our lab is part of the Center for Lipid and Atherosclerosis Studies (CLAS), formerly the Lipid Research Group at the University of Cincinnati. The CLAS includes several faculty with various research projects related to the pathophysiology of lipid disorders and cardiovascular disease. Faculty, students and research staff openly share resources, skills, and ideas. Faculty and senior staff meet regularly to discuss ongoing work and to design future projects.

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Recent Publications

1. Hui DY, Howles PN. Molecular mechanisms of cholesterol absorption and transport in the intestine. Semin Cell Dev Biol. 2005 Apr;16(2):183-92.
2. Camarota LM, Chapman JM, Hui DY, Howles PN. Carboxyl ester lipase cofractionates with scavenger receptor BI in hepatocyte lipid rafts and enhances selective uptake and hydrolysis of cholesteryl esters from HDL3. J Biol Chem. 2004 Jun 25;279(26):27599-606.
3. Kirby RJ, Howles PN, Hui DY.Rate of gastric emptying influences dietary cholesterol absorption efficiency in selected inbred strains of mice. J Lipid Res. 2004 Jan;45(1):89-98.
4. Huggins KW, Camarota LM, Howles PN, Hui DY. Pancreatic triglyceride lipase deficiency minimally affects dietary fat absorption but dramatically decreases dietary cholesterol absorption in mice. J Biol Chem. 2003 Oct 31;278(44):42899-905.
5. Hui DY, Howles PN.Carboxyl ester lipase: structure-function relationship and physiological role in lipoprotein metabolism and atherosclerosis. J Lipid Res. 2002 Dec;43(12):2017-30. Review.
6. Kirby RJ, Zheng S, Tso P, Howles PN, Hui DY. Bile salt-stimulated carboxyl ester lipase influences lipoprotein assembly and secretion in intestine: a process mediated via ceramide hydrolysis. J Biol Chem. 2002 Feb 8;277(6):4104-9.
7. Cai SF, Kirby RJ, Howles PN, Hui DY. Differentiation-dependent expression and localization of the class B type I scavenger receptor in intestine. J Lipid Res. 2001 Jun;42(6):902-9.
8. Abonia JP, Howles PN, Abel KJ, Black TA, Jones CA, Gross KW. Evaluating a Model of an NRE Mediated Tissue-Specific Expression of Murine Renin Genes. Hypertension. 2001 Jan;37(1):105-109.