Endocrinology, Metabolism and Clinical Nutrition

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Victor Drover, PhD

Assistant Professor of Medicine; Biochemistry
Director, HPLC Core Facility
Department of Medicine
Division of Endocrinology, Metabolism and Clinical Nutrition

Training:
          PhD, Biochemistry

   •University of Alberta, Canada

          Post-doctoral Fellowship

   • SUNY Stony Brook

Contact:
          Office: H4880 Health Research Center
          Phone: 414-456-4607
          Fax: 414-456-6570
          E-mail: victor.drover@mcw.edu


Research Area - Regulation of fatty acid transport and utilization:

Obesity, diabetes and the metabolic syndrome are all characterized by dyslipidemias and inappropriate nutrient utilization. In particular, the factors which govern the absorption of fat (i.e. triacylglycerol and fatty acids) from the intestine and its subsequent utilization by peripheral tissues such as adipose and muscle are poorly understood. Thus, the overall goal of our work is to understand the molecular mechanisms which determine the fate of dietary fat and to identify novel molecular targets for therapeutic intervention.

We have recently shown that CD36, a scavenger receptor expressed in a wide variety of cell types, is an important regulator of the secretion of triacylglycerol-containing intestinal lipoproteins called chylomicrons. Mice lacking CD36 also exhibit an impaired ability to catabolize chylomicrons in the blood. As a result, triacylglycerol and fatty acids (the main chemical component of triacylglycerol and a ligand for CD36) accumulate in the blood forcing cells to rely more heavily on glucose for energy. Based on this work, we have three primary aims:

  1. To understand the structure-function relationships in the CD36 amino acid sequence responsible for the uptake and utilization of fatty acids.
  2. To identify other proteins which direct the fate of intracellular fatty acids and which may cooperate and/or bind to CD36.
  3. To identify novel ligands for CD36.
Fatty Acid Metabolism
Fig. 1. CD36 and dietary fatty acid utilization. In the presence of CD36, fatty acids (FA) are targeted to a secretion-coupled pool within the endoplasmic reticulum (ER) and efficiently packaged into triacylglycerol (TAG)-containing chylomicrons. In the plasma, lipoprotein lipase (LPL) acts to liberate the FAs from the chylomicron-associated TAG. Clearance of these FAs by peripheral tissues via CD36 prevents feedback inhibition of LPL. Coordinated upregulation of CD36 expression by dietary FAs would enhance both FA absorption and peripheral utilization. Adapted from Drover et al., 2005.
 
We have also found that CD36 is critical for the absorption of saturated, very long-chain fatty acids (VLCFAs; i.e. those having greater than 22 carbons) in the intestine and in cultured cells. Thus, it is very likely that CD36 plays a similar role for VLCFA uptake in peripheral tissues such as adrenal and brain. Importantly, the impaired catabolism of VLCFAs in these tissues is symptomatic of a lethal, childhood disease called X-linked adrenoleukodystrophy (X-ALD). Current literature suggests that blocking the dietary absorption of VLCFAs may prevent disease progression in asymptomatic patients. We will use mouse-models of X-ALD with and without CD36 to test this hypothesis.

Together, these research projects will shed new light on the mechanisms of protein-facilitated fatty acid transport and may identify new molecular targets or treatment strategies for diseases characterized by dyslipidemias and inappropriate nutrient utilization.
 

Selected Publications

 
Drover VA, Nguyen DV, Bastie CC, Darlington YF, Abumrad NA, Pessin JE, London E, Sahoo D, and Phillips MC. 2008.  CD36 mediates both cellular uptake of very long chain fatty acids and their intestinal absorption in mice. J. Biol. Chem. (in press)
 
Hajri T, Hall AM, Jensen DR, Pietka TA, Drover VA, Tao H, Eckel R, Abumrad NA. 2007. CD36-facilitated fatty acid uptake inhibits leptin production and signaling in adipose tissue. Diabetes 56:1872-1880.
 
Sahoo D and Drover VA. 2006. The role of scavenger receptors in signaling, inflammation and atherosclerosis, in Biochemistry of Atherosclerosis, S. Kaur Cheema (ed), Springer, New York

Drover VA, Ajmal M, Nassir F, Davidson NO, Nauli AM, Sahoo D, Tso P, and Abumrad NA. 2005. CD36 deficiency impairs intestinal lipid secretion and clearance of chylomicrons from the blood. J. Clin. Invest. 115:1290-1297.

Drover VA and Abumrad NA. 2005. CD36-dependent fatty acid uptake regulates expression of peroxisome proliferator activated receptors. Biochem. Soc. Trans. 33:311-315.

Bastie CC, Hajri T, Drover VA, Grimaldi PA, and Abumrad NA. 2004. CD36 in myocytes channels fatty acids to a lipase-accessible triglyceride pool that is related to cell lipid and insulin responsiveness. Diabetes 53(9):2209-16.

Sahoo D, Trischuk TC, Chan T, Drover VA, Ho S, Chimini G, Agellon LB, Agnihotri R, Francis GA and Lehner R. 2004. ABCA1-dependent lipid efflux to apolipoprotein A-I mediates HDL particle formation and decreases VLDL secretion from murine hepatocytes. J. Lipid Res. 45(6):1122-31.

Drover VA and Agellon LB. 2004. Regulation of the human cholesterol 7-alpha-hydroxylase gene (CYP7A1) by thyroid hormone in transgenic mice. Endocrinology. 145(2):574-81.

Agellon LB, Drover VA, Cheema SK, Gbaguidi GF and Walsh A. 2002. Dietary cholesterol fails to stimulate the human cholesterol 7-alpha-hydroxylase gene (CYP7A1) in transgenic mice. J. Biol. Chem. 277(23):20131-20134.

Drover VA, Wong NCW, and Agellon LB. 2001. A distinct thyroid hormone response element mediates repression of the human cholesterol 7-alpha-hydroxylase (CYP7A1) gene promoter. Mol. Endocrin. 16(1):14-23.
 
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