Murray W. Huff
Murray W. HuffProfessor, Department of Medicine
Professor, Department of Biochemistry
University of Western Ontario
Director, Vascular Biology
Atherosclerosis Research Group
John P. Robarts Research Institute (London, Ontario)
Career Investigator for The Heart and Stroke Foundation of Ontario
Vascular Biology Group
The John P. Robarts Research Institute
University of Western Ontario
100 Perth Drive
London, Ontario
N6A 5K8
Phone... (519) 663-3793
FAX... (519) 663-3789
Email... mhuff@julian.uwo.ca
Web... http://www.lhsc.on.ca/medicine/names/mhuff.htm
Dr. Murray W. Huff obtained received his undergraduate honors degree in Biochemistry from McMaster University, and his doctorate from the University of Western Ontario. In 1981 he began as honorary lecturer in the Department of Biochemistry at the University of Western Ontario, where he has risen to his current position (interrupted by one year of post-doctoral research at the Baker Medical Research Institute, Monash University, Melbourne, Australia).
Dr. Huff's primary research interests include the synthesis, secretion and metabolism of apolipoprotein B, and the effects of inhibitors of HMG-CoA reductase and of acyl coenzyme A:cholesterol acyltransferase (ACAT). His career publications number 60, and his scientific contributions have been recognized by numerous awards from Canadian Societies, including the Heart and Stroke Foundation of Ontario which elected him to its Chair for the period 1995-97.
The enzyme acyl-coenzyme A: cholesterol acyl transferase (ACAT) is an endoplasmic reticulum bound enzyme that catalyses the formation of cholesteryl esters from cholesterol and long chain fatty acids in a wide variety of cells. ACAT plays a major role in cellular cholesterol homeostasis. Cholesteryl esters are stored as cytoplasmic storage droplets or, in lipoprotein secreting cells, can be packaged in the hydrophobic core of lipoproteins for transport. In early atherogenesis, macrophages and smooth muscle cells accumulate large quantities of cholesteryl ester, a process catalysed by ACAT. The cholesterol is derived from atherogenic lipoproteins present in the arterial intima. Intestinal and hepatic ACAT synthesize the majority of cholesteryl esters transported in lipoproteins with atherogenic potential, namely, chylomicron remnants, VLDL remnants and LDL. Thus, there is considerable interest in the potential for ACAT inhibitors to prevent atherogenesis through beneficial effects in the liver, intestine and the arterial wall.
Human ACAT (Acact) has been cloned and appears to be predominant in macrophages and adrenals (1). Recently, two other human genes have been discovered that encode ACAT related proteins, termed ARGP-1 and ARGP-2 (2). ARGP-1 appears to be specific for liver and intestine and may be responsible for cholesteryl esterification in these tissues. Studies in Acact knockout mice support this contention (3). In homozygous knockout mice, peritoneal macrophage and adrenal cholesteryl esters were significantly depleted relative to control mice. In contrast, liver cholesteryl ester was unaffected in knockout mice fed a chow or high fat diet. These results raise the interesting possibility for tissue specific regulation of cholesteryl esterification.
In vitro studies from my laboratory and others indicates that the availability of cholesteryl ester may play a key role in the regulation of hepatic secretion of apoB-containing lipoproteins. These studies suggest a direct link between liver ACAT activity and the assembly of these lipoproteins, a process that occurs in the endoplasmic reticulum. Using apoB kinetic studies, we provided the first in vivo evidence, in a large animal model, that treatment with an ACAT inhibitor could decrease hepatic apoB secretion (4). In miniature pigs fed a low fat, low cholesterol diet, intravenous administration of the ACAT inhibitor DuP 128, decreased VLDL apoB secretion into plasma, which was associated with a significant decrease in hepatic ACAT activity. Although VLDL concentrations were decreased LDL concentrations were unaffected. Like most ACAT inhibitors DuP 128, is poorly absorbed and when given orally, has low systemic availability.
Recently, we demonstrated that oral administration of the ACAT inhibitor CI-1011 significantly reduces VLDL apoB secretion in miniature pigs fed a diet containing typical amounts of fat (34% of calories) and cholesterol (400 mg/d) (5). VLDL apoB secretion into plasma was decreased by 40%, conversion to LDL decreased by 50% and direct LDL secretion was reduced by 55%. VLDL and LDL fractional clearance rates were unaffected resulting in significant reductions in both plasma VLDL and LDL concentrations. This provided the first proof of principal, in vivo, that oral administration of an ACAT inhibitor could regulate hepatic apoB secretion providing further evidence for a coordinate regulation of cholesteryl esterification and apoB secretion.
Using the same miniature pig model, we recently demonstrated that the HMG-CoA reductase inhibitor, atorvastatin, decreased VLDL apoB secretion into plasma, an effect we attributed, in part, to a decreased availability of cholesterol to the ACAT substrate pool, resulting in decreased cholesteryl ester for association with apoB (6).
In a cholesterol-fed rabbit model, Bocan et al demonstrated that CI-1011 significantly reduced ileal-femoral lesion and macrophage area, without changing plasma cholesterol, suggesting a direct effect of CI-1011 on ACAT in lesion macrophages (7). Collectively, these results indicate that regulation of ACAT at multiple tissue sites may have a significant impact on atherogenesis.
Click here 
to download a MedLine search report of Dr. Huff's recent publications
(126 KB)
Version 2.1A(6), revised April 14, 1998