Edward A. Fisher
- ADJUNCT PROFESSOR Medicine, Cardiology
- ADJUNCT PROFESSOR Developmental and Regenerative Biology
- ADJUNCT PROFESSOR Pediatrics
- ADJUNCT PROFESSOR Anatomy and Functional Morphology
M.D., New York University
Duke University Hospital
National Institute of Health
Lipid disorders in adults and children
Specialty: Pediatric Cardiology, Cardiology
Am Board of Pediatrics (Pediatrics)
The Laboratory of Lipoprotein Research focuses on the production of the apoprotein B (apoB)-containing hepatic lipoproteins and their accumulation in the arterial wall, which leads to atherosclerosis. These two research areas will be discussed separately:
1) Hepatic lipoprotein metabolism: ApoB is the major protein of VLDL and LDL lipoprotein particles and in epidemiologic studies, coronary artery disease risk is strongly correlated with plasma cholesterol and apoB levels. This has stimulated research into the molecular mechanisms by which hepatic apoB gets assembled with lipids and is secreted. Unlike most hepatic secretory proteins, secretion of apoB is regulated not by its rate of synthesis, but by the rate of its degradation. We reported in 1997 our discovery that this degradation is accomplished by the proteasome. This result was unexpected because the proteasome is in the cytosol, whereas, as a secretory protein, apoB normally should be segregated from the cytosol by intracellular membranes, such as those of the endoplasmic reticulum (ER). Since our report, others have noted similar findings for other disease-causing proteins, such as CFTR (cystic fibrosis) and a1-anti-trypsin (pulmonary disease). This type of degradation has been dubbed "ERAD" (ER-associated degradation) and it now clear that it exerts "quality control" by preventing abnormally folded proteins from traveling further in the secretory pathway. What makes apoB abnormally folded? If sufficient lipids do not associate with the protein while it is still being translated, domains of apoB are not properly stabilized, resulting in a malfolded conformation. This implies that when there is a low level of lipid synthesis, ERAD would degrade the apoB no longer needed for lipoprotein assembly. This represents an impressive coordination between the ER and cytosol to metabolically regulate apoB secretion. In order to further understand hepatic lipoprotein assembly and secretion, we are currently applying a variety of approaches- from cell free systems to tissue specific knockout mice- to intensively investigate the molecular and topological factors directing apoB to the cytosolic proteasomes or to assembly with lipids and exit from the ER.
2) Atherosclerosis and restenosis: A pathological effect of VLDL and LDL is to deliver atherosclerosis-causing cholesterol to the arterial wall. This, of course, leads to coronary artery disease (CAD), the major killer of people in the US and other developed countries. To develop animal models to focus on two highly desirable goals in the treatment of CAD- regression of pre-existing plaques and the reduction of restenosis following angioplasty, we have turned to the mouse. Since the reports in 1992 of the "apoE knockout (apoEKO)" mouse, which has hypercholesterolemia and spontaneously develops plaques with many features of human lesions, this animal has become the most widely used model for studies of atherosclerosis. To study the molecular factors in the arterial wall that promote lesion regression, we first let lesions of different complexity form in an apoE KO mouse, then replace a part of the aorta of a recipient mouse with a lesion-bearing segment. The recipient is chosen to have a different lipoprotein profile from the donor E KO mouse (for example, a normolipidemic wild type mouse [as shown below], or an apoE KO mouse made transgenic for human apoAI to produce high levels of HDL). At time points after the transplantation, changes in the arterial wall can be followed (see below) non-invasively by MRI (right panel) or invasively by standard histopatholgically (middle panel). Note the massive remodeling of the lesion by two months after transplantation into a normolipidemic recipient. Besides showing, for the first time, that advanced lesions can be significantly remodelled, we have in place the system to test more subtle alterations in the lipoprotein profile, such as an isolated elevation in HDL. To identify the molecules important for the regression process, a number of standard (immunohistochemistry) and emerging (laser capture microscopy and gene arrays) techniques are being applied.
Legend: Two months after transplantation from an E KO mouse fed a high fat diet for 30 weeks into either a wild type mouse (top row) or another E KO mouse (bottom row), the mice were subjected to in vivo MRI, then sacrificed. The gross and histopathology (left and middle panels) show a complex, severely stenotic lesion in the E KO to E KO transplantation, but there is remarkable remodeling of the lesioned aorta in the E KO to wild type transplantation. Note that the MRI can readily detect the difference in wall thickness between the two aortae (arrows).
Restenosis is a major complication of angioplasty and related procedures, which are therapeutically applied to hundreds of thousands of patients per year with unstable coronary artery disease. We have recently discovered that particular non steroidal inflammatory drugs (NSAIDs) can inhibit restenosis in a mouse model of arterial injury. We are in the process of exploring the molecular mechanisms by which NSAIDs affect the proliferation of smooth muscle cells and their abnormal migration from the medial layer of the artery to the neointima. Training opportunities: Each project area has approximately 5-6 associated investigators, consisting of fellows (PhD and MD), research assistants, and graduate students. There are extensive collaborations with faculty both in the CVRP and Mount Sinai and outside (particularly Rockefeller University and Columbia P&S). The research is primarily supported by grants from the NIH and industry.
Fisher DC, Fisher EA, Budd JH, Rosen SE, Godlman ME. The incidence of patent foramen ovale in 1,000 consecutive patients. A contrast transesophageal echocardiography study. Chest 1995 Jun; 107(6): 1504-9.
Fisher EA. Regulation of the production of lipoproteins containing apolipoprotein B. In: Molecular Cardiology. NY, Marcel Dekker, Inc.; 1997.
Zaiou M, Azrolan N, Hayek T, Wang H, Wu L, Haghpassand M, Cizman B, Madaio MP, Milbrandt J, Marsh J, Breslow JL, Fisher EA. The full induction of human apoprotein A-I gene expression by the experimental nephrotic syndrome in transgenic mice depends on cis-acting elements in the proximal 256 base-pair promoter region and the trans-acting factor early growth response factor 1. J Clin Invest 1998; 101: 1699-1707.
Fayad ZA, Fallon JT, Shinnar M, Wehrli S, Dansky HM, Poon M, Badimon JJ, Charlton SA, Fisher EA, Breslow JL, Fuster V. Noninvasive In vivo high-resolution magnetic resonance imaging of atherosclerotic lesions in genetically engineered mice. Circulation 1998; 98: 1541-1547.
Weng W, Li L, van Bennekum AM, Potter SH, Harrison EH, Blaner WS, Breslow JL, Fisher EA. Intestinal absorption of dietary cholesteryl ester is decreased but retinyl ester absorption is normal in carboxyl ester lipase knockout mice. Biochemistry 1999; 38: 4143-4149.
Schecter A, Spirn B, Rossikhina M, Giesen PL, Bogdanov VY, Fallon J, Fisher E, Schnapp LM, Nemerson Y, Taubman M. Release of active tissue factor by human arterial smooth muscle cells. Circ Res 2000 Jul 21; 87(2): 81-2.
van Bennekum AM, Fisher EA, Blaner WS, Harrison EH. Hydrolysis of retinyl esters by pancreatic triglyceride lipase.. Biochemistry 2000 Apr 25; 39(16): 4900-6.Previously [van Bennekum, A. M., et al. (1999) Biochemistry 38, 4150-4156] we showed that carboxyl ester lipase (CEL)-deficient (CELKO) mice have normal levels of pancreatic, bile salt-dependent retinyl ester hydrolase (REH) activity. In the present study, we further investigated this non-CEL REH activity in pancreas homogenates of CELKO and wild-type (WT) mice, and rats. REH activity was detected in both the presence and absence of tri- and dihydroxy bile salts in rats, WT mice, and CELKO mice. In contrast, pancreatic cholesteryl ester hydrolase (CEH) activity was only detected in the presence of trihydroxy bile salts and only in rats and WT mice, consistent with CEL-mediated cholesteryl ester hydrolysis. Enzyme assays of pancreatic triglyceride lipase (PTL) showed that there was a colipase-stimulated REH activity in rat and mouse (WT and CELKO) pancreas, consistent with hydrolysis of retinyl ester (RE) by PTL. Pancreatic enzyme activities related to either CEL or PTL were separated using DEAE-chromatography. In both rats and mice (WT and CELKO), REH activity could be attributed mainly to PTL, and to a much smaller extent to CEL. Finally, purified human PTL exhibited similar enzymatic characteristics for triglyceride hydrolysis as well as for retinyl ester hydrolysis, indicating that RE is a substrate for PTL in vivo. Altogether, these studies clearly show that PTL is the major pancreatic REH activity in mice, as well as in rats.
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Dr.Fisher is not currently required to report Industry relationships.
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