Profile

Education & Training

• B.S., North Carolina State University , 1973
• M.S., Wake Forest University , 1976
• Ph.D., Wake Forest University , 1979
• Fellowship, Boston University School of Me, 1981

Memberships

• Aha - Council On Arteriosclero

Recent Publications

All Publications

For a listing of recent publications, refer to PubMed, a service provided by the National Library of Medicine.

• WFBMC
• All

For a list of earlier publications, visit the Carpenter Library Publication Search.

Current Research:

My lab has several National Institutes of Health (NIH)-funded projects that focus on the pathogenesis of complex, chronic diseases such as atherosclerosis (i.e., hardening of the arteries), diabetes, obesity, and hepatosteatosis (i.e., fatty liver). We study the effect of lipid metabolism and inflammation on the development and progression of complex metabolic diseases. To accomplish the goals of our grant projects, we use an interdisciplinary approach that includes transgenic/gene-targeted mouse models of human disease, molecular biology, cell biology, biochemistry, mass spectrometry, and vascular wall biology.

Liver ABCA1, Lipoprotein Metabolism and Atherosclerosis (HL119962)

ATP binding cassette transporter A1 (ABCA1) effluxes phospholipid and free cholesterol from cells, forming nascent high density lipoproteins (HDLs). Because ABCA1 is variably expressed in most cells, we generated hepatocyte-specific ABCA1 KO (HSKO) mice to study the role of hepatocyte ABCA1 in lipid mobilization, transport, and metabolism. Our previous studies showed that hepatocyte ABCA1 regulates the production and catabolism of all three major plasma lipoprotein classes (VLDL, LDL and HDL) that affect coronary heart disease development. In preliminary studies, we found that hepatocyte ABCA1 also reguates hepatic insulin and inflammatory signaling, suggesting the function of hepatocyte ABCA1, while not fully elucidated, is more complex than facilitating bulk cellular cholesterol export and nascent HDL formation. The goal of this project is to determine the role of hepatocyte ABCA1 in lipid mobilization and transport in HSKO mice and humans. In specific aim 1, we are examining the role of hepatocyte ABCA1 expression in hepatic insulin signaling, inflammation, and lipogenesis. Metabolic phenotype, plasma VLDL metabolism, hepatic lipid synthesis, hepatic insulin receptor signaling, and hepatic plasma membrane lipid composition are being determined in chow and high fat-fed wild type and HSKO mice. In specific aim 2, the role of hepatic ABCA1 expression on cholesterol flux from plasma HDL to feces will be examined. We are investigating the plasma decay, hepatic uptake, re-secretion into plasma, and biliary and fecal excretion of HDL FC and CE, relative to apoA-I, in HSKO vs. WT mice. In specific aim 3, the extent to which dietary polyunsaturated (poly) fat, relative to saturated (sat) and monounsaturated (mono) fat, reduces ABCA1 expression in human liver, intestine and adipose tissue will be explored. Interrelationships among tissue ABCA1 RNA and protein expression, plasma HDL cholesterol concentration, particle number and size, and plasma HDL FC efflux capacity as a function of dietary fat saturation will be determined. In specific aim 4, we will determine whether rare coding ABCA1 sequence variants unique to African Americans (AA) (absent in European Americans, EA) affect lipid efflux as well as plasma HDL cholesterol concentration, particle number and size, and plasma HDL efflux potential. Associations between these measurements and coronary artery calcified plaque score, a measure of CHD, will be examined.

Atheroprotective Mechanisms of Borage and Echium Oils (AT002782)

This project is part of the Wake Forest Center for Botanical Lipids and Inflammatory Disease Prevention. We have demonstrated that Echium oil (EO), a botanical oil enriched in stearidonic acid (18:4 n-3), the immediate downstream product of the rate-limiting delta-6 desaturation of alpha-linolenic acid (18:3 n-3), reduces plasma lipids, inflammation, and atherosclerosis similar to fish oil (FO), but we do not know the exact mechanisms for the protection. EO also contains 11% gamma-linolenic acid (GLA, 18:3 n-6), which is the delta-6 desaturation product of linoleic acid (18:2 n-6) and thus, can provide substrate for conversion to anti-inflammatory series 1 prostaglandin (PGE1). However, we do not know whether a botanical oil that is enriched in GLA, such as borage oil (BO; 25% GLA), is equally protective or less protective than EO. We are investigating whether EO and BO are equally atheroprotective and to determine anti-atherogenic mechanisms of these botanical oils. Our primary hypothesis is that both EO and BO will reduce atherosclerosis relative to palm oil (PO), by attenuating the rise of proinflammatory monocytes in blood and the trafficking of monocytes into atherosclerotic lesions (specific aim 1). Furthermore, we hypothesize that EO and BO will result in alternative activation of macrophages, relative to PO, resulting in less inflammatory macrophages (specific aim 2). Finally, we propose that the polyunsaturated fatty acid-induced macrophage alternative activation will occur through multiple mechanisms that include antagonism of proinflammatory gene transactivation, PPAR gamma-dependent transactivation of anti-inflammatory genes, and PPAR gamma-dependent transrepression of pro-inflammatory genes (specific aim 3). The proposed mechanistic studies should allow us to determine the best botanical oils or combinations to move into human trials to test for reduction of atherosclerosis risk and inflammation and to improve our basic information regarding the mechanism of action of botanical oils in chronic disease prevention.

The Role of ApoA-IV in Hepatic Lipid Mobilization (HL119983)

An emerging trend suggests that apoB lipoprotein particle number, and not LDL cholesterol, may best predict susceptibility to atherosclerotic cardiovascular disease. As very low density lipoprotein (VLDL) particle size is heterogeneous, reflecting the elasticity of the apoB lipoprotein assembly process, an unanswered question with relevance to many aspects of the metabolic syndrome is how the hepatocyte integrates particle number with particle size to achieve a given rate of hepatic lipid efflux. We are exploring the hypothesis that apolipoprotein A-IV (apoA-IV) is acutely regulated and serves an important role in hepatic lipid efflux by promoting nascent VLDL particle expansion. Defining this previously unknown role of apoA-IV in hepatic lipid metabolism and understanding the mechanism by which it functions has important translational potential, as it is likely that if VLDL-mediated lipid efflux could be achieved by a process of particle expansion at the expense of particle number, a less atherogenic lipoprotein profile may result, while still protecting the liver from steatosis. To explore and validate this hypothesis, three specific aims are being conducted. Aim 1 will define the physiologic and pathophysiologic settings that regulate apoA-IV expression in liver and will establish whether it is hepatic triglyceride (TG) accumulation that induces apoA-IV expression or whether the regulation of apoA-IV is linked to processes associated with enhanced assembly and secretion of VLDL. Aim 2 will establish the impact of apoA-IV on TG secretion and hepatic lipid content and pathophysiology. These studies are supported by preliminary data demonstrating that overexpression of apoA-IV in mouse liver both dramatically induces TG secretion, reducing hepatic lipid burden. Finally, Aim 3 will focus on the mechanism by which apoA-IV promotes TG secretion and will explore the hypothesis that a direct apoA-IV-apoB interaction alters the trafficking kinetics of apoB and promotes greater incorporation of lipid into nascent VLDL particles, while reducing total VLDL particle production.