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Cardiology and metabolism

Impaired ABCA1 As An Atherogenic Complication of Diabetes

We welcome you to a selection of talks from "Disorders of Lipid Metabolism." We are honored to present to you recognized research leaders who present their current data on topics relevant to disorders of lipid metabolism. Thank you for participating in this self-study course.

Dr. Oram's presentation: Atherosclerotic cardiovascular disease is the most common cause of mortality and morbidity in both types 1 and 2 diabetes. There is evidence that abnormal high-density lipoprotein (HDL) metabolism plays a role in diabetes-induced atherogenesis. It is believed that HDL is cardioprotective because of its ability to mobilize excess cholesterol from macrophage foam cells in atherosclerotic lesions. A cellular ATP-binding cassette transporter called ABCA1 mediates this cholesterol export process by transferring cellular cholesterol and phospholipids to HDL apolipoproteins. Dr. Oram will review his recent studies in mouse models of diabetes that suggest that inducing diabetes selectively reduced ABCA1 protein, but not mRNA levels in macrophages and the kidney, consistent with the idea that diabetic factors destabilize ABCA1 in some tissues in vivo. These observations support the possibility that an impaired ABCA1 pathway contributes to the accelerated atherosclerosis and nephropathy associated with diabetes and the metabolic syndrome.

Diabetic Heart Diseases

Dr. Goldberg's presentation: The major causes of mortality in patients with diabetes are disorders of the cardiovascular system. The heart is the most energy-requiring organ in the body. Although the primary source of cardiac energy is fatty acids, hearts will increase their use of glucose during diabetes, with heart failure or ischemia, and in the presence of abnormalities in fatty acid oxidation. Although in some of these situations switching from fatty acid to glucose may be a compensation, it is also possible that abnormalities of cardiac lipid utilization are pathological. Dr. Goldberg will discuss the data from studies of mice with cardiac dysfunction associated with excess lipid storage, which suggest that ceramide and probably other lipids, such as diacylglyecerol, can be cardiotoxic.

Generation of Lipid-free/Lipid-poor Apo AI For Reverse Cholesterol Transport From Lesions

Dr. Curtiss' presentation: An early event in reverse cholesterol transport (RCT) involves the transfer of free cholesterol and phospholipid from cell membranes to small lipid-poor or lipid-free apolipoprotein (apo) AI. Apo AI is not produced locally and, unlike HDL, is present in very small amounts in plasma. Phospholipid transfer protein (PLTP) is an LXR-regulated gene product in macrophages. The lipid transfer activities of PLTP studied in vitro convert triglyceride-rich spherical HDL₃ into larger and smaller particles with a concomitant release of the lipid-poor apo AI. The generation of these lipid-poor, preβ-migrating molecules (preβ-HDL) is a prerequisite for the transfer of cholesterol out of cells via the cell membrane-bound ATP-binding cassette A1 (ABCA1). In this presentation Dr. Curtiss will present data from a series of experiments that suggest that macrophage produced PLTP may be functionally different from plasma PLTP that is predominately hepatic derived.

Nuclear Receptors Controlling Lipid and Glucose Homeostasis

Dr. Staels' presentation: Recent studies have outlined the importance of the “Clock genes” in the development of metabolic disorders predisposing to atherosclerosis. The Clock genes cross-talk with several nuclear receptors that regulate hepatic and adipose lipid metabolism as well as vascular inflammation, such as the PPARs, FXR, RORa, and Rev-erba. Activation of PPARs induces beneficial effects, not only on lipid and glucose metabolism, but also on endothelial function and vessel wall inflammation, and may alter the process of atherosclerosis, especially in subjects with the metabolic syndrome and type 2 diabetes. These findings identify several nuclear receptors as modulators of cardiovascular risk factors and as determinants of the circadian regulation of metabolic pathways. These nuclear receptors may thus serve to integrate metabolic and circadian signals.

Role Of PCSK9 In Regulating Plasma LDL Levels

Dr. Horton's presentation: Proprotein convertase subtilisin-like kexin type 9 (PCSK9) is a newly discovered serine protease that controls the level of LDL cholesterol in plasma. In humans, mutations that increase PCSK9 activity cause hypercholesterolemia and coronary heart disease. Conversely, nonsense mutations in PCSK9 result in significantly lower plasma LDL cholesterol levels and in a significant reduction in the development of cardiovascular disease. PCSK9 is expressed at highest levels in cells that synthesize apoB-containing lipoproteins, such as the small intestine. Data from a series of in vivo studies suggest that one function of PCSK9 is to post-transcriptionally regulate the expression of LDLR protein. Although the biologic importance of PCSK9 is clear, its mechanism and cellular site of action have been only partially defined. In this presentation, Dr. Horton presents data to further clarify the mechanism of PCSK9’s action.

Genomic Variation and Metabolic Traits

Dr. Hegele's presentation: Hypertriglyceridemia (HTG) is a defining component of the metabolic syndrome and is associated with increased coronary heart disease (CHD) risk. Plasma triglyceride (TG) concentration >10 mmol/L is seen in ~1 in 600 adult North Americans. While both genetic and lifestyle factors determine plasma TG concentration, the genetic determinants of severe HTG are poorly defined. We resequenced >2 million base pairs of genomic DNA from 170 patients with severe HTG to find coding sequence variants in candidate genes – LPL, APOC2, APOA5 and GPIHBP1 - compared to 472 matched normolipidemic controls. The data shows that both common and rare DNA variants in candidate genes were found in a substantial proportion of severe HTG patients. The findings underscore the value of genomic resequencing to understand the genetic contribution in complex lipoprotein and metabolic disorders.

Control of Lipid and Glucose Metabolism by The Nuclear Receptors FXR and LXR

Dr. Edwards' presentation: The nuclear receptor FXR controls the expression of genes that affect a surprising number of metabolic pathways. Recent studies with mice have shown that activation of FXR following oral administration of either physiological or synthetic agonists (bile acids or GW4064, respectively) or following hepatic over-expression of a constitutively active form of FXR, results in both hypolipidemia and hypoglycemia. Studies with wild type and db/db mice demonstrate that activated FXR results in decreased plasma HDL, triglyceride, and cholesterol levels. Such changes are not observed following treatment of FXR null mice with a specific FXR agonist. These studies suggest that activation of FXR might prove to be beneficial for the control of both lipid and glucose metabolism in patients with type 2 diabetes.

HDL Proteomics: Pot of Gold or Pandora's Box?

Dr. Heinecke's presentation: We have used 2-dimensional liquid chromatography ESI-MS/MS to test the hypothesis that proteins implicated in inflammation might be enriched in the HDL of subjects with coronary artery disease (CAD). Unexpectedly, our analytical strategy identified multiple complement regulatory proteins and a diverse array of distinct serpins with serine-type endopeptidase inhibitor activity. Many acute phase response proteins were also detected, supporting the proposal that HDL is of central importance in inflammation. Mass spectrometry and biochemical analyses demonstrated that HDL₃ from subjects with CAD was selectively enriched in apolipoprotein E, raising the possibility that HDL carries a unique cargo of proteins in humans with clinically significant cardiovascular disease. Dr. Heinecke’s observations suggest that HDL carries a unique cargo of proteins in CAD subjects and that certain of these proteins might make previously unsuspected contributions to the anti-inflammatory properties of HDL.

Adipokines: Impact On The Metabolic Syndrome

Dr. Scherer's presentation: Adipocytes are highly active endocrine cells that play a central role in overall energy homeostasis and are important contributors to some aspects of the immune system. They do so by influencing systemic lipid homeostasis, but also through the production and release of a host of adipocyte-specific and adipocyte-enriched hormonal factors, cytokines, and extracellular matrix components (commonly referred to as “adipokines”). Adiponectin is an adipocyte secretory protein whose circulating levels are decreased in obese and diabetic states. Adiponectin plays a role in liver insulin sensitivity and whole-body metabolism and has been implicated in cardiovascular health as well. The association between adiponectin levels and cardiovascular risk independent of other variables suggests that adiponectin mediates direct effects on vascular health, as opposed to indirect effects through insulin sensitivity and diabetes.

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