Lipid Metabolism

Cardiovascular disease (CVD) is the leading cause of death in the United States. Well-known risk factors for CVD include a high blood level of low density lipoprotein (LDL), the bad form of cholesterol, and a low level of high density lipoprotein (HDL), the good form of cholesterol.  Diabetes and metabolic syndrome represent other important risk factors for CVD. Indeed, CVD is the major cause of death in both type 1 and type 2 diabetes.

Almost one quarter of all Americans have some form of CVD, which accounts for 30% of deaths nationwide. CVD includes the following:

  • Atherosclerosis. Atherosclerosis is the buildup of plaque on the inner wall of an artery. It is implicated in most CVD. Stable plaque causes arteries to narrow and harden. Unstable plaque can cause blood clots, leading to heart attack, stroke and other disorders.
  • Coronary Artery Disease (CAD).  Afflicting 13 million Americans, CAD is the leading cause of CVD mortality, causing half a million U.S. deaths each year. It occurs when atherosclerosis of the coronary arteries decreases the oxygen supply to the heart, often resulting in a heart attack when cardiac muscle is deprived of oxygen. Over time, CAD can weaken the heart muscle, contributing to heart failure.
  • Myocardial Infarction (MI).  Also called a heart attack, MI occurs when the supply of blood and oxygen to an area of heart muscle is blocked, usually by a clot in a coronary artery. Each year, more than a million Americans have an MI, and almost half of those consequently die.
  • Sudden Death.  In 1/3rd of individuals with CVD, sudden death is the first manifestation of disease. Currently available tests, such as those that measure LDL and HDL levels, are weak predictors of risk for sudden death and MI. It is thus critical to develop new methods for identifying apparently healthy subjects at risk for CVD.

Scientists at the UW Diabetes Institute (DI) are deciphering the cellular and molecular mechanisms underlying the pathogenesis of CVD, with a focus on HDL and LDL. They also have a major interest adipose tissue and inflammation, which play key roles in the vascular complications of obesity, insulin resistance, and type 1 and type 2 diabetes.

Adipose Tissue
Adipose Tissue
Sections of adipose tissue (fat tissue) from a lean mouse (left) and an obese insulin resistant mouse (right).  The adipose tissue from the lean mouse has smaller fat cells (adipocytes) and shows no sign of inflammation.  The adipose tissue from the obese insulin resistant mouse has larger adipocytes (white) and infiltration by inflammatory blood cells (red).  Adipose tissue inflammation is believed to contribute to insulin resistance.  Images courtesy of the laboratory of Alan Chait, MD.×

One area of research, spearheaded by Dr. Jay Heinecke, centers on inflammatory changes in HDL, the good form of cholesterol that normally protects individuals against CVD.  Dr. Heinecke’s work centers on using state-of-the-art mass spectrometric approaches to define the proteins that render HDL cardioprotective.  His research group also has a major interest in how HDL removes cholesterol from cells in the artery wall, and how macrophages –white blood cells that play a key role in cholesterol accumulation and CVD- are affected by HDL. For example, Dr. Baohai Shao works on mechanisms whereby HDL is damaged by diabetes, thereby contributing to the reduced removal of cholesterol from cells, and Dr. Tomas Vaisar and Dr. Andy Hoofnagle research the protein cargo associated with HDL in disease states characterized by lipid abnormalities, cardiovascular complications and inflammation, and the consequences of altered HDL protein cargo.

Additional research on the role of HDL metabolism, performed by Dr. Chongren Tang, focuses on how the interaction of HDL components with cellular proteins removes cholesterol from cells and activates anti-inflammatory pathways.  Damage to these processes may contribute to the increased CVD associated with insulin resistance and diabetes.

Another very active area of research in the DI focuses on the link between obesity, inflammation, diabetes and atherosclerosis, spearheaded by Dr. Alan Chait and Dr. Savitha Subramanian.  Inflammation in adipose tissue can lead to the development of insulin resistance and diabetes, and to the development  of atherosclerosis.   Dr. Chait’s research also focuses on how lipoproteins interact with and are retained in the artery wall, a process that contributes to atherosclerosis.

A related area of research focuses on the link between fatty acids and inflammation, which is described under Cardiovascular Complications of Diabetes, Insulin Resistance and Obesity”.