Lipoprotein Metabolism

Cardiovascular disease (CVD) is a common chronic disease caused by atherosclerosis that often first starts in childhood. In the United States, one person dies from CVD every 33 seconds, amounting to approximately 2,580 deaths per day. In 2022, an estimated 3.65 million deaths occurred worldwide due to cardiovascular disease.

Excess circulating cholesterol in the blood is one of the main drivers of atherosclerosis, which is the deposit of excess cholesterol into the arterial wall. Cholesterol, however, plays a vital role in normal cellular processes; hence, its cellular and whole-body distribution is subject to complex, dynamic regulation by circulating lipoproteins and enzymes. Dr. Remaley’s laboratory seeks to better understand lipoprotein metabolism and to translate new insights gained from basic biochemistry, cell biology, animal models and clinical trials into much needed clinical advances in the diagnosis, treatment and prevention of cardiovascular disease.

One focus of Dr. Remaley’s laboratory is on the beneficial role of high-density lipoprotein (HDL), the so-called “good cholesterol.” HDL, which is a complex of the protein apoA-I with phospholipids, removes excess cholesterol from peripheral tissues, such as the arterial wall, and transports it to the liver and intestine for excretion from the body. It has been shown that this process—the reverse cholesterol transport pathway—can be markedly stimulated by infusing HDL made with either purified or recombinant apoA-I and phospholipids. HDL infusion has been proposed as an acute therapy for patients with acute coronary syndrome who are at imminent risk for developing myocardial infarction. His laboratory has developed small synthetic peptide mimetics of apoA-I, and like the full-length protein, these peptides mobilize excess cholesterol from cells and have been shown to reduce atherosclerosis and inflammation in animal models and are currently being tested by his group in early-stage clinical trials.

Dr. Remaley’s laboratory also investigates “bad cholesterol”, in other words cholesterol that is transported on low-density lipoproteins (LDL). The deposition of LDL into the vessel wall is one of the main drivers of atherosclerosis, the underlying pathogenic process that leads to cardiovascular disease. Using CRISPR-Cas9 screening, his laboratory has identified new genes related to the cellular uptake of LDL. His group has also recently solved the structure of LDL and how it binds to its receptor using cryo-electron microscopy (cryoEM), which may lead to new therapeutic strategies for lowering LDL.

Another focus of the Lipoprotein Metabolism Laboratory is the development of new cardiovascular biomarkers. The lab has pioneered a method for calculating LDL cholesterol, which is now widely used in clinical laboratories worldwide for routine diagnostics of hypercholesterolemia.

In Dr. Remaley’s view, it is a privilege to work at the NIH and to have the opportunity to study and learn from patients at the NIH with both common and rare genetic disorders of cholesterol metabolism.  It often leads to new insights that cannot be obtained in any other manner and inspires him and his co-workers to translate their basic science findings in lipoprotein metabolism into new therapies and diagnostic tests for cardiovascular disease.