Genetics, Medicine and Translational Research
The University of Texas Southwestern Medical Center
Dr. Hobbs is also a professor of internal medicine and molecular genetics and director of the Eugene McDermott Center for Human Growth and Development at the University of Texas Southwestern Medical Center.
Human Genetics of Lipoprotein Metabolism
Throughout the course of human evolution, fluctuations in food supply have influenced the selection of genes that optimize the extraction, storage, and utilization of dietary nutrients. However, in modern history, food has become more abundant and humans have become less active. As a result, our bodies are more inclined to develop diseases of dietary excess, such as diabetes and atherosclerosis. Helen Hobbs is trying to address this situation by searching for genetic factors that contribute to, and protect us from, these conditions.
In 1999, Hobbs and her colleagues established the Dallas Heart Study (DHS), with an aim to identify factors that contribute to coronary heart disease. Using data collected from the study’s more than 3,500 participants, the scientists learned that mutations in a protein called PCSK9 lower levels of low-density lipoprotein (LDL) – the cholesterol that contributes to the buildup of artery-clogging plaques. Several pharmaceutical companies have since used these findings to develop drugs that inactivate PCSK9 and lower cholesterol.
Fatty liver disease – a buildup of fat in the liver – is also on the rise in the Western world. One-third of the participants in the DHS were found to have hepatic steatosis, or fatty liver. Hobbs’s team screened the genomes of these individuals, looking for genes that contribute to the disease. They discovered that mutations in a protein called PNPLA3 are strongly associated with elevated hepatic fat content. A second screen revealed another player – a protein called TM6SF2. As in the case of PNPLA3, mutation in this protein leads to increase in fat content. Using mouse models that mimic the human disease, Hobbs’s team has shown that TM6SF2 normally helps the liver secrete triglyceride-rich lipoproteins.
Hobbs’s team has also discovered three genes – ABCG5, ABCG8, and ARH (LDLRAP) – that help maintain the proper balance of sterols in the body. Mutations in these genes lead to a buildup of cholesterol in the blood, and subsequent coronary heart disease.
Grants from the National Heart, Lung, and Blood Institute provide partial support for these projects.
A person’s risk of heart disease can’t be blamed solely on eating too many cheeseburgers and other foods high in saturated fat. Genetics plays a role too. By identifying and exploring the function of genes that influence cholesterol levels, Helen Hobbs is laying the groundwork for the development of new cholesterol-lowering drugs to reduce heart disease risk.
Hobbs was chief resident at UT Southwestern Medical Center in Dallas when she decided to give research a try. Her mentor, Donald Seldin, then the school’s head of medicine, arranged for her to work as a postdoctoral fellow in the laboratory of two well-established investigators – Michael Brown and Joseph Goldstein – who later were awarded a Nobel Prize for discovering the cell-surface receptor for low-density lipoprotein (LDL) cholesterol and demonstrating its role in cholesterol metabolism. LDL cholesterol contributes to the buildup of artery-clogging plaques, and high LDL levels are a major risk factor for heart disease.
When she joined the Brown-Goldstein laboratory, the pair was trying to understand how mutations in the LDL receptor gene affect its function. One of Hobbs’s first research successes was finding a mutation that alters the receptor’s ability to bind LDL cholesterol.
Since setting up her own laboratory at UT Southwestern in the late 1980s, Hobbs has discovered genetic defects that cause very high and very low blood levels of cholesterol, and studied the faulty proteins that underlie these disorders. Her findings may help determine how the body normally regulates cholesterol by removing it from the bloodstream. In 2001, Hobbs identified a genetic defect that causes a rare high-cholesterol disorder called autosomal-recessive hypercholesterolemia. People with the disease have normal, functioning LDL receptors but can’t remove LDL cholesterol from the bloodstream. Hobbs and her colleagues also discovered two genes, ABCG5 and ABCG8, that help maintain the proper balance of sterols in the body. Mutations in either gene can lead to a buildup of cholesterol in the blood.
Hobbs also runs the Dallas Heart Study, a study of more than 6,000 Dallas County residents that is designed to uncover the risk factors for heart disease and find new treatments. Using data from the ongoing study, which began in 1999, Hobbs identified two genetic mutations linked to low levels of LDL cholesterol. The beneficial gene alterations were found almost exclusively among African Americans, even though as a group African Americans have a higher risk of heart disease than other populations. One out of 50 African Americans in the study had either one or the other of the mutations, which increase the amount of cholesterol the liver removes from the body. The insights from these studies have contributed to the rapid development of a new class of cholesterol-lowering agents.
More recently, Hobbs has studied the pathways and processes that determine where fat accumulates in the body, whether in adipose tissue, the liver, or other tissues. She identified a new protein that directs fat to adipose tissue for storage, as well as genetic variations that contribute to fatty liver disease, a burgeoning health problem.