Current Research
Disorders of Lipid Trafficking and 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.

Figure 1: Sequence variation associated with elevated liver triglyceride content...

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.

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