Liza Makowski

Makowski listened to Dr. Charles Serhan lecture about the role of fatty acids and their derivatives, called eicosanoids, in inflammation. No one knew how eicosanoids were transported in white blood cells called macrophages, activated during inflammatory responses. As she sat in the lecture, she hypothesized that macrophages could contain specific proteins that bind fatty acids. The concept was unusual. Traditionally, macrophages were thought of as cells that help clean the immune system by eating foreign agents, not as cells that capture fat.

"After class, I stormed into my thesis advisor’s office and said, ‘We have to look into this,’" recalled Makowski.

Makowski’s advisor was Gökhan Hotamisligil, associate professor in the Department of Nutrition. His lab was heavily involved in researching a family of proteins that bind to lipids, or fat, inside the cells and that play important roles in a cluster of illnesses referred to as the metabolic syndrome: obesity, diabetes, hypertension, fatty liver disease, high blood pressure, and heart disease. Makowski was working in his lab as part of the PhD Program in Biological Sciences in Public Health in the Division of Biological Sciences at HSPH. She was also pursuing a master’s degree in medical sciences at HMS as a Markey Fellow.

Her hunch about lipid-binding proteins proved correct, providing Makowski with a thesis that she successfully defended in November and with a new insight into metabolic diseases.

Guided by Hotamisligil, Makowski worked with a team of researchers from HSPH, Vanderbilt University Medical Center, Bristol-Myers Squibb Pharmaceutical Research Institute, and the University of Louisville School of Medicine. She bred mice resistant to atherosclerosis and with her colleagues demonstrated that macrophages containing a protein called "aP2" trap fat and cholesterol. The engorged macrophages secrete proteins that instigate the development of vascular lesions and plaques–potentially clogging arteries and leading to an increased risk of heart attack or stroke.

The finding was the first time that any fatty-acid binding protein had been identified in the macrophage or in any other immune cell. The research also revealed a previously unforeseen pathway to the development of atherosclerosis.

"It was a truly outstanding discovery, and Liza deserves credit," said Hotamisligil.

The team published its findings in the June 2001 issue of Nature Medicine, with Makowski listed as lead author.

In the same paper, the scientists tested whether aP2 in fat cells, or adipocytes, and in macrophages independently affected the development of atherosclerosis and another metabolic disease, diabetes. The team demonstrated that aP2 controls the development of both diseases through different, specific mechanisms.

The research shed light on the role of fatty acid binding proteins in metabolic syndrome.

"Conceptually, the research presented a common locus from which metabolic and inflammatory problems could be controlled simultaneously," said Hotamisligil. "These problems co-exist, and they are a global menace to society."

Makowski presented the team’s research at two major scientific conferences in August. She will receive her degree this spring, after which she plans to stay in Hotamisligil’s lab to conduct post-graduate work. She is studying two more proteins that bind fatty acids and eicosanoids. Using three types of specially bred mice, Makowski is trying to determine why atherosclerosis develops to a greater extent in some types of mice lacking fatty acid binding proteins than in others, looking specifically at the role of the two proteins in macrophage biology.

The work is expected to help illuminate further how fatty acid binding proteins may be used to affect disease development, how the proteins regulate lipids, and what biological effects the lipids may have in cells.

Makowski hopes that the research may one day lead to drug therapies that will prevent or treat metabolic diseases.

"This thesis evolved into a great project with the support of Gökhan," said Makowski. "He treats you like a peer, so you are often held to high standards."