August 2012

Friends and lipids

Michael S. Brown and Joseph L. Goldstein over the years, figure taken from Brown and Goldstein Reflections article in JBC 
Mike Brown (right) and Joe Goldstein
have a friendship that has
stood the test of time.

Friendships bring good conversation and laughter. In the case of Michael S. Brown and Joseph L. Goldstein at the University of Texas Southwestern Medical Center at Dallas, a friendship also brings scientific breakthroughs and a Nobel Prize. In a recent Journal of Biological Chemistry Reflections article, Brown and Goldstein described the genesis of their 46-year friendship as well as their research endeavors.

Brown and Goldstein first met in 1966 in Boston as medical interns at the Massachusetts General Hospital. Brown was from Philadelphia. Goldstein was from a small town in South Carolina. Despite their different backgrounds, “we were drawn together by a shared fascination with clinical medicine and medical science and a desire to one day make discoveries of significance to both,” they write in the article.

After several years of research training at the National Institutes of Health, Brown and Goldstein moved in the early 1970s to UT-Southwestern. They began to study homozygous familial hypercholesterolemia, a rare disease of high cholesterol levels that causes devastating cardiovascular problems in children with the condition.

Between 1972 and 1985, Brown and Goldstein established the disease’s underlying molecular mechanisms, leading to the discovery of the low-density lipoprotein receptor, its role in receptor-mediated endocytosis and how it controls blood cholesterol levels. In 1985, they were jointly awarded the Nobel Prize in medicine or physiology “for their discoveries concerning the regulation of cholesterol metabolism.”

In their Reflections article, Brown and Goldstein opted not to focus on their famous work but instead discussed six projects they have pursued over the years. One project involved the study of macrophages that have receptors that scavenge abnormal macromolecules, including ones in atherosclerotic plaques. Other researchers have gone on to show that these scavenger receptors play roles in innate immunity, microbial pathogenesis and various pathologic processes, such as atherosclerosis. Another project led to the finding that blindness in little boys with an X-linked retinal disease called choroideremia involved Rab proteins. These proteins, which regulate vesicle fusion reactions, could not be modified with geranylgeranyl groups in the boys with the disease.

Another project tackled Niemann–Pick C disease, a lysosomal storage disease. The project revealed that the membrane protein NPC1 has a cholesterol binding site in its soluble NH2-terminal extension, not in its membrane domain. The finding now gives a mechanistic explanation for the disorder.

A project with ghrelin resulted in the identification of the enzyme that covalently attaches an octanoyl chain to ghrelin, which is essential for ghrelin’s biological activity, and the demonstration that octanoyl-ghrelin maintains blood sugar during chronic starvation.

The two remaining projects involved the identification of monocarboxylate transporters and the possibility of the first effective treatment for a disease of the adipose tissue called lipodystrophy.

For their voluminous scientific output, Brown and Goldstein credit their students and postdoctoral fellows, their institute and philanthropic support from members of the Dallas community, including Ross Perot. The support has been critical. “When we embarked on each of our six excursions, we had no preliminary data of the type required by review committees of the National Institutes of Health,” Brown and Goldstein note in their article. All they had, they say, were “outrageous hypotheses.”

 

Raj_MukhopadhyayRajendrani Mukhopadhyay (rmukhopadhyay@asbmb.org) is the senior science writer for ASBMB Today and the technical editor for The Journal of Biological Chemistry. Follow her on Twitter at www.twitter.com/rajmukhop.

 


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