By Marlene Cimons, National Science Foundation
Gregory Tochtrop likes to describe bile acids as evolution’s answer to Dawn® dishwashing detergent. “Dawn detergent takes all the grease and fats from your dishes, and makes them soluble in your dishwater, so that all the grease on your plates goes down the drain,” he says. “Bile does the same thing.”
Tochtrop, assistant professor of chemistry and pharmacology at Case Western Reserve University, studies bile acids, which are made by the liver and secreted by the gallbladder into the small intestine during digestion. After the bile makes the dietary lipids soluble, most, but not all, of the bile acids return to the liver through the body’s own recycling system, and the process begins all over again.
Tochtrop wants to figure out how bile acids signal the liver that it’s time to replenish the small amount of bile acids that the body excretes through waste, what role intestinal bacteria play in the composition of bile acids, and how that affects the signaling process.
Not all bile acids are alike. Human bacteria that live in the intestine--and everyone’s bacteria are different--interact with the bile acids to change their makeup.
“We don’t just make one bile acid, we make a family of them, and no one knows why,” he says. “It turns out that some bile acids are better at signaling than others. I’m trying to figure out how different compositions of the bile acid pool initiate these signals, and how they compare to one another. Humans make six different bile acids, which are converted into more than 100 bile acids by the bacteria that live in our intestine.”
He believes that the composition of an individual’s bile acid pool affects how he or she uses cholesterol, and that intestinal bacteria may be involved in bile acid makeup--a research path that could lead to important insights, including possible new therapeutic approaches, to controlling cholesterol levels.
Having high blood cholesterol raises the risk of developing heart disease, the leading cause of death in the United States. About one of every six adult Americans has high blood cholesterol, according to the Centers for Disease Control and Prevention.
“There are people who live very healthy lifestyles and still can’t control their cholesterol,” he says. “The question becomes: if we take cholesterol into our diet and use it to make bile acids in the liver, are some people more efficient than others at converting that cholesterol and excreting it?”
Tochtrop is conducting his research under a National Science Foundation (NSF) Faculty Early Career Development (CAREER) award, which he received in 2009 as part of NSF’s American Recovery and Reinvestment Act. The award supports junior faculty who exemplify the role of teacher-scholars through outstanding research, excellent education and the integration of education and research within the context of the mission of their organization. NSF is funding his work with about $900,000 over five years.
He and his team are synthesizing bile acids in the lab and converting them into the entire family of bile acids, then seeing how they interact with known signaling proteins found in the liver and the intestine. “We are trying to understand the signaling process, how having diversity in that bile acid pool will affect it,” he says.
The recommended daily allowance of cholesterol is 300 milligrams, enough for the liver to make replacement bile for the small amount that is lost through the natural process. “Every time you have a meal and it passes from your stomach to your intestine, the gallbladder releases about 20 grams [20,000 milligrams] of bile acids, of this detergent,” he says. “On any given day, you will have 100 grams [100,000 milligrams] of bile acid go through your intestine.”
Producing bile acids “is the major usage of cholesterol in the body,” he adds. “If you understand bile acid metabolism, you understand cholesterol metabolism.”
Thus, “if you have high cholesterol, and you can prevent bile acids from being reabsorbed in the intestine--and they are excreted--then your body will be required to make new bile acids from cholesterol, preventing the building of more cholesterol than you need,” he adds.
In fact, the first generation of cholesterol-lowering drugs tried to exploit this mechanism by preventing the recycling of bile acids. But the side effects were unpleasant, and drug companies, for the most part, abandoned this approach.
“If you can understand how these more than 100 different bile acids signal both the small intestine and the liver to use cholesterol, you potentially could design a molecule, like a drug, that could increase the conversion of cholesterol into bile acid with the net effect of reducing serum cholesterol,” he says.
Furthermore, “you potentially could say that the composition of an individual’s intestinal bacteria controls their serum cholesterol levels,” he adds. “That would be a very important finding. Let’s say we identify one specific bile acid that will inhibit our body’s ability to convert cholesterol to bile acid. Let’s say it’s made by one particular strain of bacteria made in the gut. That’s a pretty powerful connection, that having this bacterial strain in the gut could cause you to have cholesterol problems.”
Ultimately, the result could be a drug or a microbiological strategy that would inhibit the bacteria’s ability to make this harmful bile acid, providing a targeted new way to reduce serum cholesterol. “I think this would be a wonderful example of how looking at a very fundamental basic science question could have important translational implications on human health,” he says.
Studying Digestive Health
Research could help control cholesterol levelsAugust 13, 2012 RSS Feed Print
By Marlene Cimons, National Science Foundation