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RESEARCH BRIEFS
Digestive Protein Directs Fats to Immune SystemTrafficking of dietary fats from the intestine to liver to blood depends on specialized transfer proteins that move lipids onto carrier proteins for circulation throughout the body. Now one such transfer molecule, microsomal triglyceride transfer protein (MTP), has been identified as a key player in directing some fats toward a different fate, one in which they activate T cells and cause inflammation.
The microsomal triglyceride transfer protein (MTP), long known to load lipids onto apoB for transport into the bloodstream as very low density lipoprotein (VLDL), also loads CD1d, which presents lipid antigens to immune T cells. (Image adapted from original by Stephanie Betz) "We show that MTP is not just involved in fat digestion, but also plays a critical role in the immune system," said Richard Blumberg, HMS associate professor of medicine at Brigham and Women's Hospital and senior author of the study, appearing in the May Nature Medicine. Besides illuminating a basic cellular process by which lipids can stimulate an immune response, the results suggest that MTP inhibitors could be useful for treating diseases like hepatitis and colitis. Blumberg and his colleagues show that in cells, MTP is complexed with the immune protein CD1d, a member of the family of major histocompatibility antigens that present lipid antigens to T cells. The researchers found that cells lacking MTP could not activate CD1d-dependent T cells. Mice that lacked liver and intestinal MTP did not develop CD1d-associated autoimmune hepatitis or colitis as severely as normal mice. Because mice (and a rare few humans) that lack MTP have low blood triglyceride and cholesterol, several pharmaceutical companies have worked on MTP inhibitors for heart disease, according to Blumberg. But the side effect of blocking MTP is a toxic accumulation of fats in the cells of the liver and intestine. "The challenge ahead will be to design therapeutics that specifically inhibit the effects of MTP on CD1 pathways with minimal toxicity," said Blumberg. BWH has filed a patent for use of MTP inhibitors for a variety of inflammatory conditions like asthma and multiple sclerosis, in addition to hepatitis and colitis. --Pat McCaffrey
Small, Frequent Doses of Caffeine Best for Staying AwakeCaffeine is the world's most widely used stimulant, yet scientists still do not know exactly how it staves off sleep. Researchers at Brigham and Women's Hospital, HMS, and other institutions have discovered that the stimulant works by thwarting one of two interacting physiological systems that govern the human sleep-wake cycle. The researchers, who report their findings in the May issue of the journal Sleep, propose a novel regimen--frequent low doses of caffeine--to help shift workers, medical residents, truck drivers, and others get a bigger boost from their tea or coffee."Most people take a huge jolt of coffee in the morning to jumpstart their day. They get the super grande latte from Starbucks," said Charles Czeisler, who was recently appointed the Frank Baldino Jr., Ph.D. professor of sleep medicine at HMS (see Bulletin). "Their caffeine levels soar only to fall as the day progresses in the face of rising sleepiness. They might be better off taking much smaller, more frequent doses of caffeine, equivalent to a quarter of a cup of coffee, as the day wears on." Though many studies have measured caffeine's sleep-averting effects, most do not take into account that sleep is governed by two opposing but interacting processes. The circadian system promotes sleep rhythmically--an internal clock releases melatonin and other hormones in a cyclical fashion. In contrast, the homeostatic system drives sleep appetitively--it builds the longer one is awake. If the two drives worked together, the drive for sleep would be overwhelming. As it turns out, they oppose one another. Czeisler, who also leads the Division of Sleep Medicine at HMS, and his colleagues had reason to suspect that caffeine might be working to blunt the homeostatic system. For one thing, caffeine is thought to block the receptor for adenosine, a chemical messenger involved in the homeostatic drive for sleep. If this were true, caffeine would be most effective when administered in parallel with growing pressure from the homeostatic system and also with accumulating adenosine. To test their hypothesis, the scientists sequestered 16 male subjects in private suites, free of time cues, for 29 days. By regulating the lighting in the rooms, the researchers were able to extend the normal 24-hour day to 42.85 hours, which allowed subjects to stay awake for longer periods. The extended day was also designed to derail the subjects' circadian system while maximizing the effects of the homeostatic push for sleep. Following a randomized, double-blind protocol, subjects received either one caffeine pill, containing 0.3 mg per kilogram of body weight, roughly equivalent to two ounces of coffee, or an identical-looking placebo. They took the pills upon waking and then once every hour. The goal of the steady dosing was to build up caffeine levels in a way that would coincide with--and ultimately, counteract--the progressive push of the homeostatic system, which grows stronger the longer a subject stays awake. The strategy worked. Subjects who took the low-dose caffeine performed better on cognitive tests. They also exhibited fewer accidental sleep onsets, or microsleeps. EEG tests showed that placebo subjects were unintentionally asleep 1.57 percent of the time during the scheduled wake episodes, compared with 0.32 percent for those receiving caffeine. Despite their enhanced wakefulness, the caffeine-taking subjects felt sleepier than their placebo counterparts, suggesting that the wake-promoting effects of caffeine do not replace the restorative effects of sleep. The behavioral differences between the groups appear to be due to caffeine's effects on the homeostatic rather than circadian system, as the researchers hypothesized. Czeisler and his colleagues took minute-by-minute measurements of core body temperatures and hourly blood melatonin levels--two key indicators of circadian rhythms--and found little difference between subjects. Members of both groups were unable to synchronize their circadian periods to the 42.85-hour day. Czeisler and his colleagues therefore suggest that shift workers, medical residents, truck drivers, and others who need to stay alert consider taking frequent low doses of caffeine. --Misia Landau
Tobacco Use in India Hits the Poor HardestA national survey of tobacco use in India has found that people with the lowest standard of living smoke and chew tobacco at nearly triple the rate of more educated and affluent citizens.Tobacco consumption is likely to contribute to maintaining or worsening the existing health disparities between the rich and poor in India, according to the authors of the study. International researchers surveyed the smoking and chewing habits of more than 300,000 adults in 26 Indian states in 1998 and 1999. The data, the first available on the health habits of the Indian population, showed that people with the lowest levels of education were almost three times more likely to smoke or chew tobacco than those with the highest. Men used tobacco more often than women. Lower income and caste were associated with higher levels of tobacco use, and people who lived in rural areas and towns smoked and chewed more than city dwellers. "This study shows that tobacco consumption is not a random event. It is very tied to the social and geographic circumstances of individuals," said S. V. Subramanian, HSPH assistant professor of society, human development, and health and lead author on the study, which appears in the April 3 British Medical Journal. Efforts to curtail tobacco use around the world must be tailored to the economic and educational situation of users, Subramanian said. The study suggests that local action to discourage tobacco use could yield results. One Indian state that enacted laws restricting tobacco sales and smoking in public had the lowest levels of tobacco use reported in the survey. Despite this local success, Subramanian stressed that international health organizations must also play a role in curbing the movement of multinational tobacco companies into poorer countries. --Pat McCaffrey |
