ISLAMABAD – Scientists have verified cholesterol-cancer link with new genetic evidence, raising the possibility that cholesterol medications could be useful in the future for cancer prevention or to augment existing cancer treatment.

The data support several recent population-based studies that suggest individuals who take cholesterol-lowering drugs may have a reduced risk of cancer, and, conversely that individuals with the highest levels of cholesterol seem to have an elevated risk of cancer.

The cancer-cholesterol question has been debated since the early 20th century, and along with it doctors and scientists have observed various trends and associations.

However, until now genetic evidence directly linking cholesterol and malignancy has been lacking, said senior author Hartmut (Hucky) Land, Ph.D., Robert and Dorothy Markin Professor and chair, Department of Biomedical Genetics, and director of research and co-director of the James P. Wilmot Cancer Centre at URMC.

“Scientifically it is very satisfying to have data that support longstanding ideas about cholesterol in the context of cancer. Our paper provides a rationale for cholesterol targeting as a potentially fruitful approach to cancer intervention or prevention strategies,” Land said.

Cholesterol is a fat-like substance supplied in foods and made in cells throughout the body. Too much cholesterol is bad for the heart and vascular system. It is typically measured as serum cholesterol by routine blood tests.

Unlike serum cholesterol that is bound to proteins, however, cholesterol also hides inside cells. While locked inside cell membranes before it is eventually exported, cholesterol has an impact on cell growth and survival. A gene, known as ABCA1, is at the crossroads of the process that shuttles intracellular cholesterol outbound.

Several years ago while conducting unrelated experiments that were published in the journal Nature, Land and colleagues first noticed the importance of ABCA1. At that time, they identified a network of approximately 100 so-called “cooperation response genes” that mediate the action of cancer genes. ABCA1 was found among these genes and is frequently turned off in presence of other mutant cancer genes.

In the latest investigation, Land and co-author Bradley Smith, Ph.D., a post-doctoral fellow in the Land lab, wanted to further understand the role of ABCA1 and cholesterol in cancer. They found that defective cholesterol exportation appears to be a key component in a variety of cancers.

The proper function of ABCA1, in fact, is critical for sensing of cell stress. If ABCA1 function is lost in cancer cells, cholesterol is allowed to build up in the cells’ mitochondria, or energy centres, making their membranes more rigid. This in turn inhibits the function of cell-death triggers that normally become activated in response to cell stresses, as for example cancer gene activation. Therefore, when functioning properly ABCA1 has anti-cancer activity - in the sense that by keeping mitochondrial cholesterol low it protects the functioning of cellular stress response systems and acts as a barrier to tumour formation and progression.

Smith and Land also demonstrated that some of the relatively rare ABCA1 mutations found in human colon cancers by other investigators disabled the gene’s ability to export cholesterol. And by re-establishing the cholesterol export function in human colon cancer cells, they inhibited the cells’ ability to grow as cancers when grafted onto mice. The URMC study, therefore, is the first to directly show how ABCA1 loss-of-function and cholesterol may play a role in cancer.

Millions of Americans take cholesterol-lowering drugs or statins, as prescribed by physicians. The drugs work by blocking the action of key enzymes in the liver, which synthesises cholesterol. Clinical trials also are evaluating statins as a tool against cancer, and some previous studies suggest that when used in combination with chemotherapy, statins might make chemotherapy more effective by sensitising certain cancer cells to chemotherapy-induced cell death.

Land, however, urges caution and further study. Doctors do not know the appropriate statin dose for cancer prevention or treatment of cancer-related conditions. Side effects cannot be ignored either, and little research has distinguished between the responses among people who take statins. “The link between cholesterol and cancer is clear,” Land said, “but it’s premature to say that statins are the answer.” The findings were published in an online journal.

Keeping food diary could be key to staying slim and fit

Adopting a fixed timetable for meals could be a more effective method of dieting than trying to cut out fatty foods, say researchers. People who snack on healthy food can put on weight if their eating patterns are not maintained properly, according to new study.

In contrast, the researchers said, sticking to strict meal times is good for the metabolism and helps the body burn off fat, allowing a more liberal choice of food, the Telegraph reported.

Previous studies have shown that both a high-fat diet and eating patterns that disrupt the natural body clock can interfere with our metabolism and raise the risk of obesity.

Scientists from the Hebrew University of Jerusalem tested the effects of timing and fat intake on four groups of mice over an 18-week period to determine whether careful scheduling of meals could lower the effects of a high-fat diet.

Half were given a high-fat diet that would normally be expected to make them obese. Of these, a quarter were fed at the same time each day and another quarter could eat as much as they liked, whenever they liked.

The other half was fed a diet that was lower in fat. Again, one quarter had a fixed feeding time, the other had not.

All four of the groups gained weight over the course of the trial, with the group that ate a high-fat diet at irregular intervals unsurprisingly gaining the most weight, while those on a low-fat, scheduled diet gained the least. But more surprisingly, the mice that had been fed a high-fat diet at regular intervals finished the trial in a better condition than those that ate low-fat foods whenever they wanted, despite both groups consuming the same number of calories overall.

The mice in the scheduled, high-fat group had 12 per cent lower body weight, 21 per cent lower cholesterol and 1.4 times higher sensitivity to insulin than the unscheduled, low-fat group.

The diet also changed their metabolism so that they burnt off the fats they ingested to produce energy in between meal times, rather than storing the fat in their bodies.

“Our research shows that the timing of food consumption takes precedence over the amount of fat in the diet, leading to improved metabolism and helping to prevent obesity,” the paper quoted Prof Oren Froy, who led the experiment, as saying.

“Improving metabolism through the careful scheduling of meals, without limiting the content of the daily menu, could be used as a therapeutic tool to prevent obesity in humans,” he suggested.

The study was published in the Journal of the Federation of American Societies for Experimental Biology

Out-of-tune protein precipitates heart failure

Researchers have unravelled how an out-of-tune protein precipitates heart failure by causing its muscle to malfunction.

Scientists have known for a while that several heart proteins - troponin I is one of them - get “out of tune” in patients with heart failure but the precise origin of the “bad notes” remained unclear.

Troponin I, found exclusively in heart muscle, is already used as the gold standard marker in blood tests to diagnose heart attacks, but the new findings reveal why and how the same protein is also altered in heart failure, the journal “Circulation” reports.

The discovery by Johns Hopkins researchers can pave the way to new and badly needed diagnostic tools and therapies for heart failure, a condition marked by heart muscle enlargement and inefficient pumping, believed to affect more than six million adults in the US alone, the researchers say.

“Our findings pinpoint the exact sites on troponin I’s molecule where disease-causing activity occurs, and in doing so, they give us new targets for treatment,” says researcher Jennifer Van Eyk, director of the Johns Hopkins Proteomics Innovation Centre in Heart Failure.

Troponin I acts as an on-off switch in regulating heart relaxation and contraction. In response to adrenaline, this protein also triggers the “flight-fight” response, according to a Johns Hopkins statement.

But when altered, troponin I can start acting as a dimmer switch instead, one that ever so subtly modulates cardiac muscle function and reduces the heart’s ability to pump efficiently and fill with blood, the researchers found.

The Hopkins team used a novel method to pinpoint the exact sites, or epicentres, along the protein’s molecule where disease-triggering changes occur. They found 14 such sites, six of them previously unknown. They said their work may spark the development of tests that better predict disease risk and monitor progression of the disease once the heart begins to fail.