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Scientists alter fat metabolism in animals to prevent most common type of heart disease


April 22, 2014
Health, Life & Non-humans

Working with mice and rabbits, Johns Hopkins scientists have found a way to block abnormal cholesterol production, transport and breakdown, successfully preventing the development of atherosclerosis, the main cause of heart attacks and strokes and the number-one cause of death among humans. The condition develops when fat builds inside blood vessels over time and renders them stiff, narrowed and hardened, greatly reducing their ability to feed oxygen-rich blood to the heart muscle and the brain.

In a series of experiments, described April 7 in the journal Circulation, the Johns Hopkins team says it identified and halted the action of a single molecular culprit responsible for a range of biological glitches that affect the body’s ability to properly use, transport and purge itself of cholesterol — the fatty substance that accumulates inside vessels and fuels heart disease.

The offender, the researchers say, is a fat-and-sugar molecule called glycosphingolipid, or GSL, which resides in the membranes of all cells, and is mostly known for regulating cell growth. Results of the experiments, the scientists say, reveal that this very same molecule also regulates the way the body handles cholesterol.

The Johns Hopkins team used an existing man-made compound called D-PDMP to block the synthesis of the GSL molecule, and by doing so, prevented the development of heart disease in mice and rabbits fed a high-fat, cholesterol-laden diet. The findings reveal that D-PDMP appears to work by interfering with a constellation of genetic pathways that regulate fat metabolism on multiple fronts — from the way cells derive and absorb cholesterol from food, to the way cholesterol is transported to tissues and organs and is then broken down by the liver and excreted from the body.

“Current cholesterol-lowering medications tackle the problem on a single front — either by blocking cholesterol synthesis or by preventing the body from absorbing too much of it,” says lead investigator Subroto Chatterjee, Ph.D., a cardio-metabolic expert at the Johns Hopkins Children’s Center. “But atherosclerosis is a multi-factorial problem that requires hitting the abnormal cholesterol cycle at many points. By inhibiting the synthesis of GSL, we believe we have achieved exactly that.”

Specifically, the experiments showed that treatment with D-PDMP led to:

  • a drop in the animals’ levels of so-called bad cholesterol or low-density lipoprotein, LDL;
  • a drop in oxidized LDL, a particularly virulent form of fat that forms when LDL encounters free radicals. Oxidized LDL easily sticks to the walls of blood vessels, where it ignites inflammation, damaging the vessel walls and promoting the growth of fatty plaque;
  • a surge in good cholesterol or high-density lipoprotein, HDL, known to counteract the effects of LDL by mopping it up; and
  • a significant drop in triglycerides, another type of plaque-building fat.

The treatment also prevented fatty plaque and calcium deposits from building up inside the animals’ vessels. These effects were observed in animals on a daily D-PDMP treatment even though they ate a diet made up of 20 percent triglycerides — the human equivalent of eating a greasy burger for breakfast, lunch and dinner. In addition, the researchers say, D-PDMP appears to precision-target the worst byproducts of aberrant cell growth signaling, such as oxidized LDL and the activity of certain chemicals that fuel vessel inflammation, without altering cell growth itself.

D-PDMP, which is already widely used in basic research to experimentally block and study cell growth and other basic cell functions, is deemed safe in animals, the investigators say. For example, animals in the current study had no side effects even when given D-PDMP doses 10 times higher than the minimum effective dose, the study found. The research team is currently designing a compound drug with D-PDMP, which they soon plan to test in other animals and, eventually, in humans.

Mice used in the experiments were genetically engineered to lack a protein essential in the breakdown of fats and thus were predisposed to atherosclerosis. The researchers fed the animals a high-fat diet over the course of several months, but also gave a third of the animals a low-dose of D-PDMP. They gave a double dose of the same inhibitor to another third and placebo to the rest.

When scientists measured the thickness of the animals’ aortas — the body’s largest vessel and one that carries blood from the heart to the rest of the body — they found striking differences among the groups. As expected, the aortas of mice that got placebo had grown thicker from the accumulation of fat and calcium deposits inside them. The aortas of mice on low-dose D-PDMP, however, were significantly thinner with little to no obstruction. To the researchers’ surprise, Chatterjee says, mice eating high-fat foods and treated with high-dose D-PDMP had nearly pristine arteries free of obstruction, indistinguishable from those of healthy mice.

Next, the researchers measured how well and how fast blood traveled through the animals’ blood vessels. Slower blood flow signals clogging of the vessel and is a marker of atherosclerosis. The vessels of mice fed a high-fat diet plus D-PDMP had normal blood flow. Mice receiving a high-fat diet without D-PDMP predictably had compromised blood flow.

When researchers examined cells from the animals’ livers — the main site of fat synthesis and breakdown — they noticed marked differences in the expression of several genes that regulate cholesterol metabolism. The activity of these genes is heralded by the levels of enzymes they produce, Chatterjee says. Mice treated with D-PDMP had notably higher levels of two enzymes responsible for maintaining the body’s delicate fat homeostasis by regulating the way cells take in and break down cholesterol. Specifically, the scientists say, the inhibitor appeared to stimulate the action and efficacy of a class of protein pumps in the cell responsible for maintaining healthy cholesterol levels by transporting cholesterol in and out of the bloodstream. In addition, mice treated that way had higher levels of lipoprotein lipase, an enzyme responsible for the breakdown of triglycerides. A deficiency in this enzyme causes dangerous buildup of blood triglycerides.

Treatment with a D-PDMP also boosted the activity of an enzyme responsible for purging the body of fats by converting these fats into bile, the fat-dissolving substance secreted by the liver.

In a final set of experiments, researchers compared the effects of treatment with D-PDMP in two groups of healthy rabbits, both fed high-fat diets, with half of them receiving treatment. Rabbits that ate high-fat food alone developed all the classic signs of atherosclerosis—fatty plaque buildup in the arteries and stiff, narrowed blood vessels. Their cholesterol levels shot up 17-fold. By contrast, rabbits treated with D-PDMP never developed atherosclerosis. Their cholesterol levels also remained normal or near-normal.

The World Health Organizations estimates that high cholesterol claims 2.6 million lives worldwide each year. More than 70 million Americans have high cholesterol, according to the U.S. Centers for Disease Control and Prevention. Current cholesterol-lowering drugs, such as statins, do not work in about one-third of people who take them, experts say.


2 Responses to Scientists alter fat metabolism in animals to prevent most common type of heart disease

  1. 14005311 April 23, 2014 at 11:01 am #

    I am completely amused by the amount of scientific research and intelligence that has gone into this study. The research and results are presented all too well; literally and figuratively.
    It has clearly been denoted that this study has resulted in a scientifically progressing resolution to the problem of heart disease or the reduced production of ‘unnecessary’ fats, through the use of D-PDMP. However, there is a constant use of the words “high-fats diet” which, by view of the reader, is connotatively used to refer to the unhealthy life-style and excessive consumption of artificially processed foods of majority of the American population – of which 70 million suffer from heart disease. In my opinion the correlation of the “fast-food” and heart failure is far too close for comfort. The statement, “animals in the current study had no side effects”, is misleading as the animals are still in current study, the long-term effects have not yet been noted.
    Taking the biology into consideration, the microdomains within the plasma membrane or otherwise known as “lipid rafts” consist mainly of cholesterol and glycosphingolipids (GSLs) – of which the synthesis is inhibited to “hit abnormal cholesterol problems at many points”. These “lipid rafts” play significant roles in numerous cellular functions. Inhibiting the synthesis of GSLs and reducing cholesterol extensively will have an effect on not only membrane transportation of organic and inorganic molecules but on signal transduction, and endocytosis – the process in which cells absorb molecules through use of energy by engulfing them.
    I personally feel the use of D-PDMP is merely ‘hiding’ behind the astonishing prevention of heart disease, to seem like a superior key to future survival. Whereas it is actually a gateway through which people can escape to excessively indulge in the luxurious processed fatty plastic that they have grown to love and refer to as ‘food’, without gaining the major deposits of fat within their bodies and appear healthy to the eyes of others.
    The realistic individual who is determined to not be a victim of heart disease will adapt his lifestyle to a healthy organic diet and daily exercise!

  2. METIN GUNDUZ April 22, 2014 at 9:56 am #

    Well ; not so fast ; it is so unlikely that the `shotgun type` D-PDMP blockage of essential chemical like Glycosphingolipids( GSLs) which is present almost all cell walls without exception ; will cure or prevent anything without `serious side effects` .
    It is not probable or even possible in the long clinic trials with careful controlled studies . It is also possible that the mice and rabbit may not be the ideal experimental animal for GSL blocage side effects in long clinical trials to make presumption on humans .
    You may have clean vessels BUT with the cost of major damage and side effects at the other tissues and functions of the body for sure .
    Simply because Glycosphingolipids are so `fundamental` for the normal functioning of cells .
    Glycosphingolipids are so essential for normal functioning of any cell with membrane in the body , starting : Fine tuning GSL cell wall receptor function , GSLs function to gate many processes in biology , it is closely associated with intracellular trans-Golgi network, and Golgi to the endoplasmic reticulum .
    Glycosphingolipid (GSLs) involved in synthesis of all Myelin sheet- insulation of axons- and of course nerve conduction .
    As well as tyrosine amino acid mediated melanosome synthesis and metabolism . They involved in normal functioning of Glial(Nerve) cells involved in Nero inflammation normal inflammatory reaction .
    Cell wall receptors are chemically are mostly structurally GSLs so their trans membrane receptor function is primarily important .
    Insulin receptor signaling and development of insulin resistance and even significant increase in HIV susceptibility as well as immune recognition and intracellular vesicle trafficking functions are all related with GSLs of cell wall .
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3119914/#A004788C230 pdf . Overview Glycosphingolipid Functions

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