[PHNUTR-L] Abnormal fat metabolism underlies heart problems in
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Public release date: 10-Aug-2007
Contact: Gwen Ericson
Washington University School of Medicine
Abnormal fat metabolism underlies heart problems in diabetic patients
St. Louis, Aug. 10, 2007 — Heart disease hits people with diabetes twice
as often as people without diabetes. In those with diabetes,
cardiovascular complications occur at an earlier age and often result in
premature death, making heart disease the major killer of diabetic
people. But why is heart disease so prevalent among diabetics?
To help answer that question, researchers at Washington University
School of Medicine in St. Louis have been analyzing the fat (lipid)
composition of heart tissue from laboratory mice with diabetes. They
have found that heart cells of diabetic mice lose an important lipid
from cellular components that generate energy for the heart, and their
latest research shows this happens at the very earliest stages of diabetes.
"Diabetic hearts run mostly on fats for fuel because glucose isn't
readily available to them," says Richard Gross, M.D., Ph.D., director of
the Division of Bioorganic Chemistry and Molecular Pharmacology and
professor of medicine, of chemistry and of molecular biology and
pharmacology. "Unfortunately, this change in metabolism distorts the
lipid composition of cell membranes causing abnormal physical properties
and cellular dysfunction."
The important lipid that the researchers found to be decreased in
diabetes is cardiolipin. "Cardiolipin" literally means heart fat, and
the term was coined because cardiolipin was first discovered in beef
hearts and is one of the most abundant lipids in heart tissue. This
lipid has unusual physical properties that are essential for the
operation of the energy-producing cell structures called mitochondria.
When mitochondria lose a lot of their cardiolipin, they malfunction.
Their malfunction not only interferes with the energy supply of heart
muscle cells, it also increases the amount of damaging oxygen-containing
substances in the cells, creating unhealthy conditions that can lead to
Interestingly, a rare genetic disorder — Barth syndrome — held a key to
identifying cardiolipin decrease in diabetic hearts. Children born with
Barth syndrome have weak hearts and often die young from heart failure.
These children have mutations that prevent cells from producing enough
cardiolipin. The connection between cardiolipin and heart disease in
Barth syndrome led the Washington University researchers to wonder if
cardiolipin was also affected in diabetic hearts.
But in order to measure cardiolipin, the researchers needed a way to
distinguish it from the numerous other lipids found in heart cells.
Fortunately, Gross and his colleagues have been developing and refining
a highly sophisticated set of techniques that allow them to separate and
quantify thousands of different lipids based on their subtle structural
differences. The set of techniques has been termed "shotgun lipidomics"
because they very rapidly determine which lipids are in tissues and blood.
"Shotgun lipidomics provide a precise way to measure changes in heart
lipid content," says first author Xianlin Han, Ph.D., assistant
professor of medicine. "We found a dramatic depletion of cardiolipin in
heart muscle as early as five days after diabetes was induced in mice."
"These results suggest that cardiolipin alterations underlie heart
dysfunction in diabetic heart disease and may be a useful biomarker for
diagnosing cardiovascular disease in diabetes," Gross says. "Measuring
alterations may be a way to tell the severity of heart disease and to
evaluate how well therapies work. In addition, these findings suggest
potential new therapeutic approaches."
Even though the research team found a depletion of an important type of
lipid in diabetic heart tissue, diabetic heart muscle cells actually
take in excess lipids. But as these lipids enter cells they activate
lipid-digesting enzymes. In previous studies, Gross and colleagues
identified a particular lipid-digesting enzyme that becomes more active
in diabetic heart muscle and contributes to the breakdown of cardiolipin.
Recently, Gross and his colleague David Mancuso, Ph.D., member of the
division, found that mice engineered to produce too much of this enzyme
in their hearts developed defects in mitochondrial function which became
worse when they were fasted — a condition that, like diabetes, causes
the heart to use lipids for fuel. A 16-hour fast caused significant
problems with the mouse hearts' ability to pump blood, again implicating
altered lipid metabolism, cardiolipin scarcity and mitochondrial
impairment in heart disease using lipid as predominant fuel.
Gross adds that in addition to the effects on mitochondria, many of the
membranes in heart cells, which are built from fatty molecules, are also
adversely affected by the diabetic heart's abnormal lipid metabolism.
Furthermore, because fatty molecules are part of cells' signaling
mechanisms, numerous aspects of cellular physiology become altered.
"The pieces of the puzzle of diabetic heart disease are now rapidly
falling into place," Gross says. "By exploiting the novel technology of
shotgun lipidomics, we have identified the increased activation of
certain lipid-digesting enzymes and the decrease of cardiolipin as
central aspects of this disorder. We hope that these kinds of studies
will enable physicians to diagnose diabetic cardiovascular disease
sooner and treat it earlier."
Han X, Yang J, Yang K, Zhao Z, Abendschein DR, Gross RW. Alterations in
myocardial cardiolipin content and composition occur at the very
earliest stages of diabetes: a shotgun lipidomics study. Biochemistry
Mancuso DJ, Han X, Jenkins CM, Lehman JJ, Sambandam N, Sims HF, Yang J,
Yan W, Yang K, Green K, Abendschein DR, Saffitz JE, Gross RW. Dramatic
accumulation of triglycerides and precipitation of cardiac hemodynamic
dysfunction during brief caloric restriction in transgenic myocardium
expressing human calcium-independent phospholipase A2γ. Journal of
Biological Chemistry 2007 Mar;282(12):9216-9227.
Funding from the National Institutes of Health supported this research.
Washington University School of Medicine's full-time and volunteer
faculty physicians also are the medical staff of Barnes-Jewish and St.
Louis Children's hospitals. The School of Medicine is one of the leading
medical research, teaching and patient care institutions in the nation,
currently ranked fourth in the nation by U.S. News & World Report.
Through its affiliations with Barnes-Jewish and St. Louis Children's
hospitals, the School of Medicine is linked to BJC HealthCare.
Kathrynne Holden, MS, RD < fivestar at nutritionucanlivewith.com >
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