According to a new article from researchers at Harvard there is a "switch" to turn on a fat and cholesterol production regulator within the cells. I believe, as I have mentioned before, that we can and should add "true life" imagery to our hypnotic suggestions.
It is a rather complex article from Science Daily.com but for those of you who are interested....here it is.
Key Fat And Cholesterol Cell Regulator Identified, Promising Target
07 Aug 2006
Researchers at Harvard Medical School and Massachusetts General Hospital have
identified how a molecular switch regulates fat and cholesterol production, a step
that may help advance treatments for metabolic syndrome, the constellation of
diseases that includes high cholesterol, obesity, type II diabetes, and high blood
pressure. The study is now published in the online version of the scientific journal
Nature and will appear in the August 10th print edition.
"We have identified a key protein that acts together with a family of molecular
switches to turn on cholesterol and fat (or lipid) production," says principal
investigator Anders Naar, PhD, assistant professor of cell biology at Harvard
Medical School and the Massachusetts General Hospital Cancer Center. "The
identification of this protein interaction and the nature of the molecular interface
may one day allow us to pursue a more comprehensive approach to the treatment of
High levels of cholesterol and lipids are linked to a number of interrelated medical
conditions and diseases, including obesity, type II diabetes, fatty liver, and high
blood pressure. This set of conditions and diseases, known as metabolic syndrome,
are afflicting a rapidly increasing portion of society and serve as a major risk
factor for heart disease, the leading cause of death in the developed world.
Treatments for diseases associated with metabolic syndrome have focused primarily on
individual elements, such as high LDL-cholesterol (targeted by the
cholesterol-lowering statin drugs). However, more effective ways to treat all of the
components of metabolic syndrome are needed. One attractive approach might be to
target the genetic switches that promote cholesterol and lipid synthesis, but it
would require a detailed understanding of the regulatory mechanisms before drug
targets can be identified.
After eating a meal, a family of proteins act as switches to turn on cholesterol and
fat (or lipid) production. This family of proteins is known as SREBPs, or sterol
regulatory element binding proteins. Between meals, the production of cholesterol
and lipids should be turned off, however, excess intake of foods, coupled with lack
of exercise, appear to disturb the normal checks and balances that control SREBPs,
resulting in overproduction of cholesterol and lipids.
In the Nature paper, the HMS and MGH Cancer Center team has shown that a protein
called ARC105, which binds to SREBPs, is essential in controlling the activity of
the SREBP family of proteins. "ARC105 represents a lynchpin for SREBPs control of
cholesterol and lipid biosynthesis genes, which may provide a potential molecular
Achilles heel that could be targeted by drugs" says Dr. Naar.
The researchers initially found that after removing ARC105 from human cells by a
process called RNAi, SREBPs were no longer able to activate cholesterol and lipid
biosynthesis genes. To validate these findings in a physiological setting, the
researchers turned to the microscopic worm C. elegans, a favorite model organism
among those studying evolutionarily conserved biological processes because of its
rapid generation time and relative simplicity of genetics, and which had previously
been used to study mechanisms of fat regulation.
Through a collaborative effort with the worm genetics group of Anne Hart, PhD, HMS
associate professor of pathology at the MGH Cancer Center, the team demonstrated
that the C. elegans homologues of SREBP and ARC105, known as SBP-1 and MDT-15,
respectively, are necessary for production and storage of fat. The worms had regular
fat production when SBP-1 and MDT-15 functioned normally, but when researchers used
RNAi to knock out function of either SBP-1 or MDT-15, the worms lost their ability
to properly store fat, lay eggs, and move normally.
"The striking effects of the RNAi knock downs in C. elegans suggest that the
ARC105/SREBP pathway may play a key role in lipid production in humans," said Laurie
Tompkins, PhD, of the National Institute of General Medical Sciences, which
partially supported the research. "This work highlights the value of model organisms
in helping us understand cellular processes that impact human health."
The research team also showed that removal of ARC105 in human cells by RNAi also
negatively affects the same key SREBP target gene as identified in C. elegans. This
suggests that the molecular switch is evolutionarily conserved (and therefore likely
Exhaustive biochemical detective work performed by the Naar group together with the
group of Gerhard Wagner, PhD, HMS professor in the Department of Biological
Chemistry and Molecular Pharmacology, identified exactly how SREBP and ARC105
interact. They found a flexible tail on the SREBP molecule that fits into a specific
groove on a region of ARC105 called KIX.
The researchers analyzed the amino acid sequence of the ARC105 protein, testing many
different sections using NMR spectroscopy to eventually find the KIX area--just one
tenth the area of the larger ARC105 protein--that specifically binds to SREBP. This
specific interaction between SREBP and ARC105 might be a target for small molecule
drugs, according to Dr. Wagner.
"While RNAi completely knocks out a protein including its other functions, perhaps
not related to fat metabolism, a small molecule is a more subtle tool that could
eliminate one protein-to-protein interaction," says Dr. Wagner. Finding a molecule
that attaches to and inhibits the flexible tail of SREBP is unlikely, but a search
for inhibitors to fit the grooved KIX site looks much more promising.
The team is already initiating high-throughput screening at Harvard Medical School's
Institute of Chemistry and Cell Biology to identify small molecule inhibitors of the
"Of course there are numerous hurdles that would need to be overcome before finding
specific and effective treatments based on these findings," says Dr. Naar. If small
molecules that specifically interfere with the interaction of SREBPs and ARC105
could be identified, careful studies in human cells and in mice would be needed to
verify the specificity and efficacy in repressing cholesterol and fat production.
"Unforeseen side effects of such small molecules in mouse studies or in human
clinical trials could also emerge, prohibiting further follow-up", cautions Dr.
Article URL: http://www.medicalnewstoday.com/medicalnews.php?newsid=48733