SINGAPORE: A*STAR
scientists in Singapore have made what is believed to be groundbreaking
discovery of the mechanism that controls obesity, atherosclerosis and,
potentially, cancer.
Scientists from the Institute of Molecular and Cell
Biology (IMCB) and the Singapore Bioimaging Consortium (SBIC) said they have
found a new signalling pathway that regulates both obesity and atherosclerosis.
The team showed, for the first time, that mice deficient
in the Wip1 gene were resistant to weight gain and atherosclerosis via
regulation of the Ataxia telangiectasia mutated gene (ATM) and its downstream
signalling molecule mTor.
A*STAR says these groundbreaking findings were published
in the journal Cell Metabolism on 3 July and may provide significant new
avenues for therapeutic interventions for obesity and atherosclerosis.
Obesity and atherosclerosis-related diseases account for
over one-third of deaths in the Western world. In Singapore, 10.8 per cent of
its population is obese, and cardiovascular disease accounted for 31.9 per cent
of all deaths in 2010.
Atherosclerosis, a progressive disease of the large
arteries, is an underlying cause of many cardiovascular diseases.
Controlling these conditions remains a major challenge
due to an incomplete understanding of the molecular pathways involved.
Obesity and atherosclerosis are accompanied by the
accumulation of lipid droplets in fat cells and in foam cells respectively.
Foam cells can subsequently rupture, damaging blood
vessels, and contributing to further progression of atherosclerosis.
The scientists discovered that Wip1 deficient mice, even
when fed a high-fat diet, were resistant to obesity and atherosclerosis by
preventing the accumulation of lipid droplets.
This appeared to be through increased autophagy, the
normal process by which the body degrades its own cellular components.
The scientists showed that the Wip1 deficient mice
exhibited increased activity of ATM which decreased mTor signalling, resulting
in increased autophagy.
This degraded the lipid droplets and suppressed obesity
and atherosclerosis.
"This is the first time that Wip1-dependent
regulation of ATM-mTor pathway has been linked to authophagy and cholesterol
efflux, thus providing an entirely new avenue for treatment of obesity and
atherosclerosis," Dr Dmitry Bulavin, senior principal investigator at IMCB
and lead author of the paper, said.
The scientists are hopeful that the ATM-mTor pathway
could similarly map onto cancer to suppress tumour progression.
Similar to suppression of obesity and atherosclerosis,
activation of autophagy in cancer cells could result in degradation of cellular
content that is essential for cancer cells to sustain rapid proliferation.
This, in turn, will result in suppression of cancer growth.
Dr Dmitry Bulavin said: "We are building on this
research to investigate if the same mechanism could also control tumour
progression and hence potentially unlock new therapeutic treatments targeting
Wip1, ATM and mTor in cancer as well and the preliminary results are
promising."
This discovery also adds to the growing significance of
ATM as an important gene with a key role in protecting us from major
pathological conditions. Previous work has established Wip1-dependent
regulation of ATM as a potent regulator of tumorigenesis via activation of tumour-suppressor
p53.
Together, these three pathological conditions -- obesity,
atherosclerosis and cancer -- account for more than 70 per cent of mortality
worldwide, making ATM-related pathways very attractive therapeutic targets.
Professor Hong Wanjin, executive director of IMCB, said,
"This is the first time that these important molecules have been
integrated into a linear pathway that plays a prominent role in controlling
obesity and atherosclerosis. It is a fine example of how fundamental research
can shed light on biological and medical questions to potentially open new
avenues of formulating therapeutic strategies for the benefit of
patients."
- CNA/wm
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