Cell biology: Flushing out fats

Dec 19, 2012
Lipid droplets, labeled with the dye ‘Oil red O’, accumulate in normal macrophages exposed to oxidated LDL (top) as they transform into artery-damaging foam cells. However, macrophages that lack the gene encoding Wip1 (bottom) rapidly eliminate cholesterol and show little lipid accumulation.   Credit: 2012 Elsevier

The Wip1 protein is important for survival, but mutations that inactivate it carry some surprising features. "A lack of Wip1 results in an excessive immune reaction to infectious organisms, in some cases killing the host," explains Dmitry Bulavin of the A*STAR Institute of Molecular and Cell Biology, Singapore. He also notes, however, that mice lacking Wip1 are considerably less prone to certain cancers. Now, research from Bulavin and his co-workers has revealed that Wip1-deficient animals also exhibit improved fat metabolism and cardiovascular health.  

Wip1 is a phosphatase, an enzyme that specializes in the targeted removal of phosphate chemical groups that modulate function of proteins such as Atm and p53. Both of these proteins regulate pathways that ameliorate potentially cancer-causing genetic damage, but have also been linked to cardiovascular health.  

To investigate whether Wip also regulates lipid processing, Bulavin's team generated mice that were deficient in both Wip1 and apolipoprotein E (apoE), a protein involved in cholesterol trafficking. Mice without apoE are vulnerable to atherosclerosis, a narrowing and hardening of the arterial walls resulting from excessive accumulation of cholesterol-laden low-density lipoprotein (LDL) particles. Wip1-deficiency mitigated this effect, and mice lacking both proteins had lower body weight and greatly reduced tendency to develop atherosclerosis relative to mice lacking only apoE.

The associated with atherosclerosis is initiated when known as macrophages begin to consume oxidized LDL particles, and gradually transform into lipid-loaded 'foam cells'. Bulavin and co-workers found that macrophages from Wip1-deficient mice are far more resistant to becoming , and that this transformation is dependent on Wip1-mediated inhibition of Atm. "Removal of just a single copy of the Atm gene resulted in a striking reversal of the suppression of obesity and atherosclerosis seen in Wip1-deficient mice," says Bulavin. 

Closer investigation revealed that the actions of Wip1 on Atm cause macrophages to pump out cholesterol rather than hoard it. This requires the cells to physically liberate cholesterol molecules from lipid droplets; Wip1 promotes this by stimulating a mechanism called 'autophagy', wherein lipid droplets are absorbed into cellular compartments, known as lysosomes, and broken down enzymatically.

The finding highlights a promising target pathway for drugs addressing cardiovascular health, but also reveals a novel function of Wip1 that may prove relevant for cancer research. "We never suspected that autophagy could be part of tumor resistance in Wip1-deficient mice," says Bulavin, "and we are now checking whether we can integrate this with other mechanisms of tumor resistance."

Explore further: Sizing up cells: Study finds possible regulator of growth

More information: Le Guezennec, X., Brichkina, A., Huang, Y.-F., Kostromina, E., Han, W. & Bulavin, D. V. Wip1-dependent regulation of autophagy, obesity, and atherosclerosis. Cell Metabolism 16, 68–80 (2012). www.cell.com/cell-metabolism/a… -4131%2812%2900240-9

add to favorites email to friend print save as pdf

Related Stories

Nicotinic acid blocks immune cells in atherosclerosis

Feb 07, 2011

Nearly all cardiac infarctions and around half of all strokes are caused by atherosclerosis. An early treatment of atherosclerosis is therefore crucial to preventing cardiovascular diseases. Stefan Offermanns’ ...

Recommended for you

The origins of polarized nervous systems

6 hours ago

(Phys.org)—There is no mistaking the first action potential you ever fired. It was the one that blocked all the other sperm from stealing your egg. After that, your spikes only got more interesting. Waves ...

New fat cells created quickly, but they don't disappear

10 hours ago

Once fat cells form, they might shrink during weight loss, but they do not disappear, a fact that has derailed many a diet. Yale researchers in the March 2 issue of the journal Nature Cell Biology descri ...

A single target for microRNA regulation

12 hours ago

It has generally been believed that microRNAs control biological processes by simultaneously, though modestly, repressing a large number of genes. But in a study published in Developmental Cell, a group ...

Sizing up cells: Study finds possible regulator of growth

Mar 02, 2015

Modern biology has attained deep knowledge of how cells work, but the mechanisms by which cellular structures assemble and grow to the right size largely remain a mystery. Now, Princeton University researchers ...

User comments : 0

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.