Dicer enzyme cuts down on fats

May 24, 2018, Ludwig Maximilian University of Munich
Dicer enzyme cuts down on fats
Dicer knockout in macrophages (right) accelerates atherosclerosis. Credit: Yuanyuan Wei, LMU

The enzyme Dicer cleaves long precursors into short RNA molecules called microRNAs. A new study reveals how Dicer enhances energy metabolism and reduces levels of fat storage in macrophages, thus slowing the progression of atherosclerosis.

Atherosclerosis is one of the primary causes of premature death in modern societies. The condition is characterized by the deposition of fat-soluble molecules – principally cholesterol and triglycerides – on the inner walls of major blood vessels. This process triggers vascular inflammation and the formation of atherosclerotic plaques, which ultimately lead to narrowing of the arteries, thus impeding the flow of blood. Cells called macrophages are responsible for the uptake and disposal of the fatty deposits that induce plaque formation. However, depending on how they have been activated, macrophages can play an insidious role in the development of atherosclerosis. Inflammatory activation promotes inflammation, while 'alternatively activated' macrophages suppress inflammation reactions. The latter degrade triglycerides by means of fatty acid oxidation, but if this pathway operates suboptimally – due to local inflammation, for example – they accumulate the engulfed fats, thus contributing to plaque development and increasing the risk of blood vessel blockage. A team of researchers in the Institute for Prophylaxis and Epidemiology of Cardiovascular Diseases at the LMU Medical Center, led by Professor Andreas Schober, has now shown that the enzyme Dicer plays an important role in the breakdown of triglycerides in alternatively activated macrophages. The findings appear in the latest issue of the journal Circulation.

Dicer slices long precursor RNAs into short snippets, which are known as microRNAs (miRNAs). miRNAs make a significant contribution to the regulation of gene activity. By binding to complementary nucleotide sequences in messenger RNAs (mRNAs), miRNAs prevent the synthesis of specific proteins. The Munich researchers used a mouse model system to study the impact of functional deletion of the Dicer gene in macrophages on . "We found that lack of Dicer in macrophages impairs their capacity for oxidative degradation of triglycerides. As a result, they accumulate more fat and develop into what are called foam cells", Schober explains. Foam cells die at a higher rate than normal macrophages, which stimulates progression of atherosclerosis.

Schober and his colleagues went on to show that the effects of Dicer knockout on macrophage function are attributable to the loss of a single microRNA, named miR-10a, which is required for normal regulation of energy metabolism in these cells, and boosts the oxidative breakdown of the fatty acids in triglycerides. In addition, they identified the relevant target of miR-10a as the mRNA that codes for the ligand-dependent nuclear co-repressor protein (Lcor). "When the interaction between the two RNAs (which reduces levels of the Lcor protein) is inhibited, progression of atherosclerosis is accelerated, as in the case of the knockout of Dicer," says Schober.

The discovery of this specific regulation of fatty acid metabolism in macrophages could lead to a novel therapeutic strategy for the treatment of atherosclerosis. Schober and his team now plan to explore ways of suppressing the negative effects of inflammation on fatty acid oxidation in alternatively activated macrophages.

Explore further: Atherosclerosis—a short cut to inflammation

More information: Yuanyuan Wei et al. Dicer in Macrophages Prevents Atherosclerosis by Promoting Mitochondrial Oxidative Metabolism, Circulation (2018). DOI: 10.1161/CIRCULATIONAHA.117.031589

Related Stories

Atherosclerosis—a short cut to inflammation

February 10, 2016
The enzyme Dicer processes RNA transcripts, cutting them into short segments that regulate the synthesis of specific proteins. An Ludwig-Maximilians-Universitaet (LMU) in Munich team has shown that Dicer promotes the development ...

Altering the appearance of macrophages to prevent atherosclerosis

February 8, 2018
It might be possible to prevent atherosclerosis by changing the appearance of macrophages, cells of the immune system that for example digest foreign substances. In her Ph.D. dissertation, Baoyan Ren examined several ways ...

Atherosclerosis: Specific microRNAs promote inflammation

March 22, 2013
(Medical Xpress)—Atherosclerosis, an inflammatory reaction, is at the root of the most common forms of cardiovascular disease. Researchers at Ludwig-Maximilians-Universitaet in Munich have now identified a microRNA that ...

Macrophage accumulation of triglycerides yields insights into atherosclerosis

October 1, 2012
A research report appearing in the Journal of Leukocyte Biology helps explain how specific immune cells, called macrophages, accumulate triglycerides to support their function. Because a characteristic finding in atherosclerosis ...

Neuron guidance factor found to play a key role in immune cell function

May 21, 2018
Macrophages are white blood cells involved in a variety of biological functions, from destroying infectious pathogens to repairing damaged tissue. To carry out their different roles, macrophages must first be activated and ...

Recommended for you

New study shows how gut immune cells are kept in control

June 22, 2018
Every day, the human gut works on a fine-tuned balance that ensures the retention of essential nutrients while preventing infection by potential armful microbes. Contributing to this surveillance system is a specialised group ...

Human immune 'trigger' map paves way for better treatments

June 21, 2018
A discovery about how human cells are 'triggered' to undergo an inflammatory type of cell death could have implications for treating cancer, stroke and tissue injury, and immune disorders.

Our intestinal microbiome influences metabolism—through the immune system

June 21, 2018
Research tells us that the commensal or "good" bacteria that inhabit our intestines help to regulate our metabolism. A new study in fruit flies, published June 21 in Cell Metabolism, shows one surprising way they do this.

Fetal T cells are first responders to infection in adults

June 20, 2018
Cornell University researchers have discovered there is a division of labor among immune cells that fight invading pathogens in the body.

How a thieving transcription factor dominates the genome

June 20, 2018
One powerful DNA-binding protein, the transcription factor PU.1, steals away other transcription factors and recruits them for its own purposes, effectively dominating gene regulation in developing immune cells, according ...

Severe stress may send immune system into overdrive

June 19, 2018
(HealthDay)—Trauma or intense stress may up your odds of developing an autoimmune disease, a new study suggests.

0 comments

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.