Nav: Home

A novel molecular link between cholesterol, inflammation and liver cancer

March 29, 2017

Hepatocellular carcinoma (HCC) is a deadly disease with no effective cure that develops in the context of liver diseases associated with chronic inflammation. A recent research article published in The Journal of Experimental Medicine describes how important a protein called c-Fos is for HCC development, because it affects cholesterol homeostasis in hepatocytes, the main cells of the liver. Using genetically modified mouse models (GEMMs), Erwin Wagner, director of the Cancer Cell Biology Programme at the Spanish National Cancer Research Centre (CNIO), and his Genes, Development and Disease (GDD) team experimentally document how c-Fos modulates premalignant hepatocyte transformation and how this is linked to cholesterol and inflammation. Maintaining healthy cholesterol levels in the organism is therefore important for preventing liver cancer.

"The critical step to identify biomarkers and develop effective preventive therapies is a better understanding of the mechanisms responsible for cancer initiation", the authors state. For that, the scientists generated new mouse models that allowed them to investigate the very early steps of HCC development in the liver, something that is not feasible with patient samples.

Using these models, the authors were able to dissect the role of c-Fos, a component of a protein complex called AP-1 they had already connected to liver diseases (1-3). Erwin Wagner´s team switched on the expression of c-Fos in hepatocytes and monitored liver and whole body physiology in mutant mice. The scientists observed cell damage that progressed over time, and measured a variety of markers for liver dysfunction and premalignant transformation of hepatocytes. Importantly, these alterations disappeared after switching off c-Fos expression.

All these changes, the authors say are due to decreased activity of a nuclear receptor crucial for cholesterol homeostasis. c-Fos induces hepatic accumulation of cholesterol and toxic cholesterol derivatives that damage hepatocytes and increase cancer risk.

Further experiments showed that removing c-Fos expression in the liver of GEMMs protects them from HCC, when exposed to chemical carcinogens. On the other hand, increasing c-Fos expression accelerates carcinogenesis. "This indicates -state the researchers- that c-Fos not only promotes but is also necessary for liver carcinogenesis and can be a useful therapeutic target to explore".

Wagner and colleagues decided to treat mice with the most commonly used cholesterol lowering drug. "We treated our mutant mice with statins and premalignant hepatocyte transformation was prevented", explains Latifa Bakiri from the GDD team and co-first author of the paper. These results suggest that statins may also prevent deleterious changes in hepatocytes caused by hypercholesterolemia and thus reduce inflammation and liver cancer. Most importantly, the study highlights the importance of maintaining a correct cholesterol balance through a healthy life style to prevent not only cardiovascular diseases, but also liver cancer.
-end-


Centro Nacional de Investigaciones Oncológicas (CNIO)

Related Cholesterol Articles:

Experimental cholesterol-lowering drug effective at lowering bad cholesterol, study shows
Twice-yearly injections of an experimental cholesterol-lowering drug, inclisiran, were effective at reducing low-density lipoprotein (LDL) cholesterol, often called bad cholesterol, in patients already taking the maximum dose of statin drugs, according to data of the ORION-10 trial presented Saturday, Nov.
Rethinking how cholesterol is integrated into cells
Cholesterol is best known in connection with cardiovascular disease, but cholesterol is also vital for many fundamental processes in the body.
Seed oils are best for LDL cholesterol
Using a statistical technique called network meta-analysis, researchers have combined the results of dozens of studies of dietary oils to identify those with the best effect on patients' LDL cholesterol and other blood lipids.
Cholesterol leash: Key tethering protein found to transport cellular cholesterol
Cholesterol is an essential component of living organisms, but the mechanisms that transport cholesterol inside the cell are poorly understood.
New way to treat cholesterol may be on the horizon
A breakthrough discovery by scientists at Houston Methodist Research Institute could change the way we treat cholesterol.
How low should LDL cholesterol go?
New analysis shows that in a high-risk population, achieving ultra-low LDL cholesterol levels, down to <10 mg/dL, safely results in additional lowering of risk of cardiovascular events.
Does boosting 'good' cholesterol really improve your health?
A new review addresses the mysteries behind 'good' HDL cholesterol and why boosting its levels does not necessarily provide protection from cardiovascular risk for patients.
Researchers zero-in on cholesterol's role in cells
For the first time, by using a path-breaking optical imaging technique to pinpoint cholesterol's location and movement within the cell membrane, chemists at the University of Illinois at Chicago have made the surprising finding that cholesterol is a signaling molecule that transmits messages across the cell membrane.
Raising 'good cholesterol' not as effective as lowering 'bad cholesterol'
Low and very high levels of HDL, or 'good cholesterol' are associated with a higher risk of dying from heart disease, cancer and other causes, according to a study today in the Journal of the American College of Cardiology.
New gene for familial high cholesterol
New research from Denmark reveals the gene that explains one quarter of all familial hypercholesterolemia with very high blood cholesterol.
More Cholesterol News and Cholesterol Current Events

Top Science Podcasts

We have hand picked the top science podcasts of 2019.
Now Playing: TED Radio Hour

In & Out Of Love
We think of love as a mysterious, unknowable force. Something that happens to us. But what if we could control it? This hour, TED speakers on whether we can decide to fall in — and out of — love. Guests include writer Mandy Len Catron, biological anthropologist Helen Fisher, musician Dessa, One Love CEO Katie Hood, and psychologist Guy Winch.
Now Playing: Science for the People

#543 Give a Nerd a Gift
Yup, you guessed it... it's Science for the People's annual holiday episode that helps you figure out what sciency books and gifts to get that special nerd on your list. Or maybe you're looking to build up your reading list for the holiday break and a geeky Christmas sweater to wear to an upcoming party. Returning are pop-science power-readers John Dupuis and Joanne Manaster to dish on the best science books they read this past year. And Rachelle Saunders and Bethany Brookshire squee in delight over some truly delightful science-themed non-book objects for those whose bookshelves are already full. Since...
Now Playing: Radiolab

An Announcement from Radiolab