ETH researchers around Markus Stoffel have discovered that vigilin, a RNA-binding protein in liver cells, controls the synthesis and release of proteins that regulate lipid and cholesterol levels in the bloodstream. Silencing of vigilin efficiently reduces atherosclerotic plaque formation.
Eating fat or drinking alcohol in excess can take a toll on our body – one becomes overweight and diabetic, leading to a condition known as fatty liver. If eating and drinking habits are changed in time, the liver usually recovers completely from the degeneration, but in severe cases the organ becomes inflamed – a condition notoriously difficult to treat. What is more, fatty liver is also leading to elevated blood fat values. The degenerated organ seeks relief by releasing fat into the bloodstream, including “good” fat in the form of high density lipoprotein (HDL), but also “bad” fat, such as low density lipoprotein (LDL) and even more worse its precursor, very low density lipoprotein (VLDL) that serves as a carrier of triacylglycerides in the blood. Too high concentrations of LDL and VLDL in the circulation can lead to the formation of atherosclerotic plaques. When such a plaque ruptures or detaches itself, there is a real risk of a vascular blockage and a heart attack or stroke.
Now scientists from the group of Markus Stoffel, Professor of Molecular Health Sciences at ETH Zurich, have been able to show that the RNA-binding protein (RBP) vigilin is upregulated in livers of obese mice and in patients with fatty liver disease. The protein seems to act as a kind of “lock keeper”, regulating the release of fats, including VLDL, from the liver into the bloodstream. Vigilin is the largest RBP of the KH domain family. It is conserved from human to yeast and is thought to play a crucial role in diverse biological processes such as sterol metabolism, carcinogenesis, control of translation, formation of heterochromatin, nuclear export of tRNA, cytoplasmic transport of RNA and metabolism of speci?c mRNAs. Yet up to date, no systematic analysis has been performed and very few mRNA targets and no precise RNA recognition element have been reported in mammals.
By using in vivo, biochemical and genomic approaches, Markus Stoffel and his group showed that vigilin indeed controls VLDL secretion through the modulation of apolipoproteinB/Apob mRNA translation. Apob is responsible for exporting triglycerides from the liver. Triglycerides also promote vascular calcification when present in concentrated form in overweight people. It appears that the primary function of vigilin is to regulate transport proteins responsible for the release of fat out of the liver. But it accomplishes this not by binding directly to these transport proteins, but rather to certain points of the associated mRNA. Crosslinking studies revealed that vigilin binds to CU-rich regions in the mRNA coding sequence of Apob and other proatherogenic secreted proteins, including apolipoproteinC-III/Apoc3 and ?bronectin/Fn1.
Thus the researchers uncovered a primary role in lipid metabolism and hepatic steatosis in mice and humans to be mediated by an RNA-binding protein. “Vigilin intervenes at the level of gene regulation, which has barely been investigated to date,” says Stoffel. Regulatory processes from DNA to mRNA are increasingly understood, but regulation of the step from mRNA to protein is something we know much less about.
The discovery that silencing of vigilin in the liver (using a new process of RNA interference) reduces the production of proteins that regulate blood lipid levels and thereby atherosclerotic plaque formation in accordingly treated mice suggests a critical role of vigilin in hepatic metabolism and a possible therapeutic approach for the prevention of cardiovascular diseases. The atomic structure of vigilin remains a mystery though - it is currently being studied by several groups around the world. The molecule has 14 different binding points - so vigilin can influence multiple proteins with a variety of possible side effects. But nonetheless the researchers believe that there is opportunity to inhibit vigilin as a pharmacological approach to treat or prevent cardiovascular diseases.
By Roland Fischer