Scientists have discovered a unique gene within specialised liver cells that has a previously unrecognised role in metabolising fat. Deactivating this gene in mice substantially improves their ability to regulate blood glucose. A researcher involved in the study says that the finding could have promising implications for humans.
When the liver is inflamed, stellate (star-shaped) cells in the liver contribute to forming scar tissue (fibrosis), which can impair liver function and progress to cirrhosis or liver cancer.
However, groundbreaking research has revealed that stellate cells also have a previously unrecognised role in how the liver metabolises fat and regulates blood glucose.
The researchers identified the gene that enables this function, providing a new perspective on the role of stellate cells. This discovery opens exciting possibilities for developing treatments targeting numerous conditions, including liver diseases and type 2 diabetes.
“Stellate cells have a key role in regulating metabolism, making them potentially important in the development or prevention of metabolic disorders. This study uncovered an additional layer in the complex regulation of metabolism. We now aim to explore whether this layer provides potential for drug therapy and to identify any signalling pathways that could be modulated to improve health,” explains a researcher behind the study, Kim Ravnskjær, Associate Professor, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense.
The research has been published in Cell Metabolism.
Stellate cells protect the liver
Kim Ravnskjær and colleagues investigated how plasmalemma vesicle-associated protein (PLVAP) affects the functioning of stellate cells. PLVAP is a well-known protein with a crucial role in the endothelial cells forming the blood vessels. Mutations in the gene coding for PLVAP can be fatal for newborns, leading to leaky blood vessels and significant fluid loss through the intestines, and this also affects mice lacking PLVAP.
PLVAP is present in stellate cells, which are located around the liver endothelial cells. Stellate cells are vital for maintaining healthy blood vessels. They further help regulate vascular tone and thereby control the amount of blood flowing into the liver. Despite the recognised role of PLVAP elsewhere in the body, its role within stellate cells in the liver has remained a mystery.
“We have long understood the role of stellate cells in forming scar tissue in the liver, but the role of PLVAP in these cells has remained unknown,” says Kim Ravnskjær.
Deactivating the gene in mice
The researchers eliminated PLVAP specifically in stellate cells in the livers of mice to investigate its role in various biological functions and signalling pathways. Surprisingly, mice without PLVAP in liver stellate cells remained healthy and did not develop any illnesses.
The researchers then made a striking discovery: During fasting, mice lacking PLVAP in their stellate cells could not transition from metabolising carbohydrate to metabolising fat in the liver.
“Under normal conditions, when the body is fasting and carbohydrate is scarce, the liver shifts to burning fat. However, these mice did not make this metabolic switch. This is the first evidence implicating stellate cells of the liver in metabolic regulation,” notes Kim Ravnskjær.
Fundamentally changing metabolism
The research revealed that the fasting that normally prompts the liver to burn fat did not do this in the mice.
The tiny fat droplets that normally form in the liver did not form, and less ketones were produced. Organs such as the brain like to use ketones as an energy source during fasting.
In addition, the genetic programmes that enable fat to be metabolised in the liver remained inactive. As a result, the fat normally taken up by the liver during fasting was redirected to the muscles.
Interestingly, the researchers found heightened insulin signalling in the mice, even in the absence of food. Furthermore, the altered metabolism in the mice improved their blood glucose regulation.
“Remarkably, deactivating a single gene in the stellate cells of the liver substantially transformed the mice’s metabolism, improving blood glucose control. These findings may have substantial implications for potential drug therapy, especially since poor glucose control is a hallmark of metabolic conditions such as diabetes and obesity,” explains Kim Ravnskjær.
Further research
Kim Ravnskjær explains that the function of PLVAP in stellate cells is likely related to how they communicate with the hepatocytes. Hepatocytes are central in regulating metabolism, but stellate cells can clearly influence hepatocytes to shift metabolism in specific directions.
As a result, Kim Ravnskjær’s future research will focus on uncovering how stellate cells tell hepatocytes to alter metabolic pathways.
“This breakthrough has revealed a new mechanism that could potentially be harnessed to promote healthier metabolism. Identifying and influencing this signal might open the door to innovative drug interventions. Remember that targeting PLVAP indiscriminately across the body’s organs could adversely affect the intestines and brain. Therefore, our research aims to discover how to selectively influence this system within the liver alone,” cautions Kim Ravnskjær.
In addition to conducting more studies in mice, Kim Ravnskjær and colleagues will also investigate whether stellate cell PLVAP affects the metabolism also in the liver of humans.
