Scientists have found a new way that liver cells communicate with each other, which could potentially be used to treat fibrosis. The liver plays a crucial role in filtering blood, breaking down toxins, and digesting fats. It also produces collagen to help repair damaged cells. However, when the liver is injured due to chronic inflammation caused by excess fat accumulation, it can produce too much collagen, leading to a condition known as metabolic dysfunction-associated steatohepatitis (MASH). In its advanced stages, MASH can progress to cirrhosis, liver cancer, and liver-related death. The cells responsible for producing collagen in the liver are called hepatic stellate cells.Hepatic stellate cells (HSC) are the focus of a recent study published in Cell Metabolism by scientists at the University of California San Diego. The researchers delved into the activation process of these cells and discovered a signaling pathway in the nucleus consisting of three components, which operates similar to a system of police overseeing other police officers.
In a healthy liver, the first molecule in the pathway suppresses a second molecule, which in turn suppresses the molecule responsible for activating genes that produce collagen. When the first molecule is diminished, the inhibition on the second and third molecules is lifted, resulting in the stimulation of collagen production.The researchers created a small piece of RNA to test the signaling pathway, known as an antisense oligonucleotide (ASO). The ASO was very effective in confirming the pathway’s behavior and also in preventing liver fibrosis, which is an excess of collagen in the liver, without causing any side effects. The researchers are currently in talks with pharmaceutical and biotech companies to license the ASO as a potential therapeutic. “While all the molecules in the pathway were known, their interactions were not. We were able to put the pathway together and demonstrate each step in this intracellular process,” said the researchers.The research focused on a signaling module and its potential impact on liver fibrosis. Jerrold Olefsky, a professor of medicine at UC San Diego Health Sciences, stated that the ASO discovered in the study has the ability to block liver fibrosis. The scientists conducted their investigations using organoids, which are small liver replicas made from three types of liver cells and fed a mixture of fatty acids, fructose, and sugars. Their findings revealed that in normal livers, a protein called TM7SF3 inhibits a splicing factor known as.hnRNPU prevents the removal of an inhibitory exon in the messenger RNA (mRNA) of TEAD1, which is a transcription factor responsible for controlling the genes responsible for collagen production. This inhibitory exon, known as exon 5, prevents TEAD1 from activating the collagen-producing genes.
In the MASH-fed organoids, TM7SF3 levels are reduced, which results in the loss of inhibition on the splicing factor. As a result, the active splicing factor removes the inhibitory exon from the transcription factor, leading to activation of the collagen-producing genes. This process is referred to as alternative splicing.
In their further investigations, they developed an ASO to prevent hnRNPU from splicing out the inhibitory exon.The ASO prevented the splicing factor from binding to the TEAD mRNA, so it couldn’t ultimately splice it out. The MASH mice treated with the ASO resulted in mostly inactive TEAD, which led to a lack of collagen production and fibrosis. These findings demonstrate the significant role of alternative splicing in influencing the development of fibrotic liver disease, as stated by Roi Isaac, Ph.D., the first author of the paper and assistant project scientist in Medicine. When ASOs are given intravenously, they can reach all cells in the body.the body, not just the target cells. By chance, the researchers discovered that within the liver, this hnRNPU mechanism only worked in stellate cells. This made their ASO very effective and specific – the perfect example of good drug design.
According to Olefsky, 25% of the U.S. population has MASH. While the scientists’ ASO could be a promising treatment, obtaining FDA approval would require large clinical trials and could cost up to a billion dollars.
Olefsky and his team identified a less common disease known as primary sclerosing cholangitis, or PSC. It is relatively rare, often fatal, and uUp until now, there have been no effective treatments available. However, when scientists tested their ASO on a mouse model with PSC, they discovered that the ASO was able to significantly halt the progression of the disease. Dr. Olefsky mentioned, “Obtaining FDA approval for PSC would be more feasible than for MASH, so we are currently in discussions with biotech and pharmaceutical companies regarding licensing the ASO for PSC.
