Healthcare, UK (Commonwealth Union) – A properly functioning liver serves as the body’s filtration system, cleansing blood, neutralizing toxins, and aiding in fat digestion. It also plays a crucial role in cell repair through collagen production, particularly when the liver is damaged. However, excessive fat accumulation leading to more collagen production can trigger chronic inflammation, leading to a condition known as metabolic dysfunction-associated steatohepatitis (MASH). In its advanced stages, MASH can progress to cirrhosis, liver cancer, and ultimately, liver-related mortality.
Hepatic stellate cells (HSC) are pivotal in collagen synthesis within the liver. A recent study in Cell Metabolism by researchers from the University of California San Diego delved into the activation mechanisms of these cells. They uncovered a three-component signaling pathway within the nucleus, likened to a regulatory system akin to “police controlling the police.”
Researchers of the study point out that in a healthy liver, the initial molecule in this pathway suppresses a secondary molecule, which in turn inhibits the molecule responsible for activating collagen-producing genes. In MASH, the presence of excess fat diminishes the levels of the initial molecule, thereby lifting inhibition on the secondary and tertiary molecules, ultimately promoting collagen synthesis.
Having identified this signaling pathway, the researchers devised an antisense oligonucleotide (ASO), a short RNA fragment, to validate its behavior. Remarkably, the ASO not only confirmed the functionality of the pathway but also mitigated liver fibrosis—excessive collagen deposition—without inducing any adverse effects. Discussions are underway regarding the potential licensing of the ASO as a therapeutic agent, with several pharmaceutical and biotech companies expressing interest.
“All the molecules in the pathway were known, but no one knew if or how they interacted. We put the pathway together, showing each step in this intracellular signaling module. That was the science of the research. The clinical message is this ASO, which can actually block liver fibrosis,” explained Jerrold Olefsky, who is a professor of medicine and assistant vice chancellor for integrative research at UC San Diego Health Sciences, as well as a senior author for the paper.
The researchers conducted their inquiries within organoids—miniature liver structures cultivated in a dish, composed of three distinct liver cell types nourished with a blend of fatty acids, fructose, and sugars known as a MASH cocktail. They observed that in healthy liver cells, a crucial protein known as TM7SF3, situated within the cell membrane, suppresses the activity of a splicing factor called hnRNPU. This factor, in turn, refrains from excising an inhibitory segment, called exon 5, from the messenger RNA (mRNA) of TEAD1, a pivotal transcription factor governing the activation of genes responsible for collagen production. By retaining exon 5, TEAD1 remains inactive, thereby preventing the activation of collagen-producing genes.
However, in the organoids exposed to the MASH cocktail, TM7SF3 levels diminish, failing to inhibit the splicing factor. Consequently, the active splicing factor removes the inhibitory exon from the transcription factor, leading to the activation of collagen-producing genes through a process known as alternative splicing.
Delving deeper into their investigation, the scientists devised an Antisense Oligonucleotide (ASO) aimed at impeding hnRNPU’s ability to excise exon 5. The ASO was engineered to bind just upstream of exon 5, where hnRNPU typically attaches. By doing so, it prevented the splicing factor from binding to the TEAD mRNA, thus impeding its excision, indicated Olefsky. When they administered the ASO to MASH-exposed mice, they predominantly observed inactive TEAD. Consequently, collagen production, as well as fibrosis, was not carried out.
“These findings show the key role of alternative splicing in shaping progression of fibrotic liver disease,” explained Roi Isaac, Ph.D., assistant project scientist, Medicine, who is also the 1st author for the paper.
The researchers stated that when ASOs are delivered intravenously, they permeate all cells throughout the body, not solely the intended ones. Interestingly, researchers discovered that within the liver, this mechanism involving hnRNPU was exclusive to stellate cells. This specificity rendered their ASO exceptionally potent and precise, exemplifying the perfect drug design.
Olefsky notes that a quarter portion of the U.S. populace suffers from MASH. Although the ASO developed by the scientists holds promise as a treatment, obtaining FDA approval would demand extensive clinical trials and potentially incur costs of up to a billion dollars.
