HSD17B13 isoform regulation in MASH
VCU investigators describe their research on HSD17B13 isoform regulation in MASH in a recent paper published in the Journal of Hepatology Reports.
Background and goal
Inside the liver, a gene called HSD17B13 can make several different RNA versions. Some of these versions skip a small piece called exon 2. Scientists have noticed that these “skipped” versions tend to be lower in people with liver disease. One version in particular, Variant B, doesn’t make a working protein, but it might still play an important role in controlling the gene. So, the researchers set out to see if this RNA could help explain why some people seem to be protected from liver damage.
What the researchers did
To explore this, the team looked at liver samples from three groups: healthy people, people with metabolic dysfunction-associated steatotic liver disease (MASLD), and those with the more severe form, metabolic dysfunction-associated steatohepatitis (MASH). They measured the different RNA versions made by the HSD17B13 gene. They also ran lab experiments using liver cells, where they added either Variant A or Variant B. Then they checked what happened to RNA levels, protein production, and how the RNA was shaped. To mimic the kind of stress seen in fatty liver disease, they exposed the cells to oleic acid.
What they found
They found that the RNA versions that skip exon 2, especially Variants B and G, were much lower in people with liver disease. When they added Variant B to liver cells in the lab, it almost completely shut down the usual HSD17B13 RNA. Interestingly, it still didn’t produce a detectable protein. Instead, the RNA folded into stable shapes, suggesting it may act more like a regulator, controlling the gene’s activity rather than making a protein itself.
What this means
Variant B seems to work like a molecular switch that turns down HSD17B13 activity. When levels of this RNA drop, the liver may be more at risk for damage. If scientists can find a way to restore it, this could become a new strategy to protect the liver in people with MASH, by adjusting gene activity without changing the DNA itself.
Who did the research?
The study was led by John Min of Virginia Commonwealth University and University of Virginia. Co-authors from VCU include Mulugeta Seneshaw and Faridoddin Mirshahi, along with co-corresponding authors Hae-Ki Min and Arun J. Sanyal, who directs the VCU Institute for Liver Disease and Metabolic Health.
A provisional patent has been filed based on these findings. The invention introduces RNA-based therapeutic methods to treat metabolic liver diseases through the modulation of HSD17B13 alternative splicing and non-coding RNA regulation.