Researchers targets a molecule called hyaluronan (HA) to treat liver disease


A possible drug target for chronic liver disease has been identified by an international research collaboration involving a University of Queensland team.

Professor Matt Sweet and Dr. Divya Ramnath from UQ’s Institute for Molecular Bioscience (IMB) worked with the study’s senior author Dr. Ekihiro Seki from Cedars-Sinai in Los Angeles, to identify genes linked to the progression of chronic liver disease.

Dr. Ramnath said they helped confirm that a molecule called hyaluronan (HA), used as a marker for liver disease, also has a role in disease progression.

The metastatic spread of tumor cells is the most lethal aspect of cancer, which often occurs through enhanced vascularization.

The initiation of angiogenesis embarks with the local release of pro- and anti-angiogenic growth factors by endothelial cells (ECs).

Such release occurs in response to disease- or injury- induced inflammation.

Vascular endothelial growth factors (VEGF) and glycosaminoglycans are important regulators [1].

The VEGF- induced cytoskeleton reorganization also plays a crucial role in the angiogenic processes [23], though the intracellular signals leading to these events are not yet clear.

A series of sequential events are involved in angiogenesis including local degradation of endothelial basement membrane by the action of proteases, formation of a lumen, proliferation and migration of endothelial cells that gives rise to a functional vessel.

The chief component of the extracellular matrix (ECM), hyaluronan or hyaluronic acid (HA) promotes tumor growth by providing a loose matrix for cancer cells to migrate and adhere [4].

Since long time, the polysaccharide HA, has been used in a wide variety of medical fields as diverse as neurosurgery to cutaneous wound healing.

HA is comprised of 10,000 repeating units of (β,1→4)-D glucuronic acid-(β,1→3)-N-acetyl-D-glucosamine [5], and its molecular weight ranges from 400 Da to several MDa.

Within the ECM the degraded fragments of HA, termed as low molecular weight hyaluronan (LMW-HA), have been reported as significant regulator of angiogenesis [6].

HA has also received great attention due to multi-functional regulation on related biological functions such as inflammation, wound healing and tumor growth [7].

Previously we identified the hyaladherin, the hyaluronic acid binding protein 1 (HABP1), from rat liver using HA-affinity column chromatography [8].

We have demonstrated for the first time, that Plasmodium falciparum infected RBCs use HABP1 as a receptor to bind to human endothelial cells [9].

hyaluronan (HA)

Our studies have shown that overexpression of HABP1 in the human liver cell line HepG2 (HepR21) induces high endogenous glutathione level and enhanced cellular proliferation along with increased endogenous level of HA and intercellular HA cables [10] whereas HABP1 overexpression leads to ROS-mediated apoptosis in normal fibroblasts [1112].

The elevated level of HA is associated with hyper-proliferative and invasive tumorigenesis [1314].

Several studies are emphasizing the involvement of HA in endothelial cell proliferation, migration and new vessel formation [15].

However, very few reports are available on the effect of HA on liver sinusoidal endothelium.

In the liver, HA is synthesized mostly by the sinusoidal pericyte and the hepatic stellate cells (HSCs); while it is degraded by the liver sinusoidal endothelial cells (LSECs) [16].

The role of HABP1 in cell-adhesion is well established and in combination with HA, it facilitates the process of adhesion and de-adhesion during mitotic stages [10].

The another major adhesion molecule, β-catenin is not only one of the key molecules regulating the hepatic zonation pattern [17] but also acts as transcriptional co-regulator and an adaptor protein for cellular adhesion.

Postnatal liver growth and development is also dependent on β-catenin activity. Extensive cell proliferation occurs in the liver after birth, in conjunction with a substantial increase in β-catenin protein and its nuclear translocation [18].

In fact liver metastasis is often supported by abnormal β-catenin expression and localization [19]. β-catenin accumulation within the nucleus or cytoplasm has been found remarkably in more than half of all cancers and is related to increased tumorigenicity [20].

The biological events that couple HA and β-catenin function to angiogenesis are still unknown.

The present study has focused on identification of HA mediated cellular behaviour of liver endothelial cells involving β-catenin activation and its influence on angiogenic signals for cellular adhesion and wound healing.

We have worked on how HA stimulates endothelial cell migration and adhesion through VEGF, leading towards angiogenesis in vitro.

The cellular roles of HA are perpetrated through molecular interactions with HA-binding proteins or hyaladherins.

In particular, we have demonstrated here the role of the VEGF receptors involved in initiating the coordinated signals that leads to actin based motility and angiogenesis.

“Testing for HA levels in the blood can indicate the severity of liver disease in patients, but until now its exact role in disease progression had not been completely understood,” Dr. Ramnath said.

“Using clinical samples provided by Professor Elizabeth Powell from UQ’s Faculty of Medicine, we were able to confirm that an enzyme which makes HA was at higher levels in patients with later stages of the disease.

“This means it’s not just a marker, it’s now a potential drug target.”

Chronic liver disease is reaching epidemic proportions with up to 30 percent of the world’s population experiencing fat build up in the liver, known as non-alcoholic fatty liver disease (NAFLD).

A proportion of NAFLD patients progress to a more severe form of the disease called non-alcoholic steatohepatitis (NASH).

“NAFLD can be slowed by changes in diet but if untreated constant liver damage and inflammation can lead to a condition associated with cirrhosis and liver cancer.

“There are currently no medications to treat some forms of chronic liver disease so new drug targets are desperately needed,” Dr. Ramnath said.

Professor Sweet said it is now understood that short forms of the HA molecule could create an immune response, causing inflammation and increased severity of the disease.

“It has been very rewarding working with Dr. Seki from Cedars-Sinai, who has gone on to show that if HA production is inhibited in mice, the severity of the disease is reduced,” he said.

“This international collaboration has advanced our knowledge of this complex and prevalent disease, and the findings from this study may ultimately provide a strategy to develop much needed treatments.”

More information: Yoon Mee Yang et al. Hyaluronan synthase 2–mediated hyaluronan production mediates Notch1 activation and liver fibrosis, Science Translational Medicine (2019). DOI: 10.1126/scitranslmed.aat9284

Journal information: Science Translational Medicine
Provided by University of Queensland


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