Anti-fibrotic therapy remains an unmet medical need in human chronic liver disease. A research team led by Professor Norifumi Kawada, from Osaka City University (OCU), reported the anti-fibrotic function of globin family members in hepatic stellate cells (HSCs), the main cell type involved in liver fibrosis. In mice with advanced liver fibrosis, injection of myoglobin (MB), (neuroglobin) NGB and (cytoglobin) CYGB can suppress liver inflammation and fibrosis.
The functions of members of the globin family have been widely studied, focusing mainly on the specific tissues in which these proteins are expressed: hemoglobin (HB) in erythrocytes, MB in muscle cells, NGB in nerve tissue and CYGB in pericytes and fibroblasts. Beyond the well-established respiratory oxygen-binding functions of heme-containing proteins, all globins are also known to be involved in the regulation of harmful reactive oxygen species (ROS), protecting cells from oxidative stress.
“Liver fibrosis occurs after repetitive and long-lasting injury or inflammation of the liver. This injury is accompanied by an accumulation of ROS that activate HSCs, followed by collagen production,” explains Dr. Kawada.
Together with Dr. Le Thi Thanh Thuy, PhD student Vu Ngoc Hieu and colleagues, Dr. Kawada observed that when culturing human HSCs under globin treatments, MB, NGB and CYGB enter cell organelles, drive out harmful intracellular ROS and reduce the direct signal regulating collagen production. “The results showed that the antioxidant capacity of globins was superior to that of the well-documented glutathione and even vitamin C,” continues Dr. Kawada.
This is great news for three members of the globin family, but what happened to HB? “We noticed that hemoglobin was not entering the cell,” says Dr. Thuy, “we suspect this is due to size, as HB is 4 times larger than its monomeric siblings.”
In the next series of experiments, Dr. Kawada and his group generated a mouse model of advanced liver fibrosis using chemical agents and applied MB, NGB and CYGB by intravenous injection. Interestingly, the therapeutic protein significantly suppressed liver inflammation and fibrosis without any side effects. Doctoral student Hieu points out, “In addition to the liver, we focused on possible side effects with the neighboring kidney. Creatinine levels remained normal throughout treatment.”
With this finding, which was published in the journal redox biology, the research team hopes to set foot on a potential therapy for liver fibrosis in the near future.
1. Hepatic fibrosis
Liver fibrosis is a scarring response to chronic liver injury and often results in cirrhosis, liver failure, portal hypertension, and hepatocellular carcinoma.
2. Hepatic stellate cells
Hepatic stellate cells reside in the space of Disse, between hepatocytes and sinusoidal endothelial cells, in the liver. Hepatic stellate cells are the primary collagen-producing cells, and hepatic stellate cell activation is a key issue in liver fibrosis.
3. Reactive oxygen species
Reactive oxygen species (ROS) include several chemically reactive molecules derived from oxygen. The state of excessive amount of ROS calls oxidative stress, which can lead to significant damage to cellular structures.
4. COL1A1 Promoter
The COL1A1 promoter region is a DNA segment located upstream of a gene encoding COL1A1. This region controls the initiation of transcription from DNA to mRNA, which is ultimately translated into the COL1A1 protein.
5. Cellless system
The cell-free system is referred to as platforms for testing biological systems in a cell-free environment.
Glutathione is a well-known antioxidant that is able to prevent damage to important cellular components caused by reactive oxygen species such as free radicals, peroxides, lipid peroxides and heavy metals.
7. Human Globins
Globins are a superfamily of heme-containing globular proteins involved in oxygen binding and/or transport. Prominent members include hemoglobin, myoglobin, neuroglobin, and cytoglobin.