Protein’s levels in placenta may be key for diagnosing, treating ICP

Intrahepatic cholestasis of pregnancy (ICP), a liver disorder that can affect a pregnant woman, leads to abnormally high levels of a protein called ERp29 in the developing placenta, a study reports.

High levels of this protein appear to interfere with the placenta’s ability to connect to the uterus and provide nutrients for the developing fetus, findings show, and researchers suggest this protein may be a useful target to diagnose and treat ICP.

The study, “The role of ERp29/FOS/EMT pathway in excessive apoptosis of placental trophoblast cells in intrahepatic cholestasis of pregnancy,” was published in Placenta.

Higher levels of ERp29 seen in placenta and blood of women with ICP

Cholestasis refers to a stalling of bile, a substance made by the liver that normally flows out to the intestines through a series of tubes called bile ducts. As excess bile accumulates in the liver and leaks into the bloodstream, it can cause liver damage as well as itching and other disease symptoms.

ICP is a specific form of cholestasis that can appear in the later stages of pregnancy due to high levels of certain hormones, which can affect bile flow. It is associated with an increased risk of adverse fetal outcomes, including preterm birth (before 37 weeks of gestation), and stillbirth.

In prior research, scientists in China found that ICP is marked by increased levels of a protein called ERp29 in the placenta, the structure that grows in the uterus alongside a developing fetus.

Normally, the placenta attaches to the wall of the uterus — placental cells grow into the uterus to form connections with the pregnant woman’s bloodstream. Through this connection, the fetus is nourished with oxygen and nutrients.

ERp29 is essential for protein folding, transport, and secretion, and its production rises in response to a specific type of cellular stress. While ERp29 has been linked to “a series of cellular processes and diseases,” the researchers wrote, its role in ICP remains unclear.

By analyzing tissue samples from 66 pregnant women with ICP and 74 women having a healthy pregnancy, the same team confirmed that ICP patients have significantly higher ERp29 levels in both their blood and placental tissues. The placenta of women with ICP also showed significantly more cell death.

Similar changes were observed in placental tissues of a rat model of ICP, suggesting that “ERp29 may have auxiliary diagnostic value for ICP,” the team wrote.

Elevated levels affect processes tied to blood and oxygen exchange

Then, through a battery of studies done in rat and cell models, the researchers showed that high levels of ERp29 suppress a cellular process called the epithelial-to-mesenchymal transition (EMT), which is critically important for the placental cells that burrow through the uterus.

“When EMT is inhibited, the invasion ability of trophoblasts [placenta cells] during pregnancy is insufficient, which often leads to the impaired development of placental vascular network,” the scientists wrote, risking the healthy exchange of oxygen and nutrients between the mother and fetus.

Specifically, high ERp29 levels were found to reduce the levels of FOS, a protein that regulates cell growth, maturation, and EMT. In turn, inducing increased FOS production was able to reverse ERp29 effects on cell EMT migration and invasion.

The scientists further demonstrated that lowering ERp29 levels in pregnant rats with ICP led to an easing of clinical symptoms and better placental health, with more regular EMT and less placental cell death.

This suggests that targeting the ERp29 protein may help to lower a risk of complications related to this form of pregnancy-related liver damage.

Together, these findings highlight that ERp29 “has a regulatory mechanism to mediate [placental cell death] in the occurrence and development of ICP,” and targeting this protein “can provide a new possibility for the diagnosis and treatment of clinical ICP,” the team concluded.

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