Health
Bile disruption associated with liver carcinoma
Significant molecular switch discovered, reveals new opportunities for treatment strategies
A recent study unveils how a crucial disruption in bile acids — substances produced by the liver to assist in fat digestion — can instigate liver ailments, including hepatocellular carcinoma (HCC), the most prevalent type of liver cancer. By uncovering a major molecular switch that oversees bile regulation, the research illuminates potential therapeutic avenues for liver cancer.
The results were released this month in Nature Communications.
A distinctive role of the liver is to create bile, which serves as a natural detergent, disassembling fats into smaller particles for easier absorption by the cells lining the small intestine. In addition to its detergent function, bile acids — a key element of bile — also perform a hormone-like role that regulates various metabolic processes. The study’s corresponding author, Yingzi Yang, a professor of developmental biology at the Harvard School of Dental Medicine, examined the intricate regulation of bile acid production and how disruption in this strict control contributes to liver damage, inflammation, and ultimately HCC.
Yang and her team at HSDM have dedicated years to exploring cell signaling. One particular pathway they investigate is the Hippo/YAP pathway — a signaling mechanism essential for managing cell growth associated with cancer.
Yingzi Yang.
Photo by Tony Rinaldo
“In this investigation, we found that YAP fosters tumor development with an unexpected function in regulating bile acid metabolism. Instead of promoting cell proliferation as anticipated, YAP serves as a suppressor, hampering the activity of an essential bile acid sensor known as FXR,” she explained.
YAP activation hinders FXR (Farnesoid X receptor), a nuclear receptor critical for bile acid equilibrium. This leads to excessive bile acid production that accumulates in the liver, which causes fibrosis and inflammation, ultimately resulting in liver cancer.
Counteracting YAP’s suppressive activity — either by boosting FXR functionality or facilitating bile acid excretion — could avert this detrimental cycle, as per the researchers. In experimental models, activating FXR, inhibiting HDAC1 that facilitates YAP’s repressive function, or enhancing the expression of a bile acid transport protein (BSEP), all contributed to a decrease in liver injury and cancer progression.
“With this discovery, it could pave the way for pharmacological interventions that stimulate FXR, which is incredibly promising,” Yang stated.
According to Yang, these findings carry further implications as more is uncovered regarding how YAP shapes metabolic regulation by managing nutrient sensing. Yang’s pursuit of this function originated from her extensive work in cell signaling within liver biology and oncology. She is also affiliated with the Dana-Farber/Harvard Cancer Center.
The Yang Laboratory employs molecular, cellular, genetic, and genomic methodologies to probe the essential roles of cell signaling in embryonic development and adult physiology. Their investigations concentrate on the mammalian skeleton and liver to delve into human biology and unravel the fundamental pathophysiological mechanisms of diseases, including cancer.
This research was partially funded by the National Institutes of Health and the National Cancer Institute.