Infants and children with liver diseases are more likely to succumb to heart failure than to liver failure, and in fact, the heart’s health often improves after a liver transplant. New research from the Annak lab, published in the journal Hepatology, demonstrates that excess bile acids in the liver cause metabolic change and stress in the heart. “That there is a connection between liver and heart disease has been known for hundreds of years,” said Dr. Sayee Anakk, assistant professor of Molecular and Integrative Physiology, whose lab studies the regulation of metabolic signaling in the liver. “High levels of bile acids in diseased livers is associated with consequent cardiac dysfunction, but we do not know the mechanisms responsible for that connection.”
Using mouse models that resembled the clinical cholestasis, or very high levels of bile acids in the liver, Anakk, with graduate student and first author Bhoomika Mathur, observed the effect of cholestasis on a key indicator of heart health.
“Healthy hearts metabolize fat as its main energy source to pump blood,” said Mathur. “Whereas, a stressed heart exposed to high levels of bile acids, switches to glucose as its energy source, and this switch in fuel metabolism is seen during heart disease.”
The researchers also discovered that increased bile acids suppressed a master regulator of mitochondrial function, Pgc1α, that is central for regulating fat breakdown. Thus, suppression of this key gene can result in reprogramming the substrate preference and heart failure.The researchers named this Bile acid mediated effect on the heart: “Cholecardia.”
“The discovery that excess bile acid affects heart metabolism was a big step forward, since this could allow us to identify potential treatment options,” said Anakk.
Based on these findings, Ms. Mathur tested whether reducing bile acid levels would be sufficient to reduce the heart defect. They treated the mouse model with Cholestyramine, an FDA approved drug to treat high cholesterol that can remove bile acids from the blood, and found that the use of Cholestyramine protects against heart failure.
The team, with Dr. Moreshwar Desai, a pediatricianatTexasChildren’sHospitalandfirst author with Bhoomika Mathur, undertook this study. “The curative potential is exciting, but we have many more questions for bile acid’s role in cardiac malfunctioning,” said Anakk.
