Rice University researchers are finding ways to extend the lives of over 17,000 Americans on the wait list for a liver transplant. By studying metabolic breakdown in liver cells during late-stage cirrhosis, they are finding clues that may lead to treatments that delay liver failure and lessen the number of patients who die while waiting for a new liver. Their most recent study was published in the Journal of Hepatology and was conducted in collaboration with the University of Texas MD Anderson Cancer Center, the University of Pittsburgh, Children’s Hospital of Pittsburgh, and the University of Nebraska Medical Center. According to lead researcher Deepak Nagrath from Rice University, “There’s never been a clear understanding of what causes liver cells to stop working during the final stages of cirrhosis. Our goal was to probe the metabolic processes inside liver cells in this stage of the disease to better understand what causes them to fail.”
To achieve this goal, the three stages of liver disease were studied: 1) steatosis, marked by fat buildup, 2) fibrosis, marked by collagen fiber deposition, and 3) cirrhosis, marked by inflammation and liver cell death. Gene expression of patients with chronic liver failure and a unique animal model were used to study energy metabolism during the three stages. “Most models cannot mimic what actually occurs in humans, but this one, which uses rats, captures all of the features, particularly the pathological features, that occur in humans,” said Dr. Nagrath. Ira Fox and Alejandro Soto-Gutierrez at the University of Pittsburgh’s McGowan Institute for Regenerative Medicine generated the rats used in the study.
The main focus of the study was ATP production. Usually, when hepatocytes are healthy, ATP is produced through oxidative phosphorylation; when liver cells become diseased, glycolysis becomes more prominent because oxidative phosphorylation cannot meet the high energy demands of the stressed cells. Since glycolysis is less efficient than oxidative phosphorylation, hepatocytes cannot sustain high levels of energy production and become dysfunctional. “It’s well-known that energy production from [oxidative phosphyorylation] goes down during cirrhosis, and many people had assumed that this was the primary driver of metabolic failure,” said Nagrath. “While we did find that mitochondrial production decreased… it didn’t change that much. Glycolysis, on the other hand, changed a great deal.”
Nagrath indicated that a new strategy for treating patients with cirrhosis could target the glucose pathway to boost glycolytic energy production and sustain patients for longer. However, he cautions that “it would only apply to patients in the final stage of liver disease, but if such treatments did prove effective, they could extend the lives of some people who are awaiting transplants.”