Science

Hepatocyte imbalance may trigger liver disease progression

Last Updated: 2006-05-26 16:20:27 -0400 (Reuters Health)

By Will Boggs, MD

NEW YORK (Reuters Health) - A decreased ratio of phosphatidylcholine (PC) to phosphatidylethanolamine (PE) in liver cell membranes predisposes mice to develop steatohepatitis leading to liver failure, according to a report in the May issue of Cell Metabolism.

"Physicians have been focused on hyperlipidemia, obesity, diabetes, and the metabolic syndrome as the main cause for steatohepatitis without mechanistic knowledge of what triggers the change from steatosis (seen in up to 15% of the population) to steatohepatitis," Dr. Dennis E. Vance from University of Alberta, Edmonton, Canada told Reuters Health. "This study provides a clue to the mechanism as well as a possible prognostic marker to predict who will develop progressive disease."

Dr. Vance and colleagues investigated the impact of different membrane PC/PE ratios on the development of steatosis and liver failure in PEMT-deficient mice fed a choline-deficient diet.

Liver damage in mouse models was independent of decreases in hepatic PC and fat accumulation, the authors report, but strongly associated with decreases in the PC/PE ratio. Further experiments indicated that the ratio of PC to PE is a key regulator of membrane integrity, with low PC/PE ratios contributing to increased membrane permeability in mouse hepatocytes.

Increasing the PC/PE ratio improved membrane integrity, the researchers note, whereas decreasing the PC/PE ratio (by inhibiting PE catabolism) increased hepatocyte damage.

Similarly, increasing the PC/PE ratio could reverse steatohepatitis in affected mice and could attenuate, but not reverse, steatosis.

"The potential relevance of these studies to human disease is indicated in a pilot study of nonalcoholic steatohepatitis (NASH) patients," the investigators write. "We found that hepatic PC/PE ratios in NASH patients were significantly lower than those in healthy human subjects."

"If the PC/PE imbalance turns out to be a central effector mechanism in mediating fatty liver disease, then one would predict that correcting the imbalance will have an important clinical role in disease management," Dr. Vance said. "Both choline and betaine - that impact on correcting the imbalance - have been used in clinical studies to treat alcohol related liver disease with some success."

"We are hopeful that these treatments in combination with other therapies -- such as anti-oxidants, for example -- may prove useful in limiting the progression of cell damage caused by the imbalance."

Dr. Vance pointed out that when they began to study deficiencies in PC biosynthesis, they were not thinking about liver disease and were surprised when their "research led to an understanding of how steatohepatitis develops in one model."

"Thus, the message that needs to be repeated is that fundamental research is the basis for understanding and the eventual treatment of diseases that are currently difficult to understand and treat."

Cell Metabolism 2006;3:321-331.