Imbalance may trigger advance from fatty liver to liver failure

An imbalance in the lipid content of the liver appears to trigger the downward spiral that leads some with fatty liver disease to advance to full-blown liver failure, according to a new study in the May Cell Metabolism.

Researchers at the University of Alberta, Edmonton found evidence in mice that a disproportionate ratio of two phospholipid constituents of cell membranes undermines membrane integrity and influences progression to the condition known as nonalcoholic steatohepatitis or NASH.

What's more, a preliminary study examining the liver composition of patients with the condition found that they too exhibit disproportionate levels of the phospholipids. The findings in mice therefore suggest that dietary or other interventions that maintain a healthy ratio of phosphatidylcholine (PC) to phosphatidylethanolamine (PE) might provide new approaches for managing NASH.

"When the PC to PE ratio in the membrane is disturbed, it appears to allow leakage of enzymes and other materials out into the bloodstream," said study author and biochemist Dennis Vance. Vance and the study's first author Zhaoyu Li are also affiliated with the Canadian Institutes of Health Research Group on the Molecular and Cell Biology of Lipids.

"The two phospholipids have different shapes," Vance added. "If you don't have a certain proportion of cylindrical and inverted cone-shaped phospholipids, they don't pack as well and leakage results." The loss of membrane integrity damages the cell, leading to the inflammatory response characteristic of NASH, they found.

NASH affects 2 to 5 percent of people in the U.S., according to the National Institute of Diabetes and Digestive and Kidney Diseases Another 10 to 20 percent of Americans have abnormal deposits of fat in their livers.

The rapid rise in obesity is responsible for this epidemic of liver disease associated with insulin resistance and metabolic syndrome, the researchers said.

The growing trend has the potential to lead to a worrying increase down the line of people in need of liver transplants, said study author Andrew Mason of the University of Alberta's department of medicine. Yet little is known concerning the requirements for the disease progression.

PC in the liver is produced either from the essential nutrient choline or by so-called phosphatidylethanolamine N-methyltransferase (PEMT), an enzyme that converts PE to PC. Choline is a member of the B family of vitamins and is found in organ meats, wheat germ, leafy vegetables, and egg yolks.

The team earlier found that mice lacking PEMT, when fed a diet deficient for choline, developed liver failure. The researchers now demonstrate that the liver failure observed in the choline-deficient mutant mice results from a loss of membrane integrity caused by a decreased PC to PE ratio.

"The ratio of PC to PE is decreased by more than 50 percent, which leads to loss of membrane integrity with ballooning hepatocytes," the most prevalent cell type found in the liver, the researchers reported. "The resultant cell damage recruits an inflammatory response typical of steatohepatitis."

In contrast, mice lacking PEMT and a second protein required for the secretion of PC into bile escape liver failure by maintaining a normal ratio of membrane components. Bile is a fluid produced by the liver that plays an important role in the intestinal digestion and absorption of fats.

"The rise in overweight children and adults has left us with a huge number of people at-risk for liver disease and we've had no way of telling who will progress from simply having fat in the liver to the fat and inflammation of steatohepatitis," Mason said. "We've had nothing to guide these patients.

"We had not conceived that a phospholipid ratio imbalance would have such an effect," he continued. "The major importance of the findings has to be that we now have new avenues for investigation and possible treatment to restore choline balance--to try to prevent the problem in the first place."

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The researchers include Zhaoyu Li, Luis B. Agellon, Theresa M. Allen, Larry Jewell, Andrew Mason, and Dennis E. Vance of the University of Alberta in Edmonton, Alberta, Canada; Masato Umeda, of Kyoto University in Kyoto, Japan.

This research was supported by grants from the Canadian Institutes of Health Research (CIHR). Z. Li is a CIHR/HSFC (Heart and Stroke Foundation of Canada) Strategic Training Fellow in Stroke, Cardiovascular, Obesity, Lipid, Atherosclerosis Research (SCOLAR) supported by a grant from Astra Zeneca. D. Vance holds the Canada Research Chair in Molecular and Cell Biology of Lipids and is a Scientist of the Alberta Heritage Foundation for Medical Research.

Li et al.: "The ratio of phosphatidylcholine to phosphatidylethanolamine influences membrane integrity and steatohepatitis." Publishing in Cell Metabolism 3, 321331, May 2006. DOI 10.1016/j.cmet.2006.03.007 www.cellmetabolism.org


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