The researchers found in mice that accumulation of cholesterol in the liver depletes a powerful antioxidant. The depleted cells are left sensitive to inflammatory factors that cause damage to the liver, they found. The buildup of other forms of fat in the liver, including free fatty acids and triglycerides, were insufficient to spark the events leading to worsening disease.
The findings suggest a key role for the type, as opposed to the amount, of fat in susceptibility to the liver condition known as nonalcoholic steatohepatitis (NASH), said José Fernandez-Checa and Carmen García-Ruiz of Consejo Superior de Investigaciones Científicas (CSIC) in Barcelona.
"To avoid the progression of liver disease, it may be important to eat less and be more conscious of the lipid content of the diet, particularly cholesterol," Fernandez-Checa said. Supplements that boost levels of glutathione--the antioxidant that becomes depleted in animals whose livers accumulate cholesterol--might also be beneficial, he added.
"These data also support a potential therapeutic role of statins in NASH development," he added. Statins are a class of drugs used to lower cholesterol in those at risk of cardiovascular disease.
Characterized by fat accumulation, inflammation, and liver damage, NASH affects 2%–5% percent of Americans. An additional 10%–20% percent of Americans have fat in their liver, but no inflammation or liver damage. Both conditions are becoming more prevalent, possibly due to the rise of obesity.
The accumulation of lipids in the liver cells, mostly in the form of fatty acids and triglycerides, had been considered the first step in the development of fatty liver disease, the researchers said. However, disease progression usually does not occur in the absence of a second hit that promotes oxidative stress, inflammation, cell death, and fibrosis.
In the current study, the researchers examined the connection between fat type and liver disease progression in mice with high levels of particular lipids in the liver as a result of their diet or genetic modifications that left them obese or unable to handle cholesterol properly.
In every case, mice with high levels of cholesterol in their livers became increasingly susceptible to two inflammatory factors known as cytokines, they found. The cholesterol accumulated specifically in the cellular powerhouses known as mitochondria, where it caused a drop in glutathione. Treatments that selectively depleted liver cells of glutathione produced symptoms that mirrored the effects of high liver cholesterol, they reported.
In obese mice, treatment with the cholesterol-lowering drug Atorvastatin prevented the cholesterol increase in mitochondria and restored antioxidant levels, offering protection from liver damage.
The new findings represent some of the first evidence for a role of cholesterol in delivering the "second hit" that leads to full-blown NASH, Fernandez-Checa said.
Earlier studies that found a poor correlation between blood cholesterol levels and fatty liver disease had led to some doubt about cholesterol's role, he added. Cholesterol metabolism is a complicated process, however, such that blood levels might not always reflect the amount of cholesterol in the liver, he said.
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