The high-cholesterol, high-fat so-called "Western diet" has accelerated an epidemic of atherosclerotic cardiovascular disease, the leading cause of death in industrialized nations. And, understanding interactions between genes and the reality of what most people eat are increasingly recognized as critical for effective treatment.
Molecules found in the nucleus of liver cells called LXRs (for Liver X Receptors) have emerged in the last few years as crucial regulators of cholesterol and lipid metabolism. "The conventional wisdomborne out of drug-development studies done before this paperwas that LXRs are good in terms of decreasing atherosclerosis and bad in terms of increased triglycerides," explains Lazar. Indeed, although LXR-based experimental drugs, which dramatically increase LXR activity throughout the body, reduce cholesterol levels in the blood, they also lead to high levels of triglycerides.
Surmising that a targeted approach might work better, the researchers used transgenic mice engineered to have an excess of LXR in their liver only, which gave the mice high levels of cholesterol and an increased risk of heart disease. They found that LXR, which senses fat in the liver, could adjust the consequences of eating a high-fat Western diet.
The team found that the increased liver LXR worsened levels of cholesterol and triglycerides in mice fed a normal, low-fat diet. However, surpri
Contact: Karen Kreeger
University of Pennsylvania School of Medicine