May 16, 2005 Philadelphia, PA) – Researchers at the University of Pennsylvania School of Medicine have discovered that a molecule found in liver cells is an important link in explaining the relationship among diet, lipid levels in blood, and atherosclerosis. The research team surmises that drugs targeted at the liver may one day help lower elevated lipids and battle cardiovascular disease. Mitchell Lazar, MD, PhD, Director of the Institute for Diabetes, Obesity, and Metabolism at Penn, and colleagues report their findings in the May 2005 issue of Cell Metabolism.
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. (Click on thumbnail to view full-size image). “The conventional wisdom–borne out of drug-development studies done before this paper–was 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, surprisingly, when the same transgenic mice with increased LXR were fed a high-fat/high-cholesterol diet, similar in composition to a standard Western diet, their blood cholesterol and triglyceride levels actually improved. Furthermore, the mice were protected from the atherosclerotic cardiovascular disease that normally results from this diet. However, the beneficial effect of the increased LXR levels was lost when mice were treated with the experimental drug.
The researchers concluded that increased expression of LXR in the liver is beneficial in a body full of natural molecules that bind to the LXR receptor, which are generated by the Western diet, but not when on a low-fat, healthy diet. However, this benefit is lost when a potent drug is added to the system. “The reason is that a different set of target genes is turned on by this synthetic molecule, as opposed to the natural molecule,” says Lazar. “We’re saying, maybe what we need are drugs that mimic the natural ligand rather than a sledgehammer like the potent pharmaceutical drugs that too powerfully activate LXRs throughout the body.” The hope is that these will decrease cholesterol without increasing triglycerides.
One of the main questions facing the study of complex metabolic diseases is, if two people eat a high-fat diet, why does one person’s cholesterol go up but the other’s does not. “If we find natural variations in people in the amount of LXR in their livers, this may help explain this conundrum of the difference in susceptibility to high cholesterol and heart disease, depending on diet,” says Lazar. “The answer is genetics. Our work suggests that one of the new genetic factors to pay attention to is the amount of LXR in the liver.”
The study was funded in part by the National Institutes of Health and a Bristol Myers Squibb Freedom to Discover Award in Metabolic Research. Study co-authors are Michael Lehrke, Corinna Lebherz, Segan Millington, Hong-Ping Guan, John Millar, Daniel J. Rader, and James M. Wilson, all from Penn.
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