The research results have led the team to predict that drugs targeted at the liver may in future help lower elevated lipids and help in the battle with cardiovascular disease.
The prevalence of the high-cholesterol, high-fat Western diet has accelerated an epidemic of atherosclerotic cardiovascular disease, and it is now the leading cause of death in industrialized nations. It has become increasingly acknowledged that understanding interactions between genes and the reality of what most people eat is critical for effective treatment.
According to research, the nucleus of liver cells has molecules called LXRs (for Liver X Receptors) which have emerged in the last few years to be crucial regulators of cholesterol and lipid metabolism.
Mitchell Lazar, MD, PhD, Director of the Institute for Diabetes, Obesity, and Metabolism at Penn, explains that conventional wisdom, borne out of previous drug-development studies, was that LXRs are good in terms of decreasing atherosclerosis and bad in terms of increased triglycerides, but 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.
Lazar and colleagues surmised that a targeted approach might work better. They 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, and they found that LXR, which senses fat in the liver, could adjust the consequences of eating a high-fat Western diet.
The research 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.
In conclusion the researchers say that increased expression of LXR in the liver is beneficial in a body full of natural molecules that bind to the LXR receptor, generated by the Western diet, but not when on a low-fat, healthy diet, this benefit is lost however when a potent drug is added to the system.
Lazar says this is because a different set of target genes is turned on by the synthetic molecule, as opposed to the natural molecule, and it is possible that what is needed are drugs that mimic the natural ligand rather than the heavy handed potency of pharmaceutical drugs that powerfully activate LXRs throughout the body. The hope is that these will decrease cholesterol without increasing triglycerides.
One of the main questions which researchers face when they study 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.
Lazar says that if natural variations are found in the amount of LXR in peoples livers, it may help explain why there is a difference in susceptibility to high cholesterol and heart disease, depending on diet, and the answer is probably genetic. Their 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.
The findings are published in the May 2005 issue of Cell Metabolism.
med.upenn/