Projects

Using genetic knockouts in mice and synthetic small molecule activators we have shown that the LXRs play important roles in limiting the progression of cardiovascular disease and they can reverse established heart disease in animal models.

Treatment with synthetic LXR agonists promotes confromational changes in LXR that increase transcriptional activity. In vivo LXR agonist treatment results in a decrease in atherosclerosis measured by the amount of lipid (red stained material) in the aorta.

Currently we are exploring links between fat/cholesterol metabolism and the inflammatory response that occurs in response to alterations in diet and to infectious agents. We have found that type I interferons induce expression of LXR and that LXR subsequently plays a role in shutting off the interferon response. Strikingly, LXR knockout mice appear to have a prolonged inflammatory response when infected with Flu virus. 

Interferon induces expression of LXR in macrophages. Macrophage LXR helps to shut off the inflammatory response and inhibit interferon signaling. 

We have developed a novel mouse model that allows reversible control of cholesterol of levels in the liver and in immune cells by driving expression of mutant version of LXR. These mice rapidly develop non-alcoholic steatohepatitis (NASH) when challenged with dietary cholesterol but disease progression can be inhibited by reactivation of LXR activity. We are currently using this model to understand the pathogenesis of NASH and other liver diseases.

Mutation of tryptophan (W) at position 441 of mouse LXR to phenylalanine (F) results in dramatic accumulation of cholesterol in the  livers of heterozygote (W/F) and homozygous W441F mice in mice fed a high cholesterol diet. Treatment with LXR agonist reverses the effect of diet.