| Description |
The liver X receptors (LXRs) are important regulators of lipid and cholesterol metabolism and control diverse pathways in development, reproduction, metabolism, immunity and inflammation. Thus, LXRs have potential as therapeutic targets for diseases as diverse as lipid disorders, atherosclerosis, chronic inflammation, cancer and neurodegenerative diseases. Taking a genetic approach centered on the single LXR gene nr1h3 in zebrafish, we tested the hypothesis that modulating intestinal LXR activity in intestinal lipid trafficking alters the development of atherosclerosis. Our lab previously demonstrated that intestinal LXR over-expression delays the transport of absorbed lipids, mitigating the development of dyslipidemia and hepatic steatosis (fatty liver) when animals are fed high-fat and high- cholesterol diets. To investigate the potential of adult zebrafish for atherosclerosis, a 10-month feeding experiment using a control diet and a high cholesterol diet was conducted with wild-type (WIK strain), XR knock -out (nr1h3z101a/z102a), and intestinal LXR-over-expressing animals (Tg(fabp2:EGFP-nr1h3)z103). Here we found that when fed a high-cholesterol diet, nr1h3z101 a/z102 a mutants exhibited higher plasma cholesterol levels and higher levels of cholesterol and cholesteryl esters in the liver. Tg(fabp2:EGFP-nr1h3)z103 animals were protected from this steatosis. This suggests that enterocyte-limited LXR activation prevents transport and delivery of cholesterol to other organs. To understand the transport of lipid absorption and to examine intravascular lipid metabolism using live imaging, an experiment was performed using 6 days post-fertilization larvae. When Tg(fabp2:EGFP-nr1h3)z103, nr1h3z101a/z102a and WIK larvae were fed with a solution of triolein (a triglyceride), cholesteryl oleate(a cholesteryl ester), and the cholesteryl ester conjugate to the fluorescent fatty acid analog BODIPY-undecanoate (CE11-BODIPY; a fluorescent molecule to track lipids), we found that intestinal over-expression of LXR delayed the appearance of fluorescent lipids in the vasculature. Understanding how LXR regulates handling of intestinal lipids provides an important step toward developing new therapies to treat therosclerosis while avoiding lipid production in the liver. |
