2050-LB: The Effect of Pharmacological Activation of Liver X Receptor (LXR) in the Heart of Obese Mice

Even though fatty acids (FAs) are the main source of energy for cardiomyocytes, in pathological conditions heart shifts its metabolism toward increased glucose reliance, which leads to excess accumulation of FAs in the form of triglycerides (TGs) and cardiac dysfunction. Therefore, we have investigated the role of liver X receptor (LXR), a nuclear receptor that regulates lipid and glucose homeostasis, in cardiac muscle during progressive obesity. As a model we used 8-week-old, male, hyperphagic MC4R knockout mice (MC4RKO), and wildtype C57BL/6J mice (WT) as a control, placed on either standard laboratory diet (Chow) or high-fat, high-fructose, high-cholesterol western diet (WD) for additional 8 weeks. Some of the WD-fed mice had their food supplemented with LXR activator, GW3965. LXR activation significantly decreased whole body and fat mass in both WT and MC4RKO mice which was accompanied by improved glucose tolerance and insulin sensitivity as indicated by glucose tolerance test and HOMA-IR score. LXR activation significantly upregulated plasma free FAs content in WT animals, decreased plasma TGs level in MC4RKO mice, and did not affect plasma cholesterol. We therefore investigated if plasma lipids changes affected cardiac metabolism. Interestingly, LXR activation significantly decreased expression of lipogenic factors, such as sterol regulatory element-binding transcription factor 1 (Srebpf1), lysophosphatidylcholine acyltransferase 1 (Lpcat1), fatty acid synthase (Fasn), when compared to WD-fed WT and MC4RKO mice. Interestingly, those changes were correlated with downregulated expression of endoplasmic reticulum stress marker, activating transcription factor 6 (Atf6) and fibrotic marker, expression of collagen 1 (Col1). Summarizing, normalization of lipid metabolism by LXR activation may have protective effect on during obesity by mitigating lipogenesis.