Antihyperlipidemic Activity of Gut-Restricted LXR Inverse Agonists.

Hyperlipidemia and increased circulating cholesterol levels are associated with increased cardiovascular disease risk. The liver X receptors (LXRs) are regulators of lipogenesis and cholesterol transport and have been validated as potential therapeutic targets for the treatment of atherosclerosis. However, efforts to develop LXR agonists to reduce cardiovascular diseases have failed due to poor clinical outcomes-associated increased hepatic lipogenesis and elevated low-density lipoprotein (LDL) cholesterol (C).

The role of REV-ERB in NASH.

REV-ERBs are atypical nuclear receptors as they function as ligand-regulated transcriptional repressors. The natural ligand for the REV-ERBs (REV-ERBα and REV-ERBβ) is heme, and heme-binding results in recruitment of transcriptional corepressor proteins such as N-CoR that mediates repression of REV-ERB target genes. These two receptors regulate a large range of physiological processes including several important in the pathophysiology of non-alcoholic steatohepatitis (NASH).