We also thank the Colorado Center for AIDS Research

Laboratory Core for access to FACS. “
“Nuclear receptors are ligand-activated transcriptional regulators of several key aspects of hepatic physiology and pathophysiology. As such, nuclear receptors control a large variety of metabolic processes including hepatic lipid metabolism, drug disposition, bile acid homeostasis, as well as liver regeneration, inflammation, fibrosis, cell differentiation, and tumor formation. Derangements of nuclear receptor regulation and genetic variants may contribute to the pathogenesis and progression of liver diseases. This places nuclear receptors into the frontline for novel therapeutic approaches for a broad range of hepatic disorders and diseases including cholestatic and fatty liver disease, drug hepatotoxicity, viral hepatitis, liver fibrosis, and cancer. (HEPATOLOGY 2011;.) Nuclear receptors Ixazomib (NRs) are

a superfamily of transcription factors that respond to natural and/or synthetic ligands including endogenous compounds such as steroid hormones, fatty acids, bile acids, vitamins, and cholesterol or exogenous ligands including various drugs and toxins.1 NRs are best described as sensors for small molecules present in the intracellular milieu, thereby translating needs of the cellular and body environment to genomic levels.1 The NR family is the largest group of transcriptional regulators in humans and consists of 48 family

members in humans.1 The glucocorticoid Proteases inhibitor this website receptor and estrogen receptor α were the first NRs cloned in 1985 and 1986, respectively. Together with other steroid hormone receptors (i.e., for mineralocorticoids, androgen, and progesterone), thyroid hormone receptor, receptors for vitamin D and vitamin A, these high-affinity NRs belong to the classical endocrine receptors (Supporting Table 1) and ligands for these receptors have been used therapeutically in daily clinical practice for decades.2 Based on sequence homology of endocrine receptors, numerous other NRs have been cloned subsequently. However, natural ligands and functions for many of these NRs were initially unknown and therefore this class of NRs has been termed “orphan NRs.” For some of the initially orphanized NRs natural ligands and ligand-dependent regulation have meanwhile been clarified and thus they became “adopted”2 (Supporting Table 1). Because they regulate lipid, glucose, and bile acid homeostasis, receptors of this class are the focus of this review as one of the most promising and investigated drug targets for metabolic disorders. In a subgroup of this class of NRs, a specific ligand could be identified, but ligand-dependent regulation has not been firmly established. These receptors are termed “enigmatic” adopted orphans2 (Supporting Table 1) and are tightly involved in hepatic metabolism and also have considerable potential as pharmacological targets.