18-20 RORα plays an important role in the regulation of metabolic pathways, particularly of lipid and steroid metabolism. 17 The effect of RORα on triglyceride homeostasis may be derived from the changes in the regulation of a number of genes that are involved in lipogenesis and fatty acid oxidation. 21-23 Recent studies have provided molecular
hints regarding the cross-talk between RORα and the network of AMPK and LXRα. LXRα suppresses the RORα-induced transcriptional expression of oxysterol 7α-hydroxylase (Cyp7b1), an enzyme that is critical for the homeostasis of cholesterol. 24, 25 Raichur et al. showed that RORα signaling is associated with regulation of the v-akt murine thymoma viral oncogene homolog 1 (AKT2)–AMPK signaling pathway. 26 Based on these observations, we hypothesized a positive role for RORα PD-1 inhibitor selleck chemical in the regulation of hepatic lipid metabolism. Here we report that RORα induces the activation of AMPK and the suppression of LXR in liver cells, thereby
leading to the beneficial effect of attenuating hepatic steatosis. ACC, acetyl-CoA carboxylase; Ad-RORα, adenovirus-RORα; AICAR, aminoimidazole carboxamide ribonucleotide; AKT2, v-akt murine thymoma viral oncogene homolog 1; AMPK, adenosine monophosphate (AMP)-activated protein kinase; ATP, adenosine triphosphate; BODIPY, boron-dipyrromethene; CA-AMPK, constitutively active AMPK; ChIP, chromatin immunoprecipitation; CS, cholesterol sulfate; Cyp7b1, oxysterol 7α-hydroxylase;
DBD, DNA binding domain; FA, fatty acid; FAS, fatty acid synthase; FFA, free fatty acid; HFD, high-fat diet; LBD, ligand binding domain; LKB1, serine–threonine kinase liver kinase B1; LXRα, liver X receptor α; LXRE, LXR response element; NADH, reduced nicotinamide adenine dinucleotide; p, phosphorylated; RORα, retinoic acid receptor–related orphan receptor α; RT-PCR, reverse transcriptase-polymerase chain reaction; SCD, stearoyl-CoA desaturase; siRNA, small interfering RNA; SREBP-1, sterol regulatory element binding protein-1; TG, triglyceride; VLDL, very low density lipoprotein. The RORα1 recombinant adenovirus was constructed IKBKE by recombination of pAdTrack-CMV encoding full-length RORα1 with an adenoviral backbone plasmid, pAdEasy-1. Information on other materials including plasmids and siRNA duplexes are described in the Supporting Materials. 1-Methyl-3-(4-pyridinyl-2-benzyl)-thiourea (JC1-38), 1-(4-benzyloxy-benzyl)-3-methyl-thiourea (JC1-40), and 1-(4-phenoxy-benzyl)-3-methyl-thiourea (JC1-42) were synthesized based on thiazolidinonde type CGP52608 as the lead compound. 18 The Surflex-Dock program in Sybyl, version 8.1.1 (Tripos Associates), was operated in Red Hat Linux 4.0 on an IBM computer (Intel Pentium 4, 2.8 GHz CPU, 1 GB) for the docking study as described in the Supporting Materials.