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Extracts of the resin of the guggul tree (Commiphora mukul) lower LDL (low-density lipoprotein) cholesterol levels in humans. The plant sterol guggulsterone [4,17(20)-pregnadiene-3,16-dione] is the active agent in this extract. We show that guggulsterone is a highly efficacious antagonist of the farnesoid X receptor (FXR), a nuclear hormone receptor that is activated by bile acids. Guggulsterone treatment decreases hepatic cholesterol in wild-type mice fed a high-cholesterol diet but is not effective in FXR-null mice. Thus, we propose that inhibition of FXR activation is the basis for the cholesterol-lowering activity of guggulsterone. Other natural products with specific biologic effects may modulate the activity of FXR or other relatively promiscuous nuclear hormone receptors., Cholesterol metabolism is tightly regulated at multiple levels, including its release in the form of bile acids. A negative feedback loop that decreases the rate of bile acid production by [...]

SHP is an orphan member of the nuclear hormone receptor superfamily that contains the dimerization and ligand-binding domain found in other family members but lacks the conserved DNA binding domain. In the yeast two-hybrid system, SHP interacted with several conventional and orphan members of the receptor superfamily, including retinoid receptors, the thyroid hormone receptor, and the orphan receptor MB67. SHP also interacted directly with these receptors in vitro. In mammalian cells, SHP specifically inhibited transactivation by the superfamily members with which it interacted. These results suggest that SHP functions as a negative regulator of receptor-dependent signaling pathways., The yeast two-hybrid system (1, 2) has proved useful in both the characterization of the heterodimeric interactions of members of the nuclear hormone receptor superfamily and the isolation and characterization [...]

In a screen for transcriptional regulators that control differentiation into the T cell lineage, a complementary DNA was isolated encoding a zinc finger protein (Ikaros) related to the Drosophila gap protein Hunchback. The Ikaros protein binds to and activates the enhancer of a gene encoding an early T cell differentiation antigen, CD3δ. During development, Ikaros messenger RNA was first detected in the mouse fetal liver and the embryonic thymus when hematopoietic and lymphoid progenitors initially colonized these organs; no expression was observed in the spleen or the bone marrow. The pattern of Ikaros gene expression and its ability to stimulate CD3δ transcription support the model that Ikaros functions in the specification and maturation of the T lymphocyte., T cell progenitors originate in the bone marrow of the adult and the fetal liver of the embryo and migrate to the thymus where they undergo T cell maturation or [...]

We have identified the xenobiotic receptor CAR (constitutive androstane receptor) as a key regulator of acetaminophen metabolism and hepatotoxicity. Known CAR activators as well as high doses of acetaminophen induced expression of three acetaminophen-metabolizing enzymes in wild-type but not in CAR null mice, and the CAR null mice were resistant to acetaminophen toxicity. Inhibition of CAR activity by administration of the inverse agonist ligand androstanol 1 hour after acetaminophen treatment blocked hepatotoxicity in wild type but not in CAR null mice. These results suggest an innovative therapeutic approach for treating the adverse effects of acetaminophen and potentially other hepatotoxic agents., Overdoses of acetaminophen (APAP; also known as 4'-hydroxyacetanilide, N-acetyl-p-aminophenol, and paracetamol) are the leading cause of hospital admission for acute liver failure in the United States (1). Ingestion of amounts [...]

Bile acids regulate the transcription of genes that control cholesterol homeostasis through molecular mechanisms that are poorly understood. Physiological concentrations of free and conjugated chenodeoxycholic acid, lithocholic acid, and deoxycholic acid activated the farnesoid X receptor (FXR; NR1H4), an orphan nuclear receptor. As ligands, these bile acids and their conjugates modulated interaction of FXR with a peptide derived from steroid receptor coactivator 1. These results provide evidence for a nuclear bile acid signaling pathway that may regulate cholesterol homeostasis., Cholesterol homeostasis is achieved through the coordinate regulation of dietary cholesterol uptake, endogenous biosynthesis, and the disposal of cholesterol in the form of bile acids. Bile acids are not simply [...]

Identification of a Thyroid Hormone Receptor That Is Pituitary-Specific THE NUMEROUS EFFECTS OF THYroid hormone on vertebrate tissues are thought to be mediated through binding to a nuclear receptor protein. [...]

Two Mechanisms for the Extinction of Gene Expression in Hybrid Cells The growth hormone gene is expressed only in specialized pituitary cells called somatotrophs (1) and has provided an excellent [...]

The article presents research on human physiology published in the 2007 issues of the periodicals "Cell Metabolism" and "Proceedings of the National Academy of Sciences". Three members of the fibroblast growth factor (FGF) family, namely FGF19, FGF21, and FGF23, have emerged as metabolic hormones that regulate bile acid biosynthesis, phosphate and calcium homeostasis, and concentrations of serum glucose and triglycerides. Research teams led by T. Inagaki and M. K. Badman show that FGF21 expression in mice is activated by a nuclear hormone receptor.

The article provides perspective on research reported by Feng et al. elsewhere in the issue on disruption of circadian rhythms, as experienced by shift workers, and a molecular mechanism that links such disruption to steatosis or nonalcoholic fatty liver disease, said to be a driver of metabolic dysregulation. The research team's studies of genome-wide localization of histone deacetylase 3 (HDAC3) binding sites in mouse liver are discussed.

Lysosomes are crucial cellular organelles for human health that function in digestion and recycling of extracellular and intracellular macromolecules.We describe a signaling role for lysosomes that affects aging. In the worm Caenorhabditis elegans, the lysosomal acid lipase LIPL-4 triggered nuclear translocalization of a lysosomal lipid chaperone LBP-8, which promoted longevity by activating the nuclear hormone receptors NHR-49 and NHR-80.We used high-throughput metabolomic analysis to identify several lipids in which abundance was increased in worms constitutively overexpressing LIPL-4. Among them, oleoylethanolamide directly bound to LBP-8 and NHR-80 proteins, activated transcription of target genes of NHR-49 and NHR-80, and promoted longevity in C. elegans.These findings reveal a lysosome-to-nucleus signaling pathway that promotes longevity and suggest a function of lysosomes as signaling organelles inmetazoans. [ABSTRACT FROM AUTHOR]

We have identified the xenobiotic receptor CAR (constitutive androstane receptor) as a key regulator of acetaminophen metabolism and hepatotoxicity. Known CAR activators as well as high doses of acetaminophen induced expression of three acetaminophen-metabolizing enzymes in wild-type but not in CAR null mice, and the CAR null mice were resistant to acetaminophen toxicity. Inhibition of CAR activity by administration of the inverse agonist ligand androstanol 1 hour after acetaminophen treatment blocked hepatotoxicity in wild type but not in CAR null mice. These results suggest an innovative therapeutic approach for treating the adverse effects of acetaminophen and potentially other hepatotoxic agents. [ABSTRACT FROM AUTHOR]

Mitogen-activated protein kinase 6 (MAPK6) is an atypical MAPK. Its function in regulating cancer growth remains elusive. Here, we reported that MAPK6 directly activated AKT and induced oncogenic outcomes. MAPK6 interacted with AKT through its C34 region and the C-terminal tail and phosphorylated AKT at S473 independent of mTORC2, the major S473 kinase. mTOR kinase inhibitors have not made notable progress in the clinic. Our identified MAPK6-AKT axis may provide a major resistance pathway. Besides repressing growth, inhibiting MAPK6 sensitized cancer cells to mTOR kinase inhibitors. MAPK6 overexpression is associated with decreased overall survival and the survival of patients with lung adenocarcinoma, mesothelioma, uveal melanoma, and breast cancer. MAPK6 expression also correlated with AKT phosphorylation at S473 in human cancer tissues. We conclude that MAPK6 can promote cancer by activating AKT independent of mTORC2 and targeting MAPK6, either alone or in combination with mTOR blockade, may be effective in cancers.

Lysosomes are crucial cellular organelles for human health that function in digestion and recycling of extracellular and intracellular macromolecules. We describe a signaling role for lysosomes that affects aging. In the worm Caenorhabditis elegans, the lysosomal acid lipase LIPL-4 triggered nuclear translocalization of a lysosomal lipid chaperone LBP-8, which promoted longevity by activating the nuclear hormone receptors NHR-49 and NHR-80. We used high-throughput metabolomic analysis to identify several lipids in which abundance was increased in worms constitutively overexpressing LIPL-4. Among them, oleoylethanolamide directly bound to LBP-8 and NHR-80 proteins, activated transcription of target genes of NHR-49 and NHR-80, and promoted longevity in C. elegans. These findings reveal a lysosome-to-nucleus signaling pathway that promotes longevity and suggest a function of lysosomes as signaling organelles in metazoans., (Copyright © 2015, American Association for the Advancement of Science.)