Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0015695 (fatty liver)
 13,941 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aryl hydrocarbon receptor (AHR), identified in studies of dioxin toxicity, has been characterized as ligand-activated transcription factor involved in diverse functions including microbial defense, cell proliferation, immunity and NAD metabolism. AHR targets of the latter function are PARPs/ARTs and CD38 that are regulating glucose and lipid metabolism via NAD-dependent sirtuins. Deregulation of these pathways may facilitate obesity and age-dependent pathologies. The present commentary is focused on AHR and CD38 signaling in liver. CD38 is functioning as ectoNADase and Ca2+ mobilizing enzyme in endoplasmic reticulum and endolysosomal membranes. Deregulation of TCDD-activated AHR and CD38 may facilitate hepatic steatosis and inflammation. However, these proteins are also involved in protection against inflammation and CD38-mediated age-related decreased NAD levels that may be responsible for neurodegeneration. Further knowledge about the complexity of these pathways is needed to avoid pathologies. Therapeutic modulation of AHR and CD38 remains a challenging task.
 ...
PMID:Functions of aryl hydrocarbon receptor (AHR) and CD38 in NAD metabolism and nonalcoholic steatohepatitis (NASH). 3146 74

The aryl hydrocarbon receptor (AHR) has been characterized as multifunctional, ligand-activated transcription factor. Recently, evidence has been obtained that AHR is involved in NAD+ and energy homeostasis in cooperation with NAD+-consuming enzymes including CD38, TiPARP and sirtuins. AHR and CD38 may adversely or beneficially modulate nonalcoholic fatty liver disease (NAFLD) which is associated with obesity, a worldwide major health problem. Although nutritional status and lifestyle are the major factors involved in the prevalence of obesity and NAFLD, modulation of AHR and CD38 has been demonstrated to provide therapeutic options. For example, inhibition of hepatic CD38 and activation of AHR, e.g., by dietary flavonoids may beneficially affect NAFLD. In addition, NAFLD-associated decrease of NAD+ may be restored by administration of the NAD+ precursor nicotinamide riboside.
 ...
PMID:Modulation of aryl hydrocarbon receptor (AHR) and the NAD+-consuming enzyme CD38: Searches of therapeutic options for nonalcoholic fatty liver disease (NAFLD). 3216 17

Aryl hydrocarbon receptor (AHR) research has shifted from exploring dioxin toxicity to elucidation of physiologic AHR functions. Control of AHR functions is challenged by the fact that AHR is often involved in balancing opposing processes. Two AHR functions are discussed. (i) Microbial defense: intestinal microbiota commensals secrete AHR ligands that are important for maintaining epithelial integrity and generation of anti-inflammatory IL-22 by multiple immune cells. On the other hand, in case of microbial defense, AHR-regulated neutrophils and Th17 cells are involved in generation of bactericidal reactive oxygen species and pro-inflammatory stimuli. However, during the process of infection resolution, 'disease tolerance' is achieved. (ii) Energy, NAD+ and lipid metabolism: In obese individuals AHR is involved in either generation or inhibition of fatty liver and associated hepatitis. Inhibition of hepatitis is mainly achieved by regulating NAD+-controlled SIRT1, 3 and 6 activity. Interestingly, these enzymes are synergistically modulated by CD38, an NAD-consuming NAD-glycohydrolase. It is proposed that inflammatory responses may be beneficially modulated by AHR agonistic and CD38 inhibiting phytochemicals. Caveats in presence of carcinogenicity have to be taken into account. AHR research is an exciting field but therapeutic options remain challenging.
 ...
PMID:Aryl hydrocarbon receptor (AHR) functions: Balancing opposing processes including inflammatory reactions. 3253 8

Aryl hydrocarbon receptor (AHR) has been characterized as multifunctional sensor, integrator and ligand-activated transcription factor of the bHLH/PAS family. Regulation of inflammatory diseases and energy metabolism are among the putative functions of AHR. Challenges in AHR research include marked species differences, and cell, tissue and context dependence of AHR functions. The commentary is focused on AHR's role in the integration between energy expenditure and microbial and non-infectious inflammation, the latter exemplified by obesity-mediated nonalcoholic fatty liver disease. One of the mechanisms controlling energy-consuming inflammation is represented by a signalsome that is involved in retinoic acid-triggered neutrophil differentiation and regulation of the NADPH oxidase complex (NOX). Established signalsome components are AHR, CD38, multiple protein kinases and adaptors. To prevent chronic inflammatory diseases, the complex interplay between a range of inflammatory responses and energy expenditure must be precisely regulated. Surviving an infection requires both pathogen clearance and tissue protection from inflammatory damage. Defenses are energy-consuming anabolic programs. Therefore, anti-inflammatory, catabolic tolerance programs by metabolic reprogramming of macrophages have evolved. Therapeutic options of AHR agonists to reduce chronic inflammatory diseases are discussed.
 ...
PMID:Aryl hydrocarbon receptor (AHR), integrating energy metabolism and microbial or obesity-mediated inflammation. 3322 91