Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatic uptake and biliary excretion of organic anions (e.g., bile acids and bilirubin) is mediated by hepatobiliary transport systems. Defects in transporter expression and function can cause or maintain cholestasis and jaundice. Recruitment of alternative export transporters in coordination with phase I and II detoxifying pathways provides alternative pathways to counteract accumulation of potentially toxic biliary constituents in cholestasis. The genes encoding for organic anion uptake (NTCP, OATPs), canalicular export (BSEP, MRP2) and alternative basolateral export (MRP3, MRP4) in liver are regulated by a complex interacting network of hepatocyte nuclear factors (HNF1, 3, 4) and nuclear (orphan) receptors (e.g., FXR, PXR, CAR, RAR, LRH-1, SHP, GR). Bile acids, proinflammatory cytokines, hormones and drugs mediate causative and adaptive transporter changes at a transcriptional level by interacting with these nuclear factors and receptors. Unraveling the underlying regulatory mechanisms may therefore not only allow a better understanding of the molecular pathophysiology of cholestatic liver diseases but should also identify potential pharmacological strategies targeting these regulatory networks. This review is focused on general principles of transcriptional basolateral and canalicular transporter regulation in inflammation-induced cholestasis, ethinylestradiol- and pregnancy-associated cholestasis, obstructive cholestasis and liver regeneration. Moreover, the potential therapeutic role of nuclear receptor agonists for the management of liver diseases is highlighted.
 ...
PMID:Principles of hepatic organic anion transporter regulation during cholestasis, inflammation and liver regeneration. 1729 2

The influence of combinatorial chemistry and high-throughput screening (HTS) technologies in the pharmaceutical industry during the last 10 years has been enormous. However, the attrition rate of drugs in the clinic due to toxicity during this period still remained 40-50%. The need for reduced toxicity failure led to the development of early toxicity screening assays. This chapter describes the state of the art for assays in the area of genotoxicity, cytotoxicity, carcinogenicity, induction of specific enzymes from phase I and II metabolism, competition assays for enzymes of phase I and II metabolism, embryotoxicity as well as endocrine disruption and reprotoxicity. With respect to genotoxicity, the full Ames, Ames II, Vitotox, GreenScreen GC, RadarScreen, and non-genotoxic carcinogenicity assays are discussed. For cytotoxicity, cellular proliferation, calcein uptake, oxygen consumption, mitochondrial activity, radical formation, glutathione depletion as well as apoptosis are described. For high-content screening (HCS), the possibilities for analysis of cytotoxicity, micronuclei, centrosome formation and phospholipidosis are examined. For embryotoxicity, endocrine disruption and reprotoxicity alternative assays are reviewed for fast track analysis by means of nuclear receptors and membrane receptors. Moreover, solutions for analyzing enzyme induction by activation of nuclear receptors, like AhR, CAR, PXR, PPAR, FXR, LXR, TR and RAR are given.
 ...
PMID:High-throughput screening for analysis of in vitro toxicity. 1915 69

Steatosis is the first step in the development of non-alcoholic fatty liver disease (NAFLD). However, the mechanisms involved in its pathogenesis are not fully understood. Many nuclear receptors (NRs) involved in energy homeostasis and biotransformation constitute a network connecting fatty acids, cholesterol and xenobiotic metabolisms; therefore, multiple NRs and their ligands may play a prominent role in liver fat metabolism and accumulation. In this study we have attempted to gain insight into the relevance of the NR superfamily in NAFLD by investigating the steatogenic potential of 76 different NR ligands in fatty acid overloaded human hepatocytes and hepatoma cells. Moreover, we have determined the mRNA expression level of 24 NRs to correlate the steatogenic potential of the ligands with the expression of their associated NRs in the cultured cells. Our results demonstrate that 18% of the examined NR ligands enhanced lipid accumulation in human hepatocytes and/or hepatoma cells. Among them, ligands of PPARgamma (e.g., thiazolidinediones), LXR (paxilline and 24(S),25-epoxycholesterol), PXR (hyperforin), CAR (3alpha,5alpha-androstenol), ERalpha (tamoxifen), FXR (Z-guggulsterone), VDR (25-hydroxyvitamin D3) and particular retinoids and farnesoids showed a significant pro-steatotic effect. The mRNA level of most of the NRs examined was well preserved in human hepatocytes, but HepG2 showed a deranged profile, where many of the receptors had a marginal or negligible level of expression in comparison with the human liver. By comparing the steatogenic effect of NR ligands with the NR expression levels, we conclude that LXR, PXR, RAR and PPARgamma ligands likely induce fat accumulation by a NR-dependent mechanism. Indeed, over-expression of PXR in HepG2 cells enhanced the steatogenic effect of hyperforin and rifampicin. However, the accumulation of fat induced by other ligands did not correlate with the expression of their associated NR. Our results also suggest that human hepatocytes cultured with free fatty acids offer a highly valuable in vitro system to investigate the pathogenesis and therapeutics of the human fatty liver.
 ...
PMID:Enhanced steatosis by nuclear receptor ligands: a study in cultured human hepatocytes and hepatoma cells with a characterized nuclear receptor expression profile. 2007 22

Recent studies confirmed a critical importance of c-Met signaling for liver regeneration by modulating redox balance. Here we used liver-specific conditional knockout mice (MetKO) and a nutritional model of hepatic steatosis to address the role of c-Met in cholesterol-mediated liver toxicity. Liver injury was assessed by histopathology and plasma enzymes levels. Global transcriptomic changes were examined by gene expression microarray, and key molecules involved in liver damage and lipid homeostasis were evaluated by Western blotting. Loss of c-Met signaling amplified the extent of liver injury in MetKO mice fed with high-cholesterol diet for 30days as evidenced by upregulation of liver enzymes and increased synthesis of total bile acids, aggravated inflammatory response and enhanced intrahepatic lipid deposition. Global transcriptomic changes confirmed the enrichment of networks involved in steatosis and cholestasis. In addition, signaling pathways related to glutathione and lipid metabolism, oxidative stress and mitochondria dysfunction were significantly affected by the loss of c-Met function. Mechanistically, exacerbation of oxidative stress in MetKO livers was corroborated by increased lipid and protein oxidation. Western blot analysis further revealed suppression of Erk, NF-kB and Nrf2 survival pathways and downstream target genes (e.g. cyclin D1, SOD1, gamma-GCS), as well as up-regulation of proapoptotic signaling (e.g. p53, caspase 3). Consistent with the observed steatotic and cholestatic phenotype, nuclear receptors RAR, RXR showed increased activation while expression levels of CAR, FXR and PPAR-alpha were decreased in MetKO. Collectively, our data provide evidence for the critical involvement of c-Met signaling in cholesterol and bile acids toxicity.
 ...
PMID:Loss of c-Met signaling sensitizes hepatocytes to lipotoxicity and induces cholestatic liver damage by aggravating oxidative stress. 2739 61