Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019209 (hepatomegaly)
 5,798 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peroxisome proliferators, such as the lipid-lowering fibrates that function as agonists for peroxisome proliferator-activated receptor alpha (PPARalpha), induce liver tumors in rodents and may produce cholestasis in humans. Considerable attention has focused on peroxisome proliferator-induced hepatocellular carcinoma, a phenomenon not noted in man, whereas limited studies examine fibrates and other therapeutic drugs that induce cholestasis, a common finding in humans. Moreover, the mechanisms by which fibrates induce hepatocyte proliferation and cholestasis are still not fully understood. We have examined the role of hepatocyte retinoid X receptor alpha (RXRalpha), an essential partner of PPARalpha, in modulating WY-14,643-induced hepatocyte proliferation and cholestasis. WY-14,643 treatment induced hepatomegaly in wild type (WT) mice that was also accompanied by induction of the expression of cyclins D1, D3, A2, and B1 and Cdc2 as well as inhibition of Wee 1. Such changes were either absent or greatly reduced in hepatocyte RXRalpha-null mice. Furthermore, neither WY-14,643 treatment nor RXRalpha deficiency affected apoptosis, indicating the importance of PPARalpha/RXRalpha in regulating Wee 1-mediated Cdc2/cyclin B1 expression for cells to enter into mitosis. WY-14,643 treatment also induced cholestasis and liver injury, which is evidenced by induction of alanine aminotransferase, alkaline phosphatase, and hepatic bile acid levels in WT mice. Hepatocyte RXRalpha deficiency protected the mice from WY-14,643-induced liver injury. WY-14,643-mediated induction of the small heterodimer partner, Mrp3, and Cyp3a11 levels was greater in hepatocyte RXRalpha-null than in WT mouse livers suggesting enhanced repression of bile acid synthesis and increased efflux of bile acids into blood for renal excretion as well as hydroxylation of bile acids because of hepatocyte RXRalpha deficiency. These data establish a crucial role of hepatocyte RXRalpha in regulating WY-14,643-mediated cell cycle progression as well as bile acid homeostasis.
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PMID:Mechanisms of resistance of hepatocyte retinoid X receptor alpha-null mice to WY-14,643-induced hepatocyte proliferation and cholestasis. 1917 32

Activation of the nuclear receptors constitutive androstane receptor, pregnane X receptor, and peroxisome proliferator-activated receptor alpha results in hepatomegaly, and these nuclear receptors are implicated in the regulation of liver regeneration. Retinoid X receptor (RXR)alpha is an essential partner of these nuclear receptors. Therefore, we studied the role of hepatocyte RXRalpha in liver regeneration using partial hepatectomy model. The results showed that hepatocyte RXRalpha deficiency caused an approximately 20-hour delay in hepatocyte proliferation after partial hepatectomy. Several pathways, including growth factors and the circadian cell cycle, were impaired due to hepatocyte RXRalpha deficiency. In addition, the expression patterns of hepatocyte growth factor, fibroblast growth factor 2, platelet-derived growth factor, and transforming growth factor alpha were altered due to lack of RXRalpha. Furthermore, the peroxisome proliferator-activated receptor alpha/brain and muscle Arnt-like protein 1/Rev-erbalpha/P21 pathway was compromised, and Cry1/Cry2 and Wee1/Per1 expression was deregulated in regenerating RXRalpha-null livers. Accordingly, the expression and regulation of cyclin D1/Cyclin- dependent Kinase (Cdk)4, cyclin E1/Cdk2, cyclin A2/Cdk2, and cyclin B1/Cdk1 after partial hepatectomy were altered in regenerating RXRalpha-null livers. Hepatocyte RXRalpha deficiency also affected the basal, as well as regeneration-induced cyclin E1 expression levels. Activation of RXRalpha by retinoic acids increased the cyclin E1 promoter activity indicating retinoic acid-mediated signaling positively controls cyclin E1 gene expression. As many of these observed changes were not documented in the regenerating livers of other nuclear receptor knockout mice, these observed effects may be hepatocyte RXRalpha specific.
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PMID:Deregulation of growth factor, circadian clock, and cell cycle signaling in regenerating hepatocyte RXRalpha-deficient mouse livers. 2003 57