Gene expression profiles associated with inflammation, fibrosis and cholestasis in mouse liver after griseofulvin

Abstract

Erythropoietic protoporphyria patients can develop cholestasis, severe hepatic damage, fibrosis, and cirrhosis. We modeled this hepatic pathology in C57BL/6J and BALB/c mice using griseofulvin and analyzed 3,127 genes for alteration of expression in the liver before and during the onset of protoporphyria, cholestasis, inflammation, and hepatic fibrosis. The two mouse strains developed different levels of pathologic damage in response to the griseofulvin. Characteristic gene expression profiles could be associated with griseofulvin-induced gene expression, disruption of lipid metabolism, and the pathologic states of inflammation, early fibrosis, and cholestasis. Additionally, some genes individually indicated an alteration of homeostasis or pathologic state; for example, fibroblast proliferation was potentially indicated by increased calcyclin (SA100a6) expression. Changes in cytochrome P450 (Cyp) gene expression were particularly pronounced, with increased expression of the Cyp2a, Cyp2b, and Cyp3a families. Decreased Cyp4a10 and Cyp4a14 expression was observed that could be associated with early pathologic change. A potential decrease in bile acid and steroid biosynthesis was indicated by the decreased expression of Cyp7b1 and Hsd3b4, respectively. DNA damage was indicated by induction of GADD45. This study illustrates how transcriptional programs can be associated with different stimuli in the same experiment. The time course of change in the gene expression profile compared with changes in pathology and clinical chemistry shows the potential of this approach for modeling causative, predictive, and adaptive changes in gene expression during pathologic change.

Gadd45 proteins: Relevance to aging, longevity and age-related pathologies

“…In view of the links between these pro-inflammatory pathways and Gadd45s (described in Sections 3.3 and 3.6), the involvement of Gadd45 family in chronic inflammation is highly plausible. As an example, the induction of Gadd45 was observed in the course of liver inflammation (Gant et al, 2003). An additional source of the pro-inflammatory molecules are senescent cells which are accumulated in aging (Coppé et al, 2010).…”

Systems Toxicology: Integrated Genomic, Proteomic and Metabonomic Analysis of Methapyrilene Induced Hepatotoxicity in the Rat

“…These omic approaches include microarrays, to assess global gene expression patterns (part of the field of genomics), high-resolution fluorescence two-dimensional gel electrophoresis and mass spectrometry to quantify and identify holistic protein changes (proteomics) and 1 H NMR spectroscopy to measure multiple metabolites (metabonomics). Hitherto such ‘omics' methods have generally been used independently to investigate disruption of complex systems − with the common rationale that measuring large numbers of parameters coupled to statistical analysis might reveal patterns of regulation within these networks. Such patterns should be related quantitatively to changes in established biological endpoints.…”

Phenotypic Anchoring of Gene Expression Changes during Estrogen-Induced Uterine Growth

“…The process by which gene expression changes are linked to changes in phenotype has been termed “phenotypic anchoring” (Cunningham et al 2003; Paules 2003; Schmidt 2003). This approach has been used successfully to identify groups of genes whose expression correlates with specific pathologic changes during griseofulvin-induced chronic liver injury (Gant et al 2003), renal toxicity (Amin et al 2004), furan-mediated hepatotoxicity (Hamadeh et al 2004), and aceta-minophen-induced hepatotoxicity (Heinloth et al 2004). In the present study we used phenotypic anchoring, in conjunction with gene ontology analysis, to define the transcriptional program associated with the response of the rodent uterus to a reference estrogen and to identify groups of genes that may drive specific histologic changes.…”