Hepatic mRNA/miRNA profiles were generated with 17581 mRNAs and 504 miRNAs meeting array QC criteria. The transcriptome of control and drained groups was largely similar with only a single differentially expressed (DE) mRNA apparent (criteria: fold change >1.5 and adjusted P value <0.05). Cholestasis resulted in pronounced changes of the transcriptional landscape when compared with control (1353 DE mRNAs, 47 DE miRNAs) and drained
(111 DE mRNAs, 2 DE miRNAs) MS-275 price groups. Overrepresentation analysis indicated a multitude of pathways affected by cholestatic conditions including ECM organization, regulation of actin cytoskeleton and biotransformation. Alterations pertaining to BS homeostasis included downregulation of BS synthesis (CYP7A1), repression of BS uptake (SLCO1B1/3) and induction of basolateral efflux transporters (SLC51A/B) in cholestatic liver. Conclusions Extrahepatic cholestasis elicits large scale alterations in hepatic mRNA and miRNA expression. A notable difference in the number of DE mRNAs/miRNAs
was apparent when comparing cholestatic with control and drained groups, with the latter two having similar serum biochemistry and identical mRNA/ miRNA profiles. Follow-up studies are required to assess the interaction between miRNA and mRNA networks and the role of the identified pathways in cholestatic liver injury. Disclosures: The Torin 1 cell line following people have nothing to disclose: Frank G. Schaap, Marlon J. Jetten, Marcel H. Herwijnen, Maarten L. Coonen, Jos C. Kleinjans, Peter L. Jansen, Steven Olde Damink Background and aims: Sclerostin, an inhibitor of the Wnt pathway is involved in the regulation of osteoblastogenesis and its role in the development of bone disease in primary biliary cirrhosis (PBC), a disease characterized by low bone formation, is unknown. Therefore, we have assessed the circulating levels and the liver gene and protein expression of sclerostin
in this cholestatic disease. Methods: Serum sclerostin levels were measured in 83 women with PBC (mean age: 60 ± 12 years) and 101 control women of the same age. Lumbar and femoral bone mineral density (BMD) as well as parameters of mineral metabolism and bone remodeling (Ca/P, PTH, 25OHD, PINP, bone Celecoxib ALP, sCTX, NTX and osteocalcin) were measured. Moreover, sclerostin gene expression in the liver was assessed in samples of liver tissue taken by biopsy in 11 PBC patients and 5 healthy controls by real time PCR, and presence and distribution of sclerostin was evaluated in liver slices from 11 patients by immunohistochemistry. The presence and severity of histologic lesions were assessed semiquantitatively in the same liver samples. Results: Seventy-seven percent of patients had low BMD (22% osteoporosis and 55% osteopenia). PBC patients had higher sclerostin levels than controls (76.7±38.6 vs. 32.5±14.7 pmol/L, p<0.001). Serum sclerostin correlated inversely with markers of bone formation PINP (p=0.05) and osteocalcin (p=0.03), and bone resorption, NTX (p=0.01) and sCTX (p=0.