This was accompanied by an early onset of severe portal hypertension in Mdr2-/- BALB/c (p < 0.001; 11.1 ±0.2 mmHg at age of 8 weeks vs. 7.3 ± 0.1 mmHg in Mdr2-/- FVB). Aggressive fibrosis in Mdr2-/-.BALB/c mice was associated with
a dramatic increase in several pro-fibrogenic transcripts such as procolla-gen α1(I), TGFβ2 and TIMP-1 (2-4 fold above parental strain levels). While the development of liver tumors in Mdr2-/-.FVB starts from 10 months, Mdr2-/- BALB/c developed liver tumors as early as 7 months of age, with a greater tumor burden compared to Mdr2-/-.FVB at age 12 months (p < 0.05). CONCLUSIONS: Mdr2-/-.BALB/c mice demonstrate Selleckchem Seliciclib unprecedented degree and rapidity of hepatic fibrosis progression among any reported mouse models. Disease progression in Mdr2-/-.BALB/c is associated with early onset portal hypertension and accelerated primary liver cancer, which is a clinically relevant KU-60019 complication of cirrhosis. This new model will facilitate development ofantifibrotic drugs and mechanisms of study in biliary fibrosis progression. Disclosures: Peter M. Kang – Grant/Research Support: Abbott Labs Yury Popov – Consulting: Gilead Sciences, Inc, Ymir Genomics; Grant/Research Support: Gilead Sciences, Inc The following people have nothing to disclose: Naoki Ikenaga,
Susan B. Liu, Deanna Sverdlov, Qingen Ke Quiescent hepatic stellate cells (HSCs) store retinoid in lipid droplets, but lose these droplets as they “activate” in response to liver injury. Whether this is required for full acquisition of the fibrotic program is unclear. We previously showed that liver X receptors (LXRs) are an important determinant for stellate cell activation. We found that
Lxrαβ-/- HSCs are intrinsically pro-inflammatory and have a “super-sized” lipid droplet. The aim of this study was to determine whether LXRs link cholesterol to retinoid storage or metabolism. We hypothesized that Lxrαβ-/-HSCs are primed for activation because of increased retinyl ester storage and derivative retinoic acid receptor (RAR) signaling. Methods: Stellate cells were purified from wild-type (WT) and Lxrαβ-/- mice (10 per genotype) by sequential in situ perfusion of Pronase/collagenase, AMP deaminase then density gradient ultra-centrifugation. Cells were collected during culture activation (ex vivo, 1, 2, 3, and 5 days) and analyzed by HPLC to quantify retinoid. Transcriptional profiling for each day was separately performed using Affymetrix gene arrays. Gene expression was determined by qPCR. Results: HPLC analysis showed Lxrαβ-/-HSCs store twice as much retinyl ester as WT at baseline. Both genotypes lose their retinoid over 5-7 days in culture, but the kinetics of lipid droplet loss are accelerated in Lxrαβ-/- HSCs, correlating with an earlier induction of fibrotic genes (Col1a1, Acta2). Increased RAR target gene expression in Lxrαβ-/- cells (Rarb, Crabp1) shows that a functional RAR ligand is present.