Graft Fibrosis Over 10 to 15 Years in Pediatric Liver Transplant Recipients: Multicenter Study of Paired, Longitudinal Surveillance Biopsies.

Previous single-center, cross-sectional studies have reported a steep increase in the prevalence and severity of fibrosis through 10 to 15 years after pediatric liver transplantation. We report a multicenter study of paired surveillance biopsies in a contemporary cohort. Children who underwent liver transplant when younger than 6 years old and had paired surveillance liver biopsies were enrolled (n = 78, 35% girls, median 1.

Cellular Location of HNF4α is Linked With Terminal Liver Failure in Humans.

Hepatocyte nuclear factor 4 alpha (HNF4α) is a transcription factor that plays a critical role in hepatocyte function, and HNF4α-based reprogramming corrects terminal liver failure in rats with chronic liver disease. In the livers of patients with advanced cirrhosis, HNF4α RNA expression levels decrease as hepatic function deteriorates, and protein expression is found in the cytoplasm. These findings could explain impaired hepatic function in patients with degenerative liver disease.

Activation of WNT/Beta-Catenin Signaling and Regulation of the Farnesoid X Receptor/Beta-Catenin Complex After Murine Bile Duct Ligation.

We have recently shown that loss of β-catenin prevents the development of cholestatic liver injury and fibrosis after bile duct ligation (BDL) due to loss of the inhibitory farnesoid X receptor (FXR)/β-catenin complex, which results in decreased hepatic bile acids (BAs) through activation of FXR. To further understand the role of Wnt/β-catenin signaling in regulating BA metabolism and cholestasis, we performed BDL on mice in which hepatocyte Wnt signaling is deficient but β-catenin is intact (low-density lipoprotein receptor-related protein [LRP]5/6 knockout [DKO]) as well as mice that have enhanced hepatocyte β-catenin expression (serine 45 mutated to aspartic acid [S45D] transgenic [TG] mice). Despite decreased biliary injury after BDL, hepatic injury, fibrosis, and inflammation were comparable in DKO and wild-type (WT) mice.

Liver-enriched transcription factor expression relates to chronic hepatic failure in humans.

The mechanisms by which the liver fails in end-stage liver disease remain elusive. Disruption of the transcription factor network in hepatocytes has been suggested to mediate terminal liver failure in animals. However, this hypothesis remains unexplored in human subjects.

Activin A is a prominent autocrine regulator of hepatocyte growth arrest.

Activin A, a multifunctional cytokine, plays an important role in hepatocyte growth suppression and is involved in liver size control. The present study was aimed to determine the cell location of activin A in the normal rat liver microenvironment and the contribution of activin A signaling to the hepatocyte phenotype to obtain insight into molecular mechanisms. Immunohistochemical and hybridization analyses identified hepatocytes as the major activin A-positive cell population in normal liver and identified mast cells as an additional activin A source.