Humans with chronic liver disease were also studied. Results: In healthy liver, hepatocytes strongly expressed D1 and stromal cells weakly expressed D3. During injury, hepatocyte expression of D1 decreased, while stromal expression of D3 increased, particularly in myofibroblasts. Repair-related changes in deiodinases were accompanied by reduced intrahepatic TH content and TH-regulated gene expression. Disrupting Hedgehog signaling in myofibroblasts reduced D3 and increased D1 expression, increased intrahepatic T4 concentration, and normalized TH-specific gene expression. Patients with advanced fibrosis
had less D1 and more D3 than patients with mild fibrosis. Their serum rT3 levels were also increased. Moreover, lower serum fT3/rT3 and fT4/rT3 distinguished advanced- from mild- fibrosis, even in individuals with similar serum levels of TSH and fT4. Conclusion: Hedgehog-dependent Talazoparib in vitro changes in liver stromal cells drive repair-related changes in hepatic deiodinase expression that promote intrahepatic hypothyroidism, thereby limiting exposure to T3, an important factor for hepatic differentiation. Changes in deiodinase expression correlate with reduced serum fT3/rT3 and fT4/rT3 ratios. Thus, increased serum rT3 may serve as a novel
biomarker of liver find more disease severity in humans. Disclosures: Manal F. Abdelmalek – Consulting: Islet Sciences; Grant/Research Support: Mochida Pharmaceuticals, Gilead Sciences, NIH/NIDDK, Synageva, Genfit Pharmaceuticals Anna Mae Diehl – Consulting: Roche; Grant/Research Support: Gilead, Genfit The following people have nothing to disclose: Brittany Bohinc, Gregory A. Michelotti, Guanhua 3-oxoacyl-(acyl-carrier-protein) reductase Xie, Herbert Pang, Ayako Suzuki, Cynthia D. Guy, Dawn L. Piercy, Leandi Kruger, Marzena Swiderska-Syn, Mariana V. Machado, Thiago A. Pereira, Ann Marie Zavacki Background: Exosomes arise by inward budding of the limiting membranes of multivesicular
bodies which, upon fusion with the plasma membrane, result in their secretion and deposition into body fluids (e.g. blood, urine). Exosomes contain a complex mixture of microRNAs (miRs), mRNAs and proteins that reflect the transcriptional and translational status of the producer cell. Since this molecular payload is a “fingerprint” of the dynamic status of their producer cells, exosomes represent a potentially valuable resource for assessing liver disease or pathology. Our goal was to profile the microRNA content of serum exosomes in experimental liver fibrosis. Methods: PureExo Exosome Isolation Kits were used to isolate serum exosomes. MiR profiling was performed on exosomal RNA from 1ml of pooled serum (5 mice; 200μl/mouse) using a mouse miRnome miR PCR Array.
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