tretinoin and Cholestasis--Intrahepatic

Topics: Adult; Cholestasis, Intrahepatic; Disseminated Intravascular Coagulation; Humans; Leukemia, Promyelocytic, Acute; Male; Renal Insufficiency; Tretinoin

Vitamin A and its metabolites has been found to be protective against cholestatic liver injury, but the exact underlying mechanisms involved in cholestatic liver injury remain unclear. The objective of this study was to determine the function and mechanisms of 9-cis-retinoic acid, the metabolite of vitamin A, in cholestatic liver injury.. The bile duct ligated (BDL) mice were treated with 9-cis-retinoic acid by intravenous injection through the tail for 10 days. The liver function and histology were assessed in the matched group and experimental group. The expression of MRP3 in liver tissue was tested by qRT-PCR, Western blotting, and IHC. Effect of RXRα sumoylation on MRP3 expression was investigated at a cellular level. Influence of 9-cis-retinoic acid on RXRα sumoylation was also tested in cells.. Our findings showed that 9-cis-retinoic acid significantly decreases the serum ALT and AST level, alleviates hepatic necrosis of the BDL-mice. We also identified MRP3, an important protective hepatobiliary transporter in cholestasis, was elevated by 9-cis-retinoic acid in vivo and in vitro. 9-cis-retinoic acid weakened the sumoylation of RXRα, which promotes the cytoplasmic location of RXRα and lightens the interaction of RXRα and RARα. Inhibition of RXRα and RARα interaction increased MRP3 expression.. 9-cis-retinoic acid alleviates cholestatic liver injury by elevating MRP3 expression through its mechanism of inhibiting sumoylation of RXRα.

Topics: Alitretinoin; Angiogenic Proteins; Animals; Bile Ducts, Intrahepatic; Cholestasis, Intrahepatic; HEK293 Cells; Hep G2 Cells; Humans; Liver; Male; Mice; Mice, Inbred C57BL; Retinoid X Receptor alpha; Sumoylation; Tretinoin; Ubiquitins; Up-Regulation

Cholestasis leads to liver cell death, fibrosis, cirrhosis, and eventually liver failure. Despite limited benefits, ursodeoxycholic acid (UDCA) is the only Food and Drug Administration-approved treatment for cholestatic disorders. Retinoic acid (RA) is a ligand for nuclear receptors that modulate bile salt homeostasis. RA also possesses immunomodulatory effects and is used to treat acute promyelocytic leukemia and inflammatory disorders such as psoriasis, acne, and rheumatoid arthritis. To test whether the supplementation of RA with UDCA is superior to UDCA alone for treating cholestasis, male Sprague-Dawley rats underwent common bile duct ligation (BDL) for 14 days and were treated with phosphate-buffered saline (PBS), UDCA, all-trans retinoic acid (atRA), or UDCA and atRA by gavage. Treatment with UDCA and atRA substantially improved animal growth rates, significantly reduced liver fibrosis and bile duct proliferation, and nearly eliminated liver necrosis after BDL. Reductions in the bile salt pool size and liver hydroxyproline content were also seen with treatment with atRA or atRA and UDCA versus PBS and UDCA. Furthermore, atRA and UDCA significantly reduced liver messenger RNA and/or protein expression of transforming growth factor β1 (Tgf-β1), collagen 1a1 (Col1A1), matrix metalloproteinase 2 (Mmp2), cytokeratin 19, α-smooth muscle actin (α-SMA), cytochrome P450 7A1 (Cyp7a1), tumor necrosis factor α, and interleukin-β1. The molecular mechanisms of this treatment were also assessed in human hepatocytes, hepatic stellate cells, and LX-2 cells. atRA alone or in combination with UDCA greatly repressed CYP7A1 expression in human hepatocytes and significantly inhibited COL1A1, MMP2, and α-SMA expression and/or activity in primary human hepatic stellate cells and LX-2 cells. Furthermore, atRA reduced TGF-β1-induced Smad2 phosphorylation in LX-2 cells.. Our findings indicate that the addition of RA to UDCA reduces the bile salt pool size and liver fibrosis and might be an effective supplemental therapy with UDCA for cholestatic diseases.

Topics: Animals; Bile Acids and Salts; Bile Ducts; Cell Proliferation; Cells, Cultured; Cholestasis, Intrahepatic; Cholesterol 7-alpha-Hydroxylase; Collagen Type I; Collagen Type I, alpha 1 Chain; Disease Models, Animal; Hepatocytes; Humans; Ligation; Liver; Male; Matrix Metalloproteinase 2; Rats; Rats, Sprague-Dawley; Smad2 Protein; Tretinoin; Ursodeoxycholic Acid