Atorvastatin attenuates hepatic fibrosis in rats after bile duct ligation via decreased turnover of hepatic stellate cells

• Published in: Journal of hepatology Vol. 53; no. 4; pp. 702 - 712
• Main Authors: Trebicka, Jonel, Hennenberg, Martin, Odenthal, Margarete, Shir, Khanwali, Klein, Sabine, Granzow, Michaela, Vogt, Annabelle, Dienes, Hans-Peter, Lammert, Frank, Reichen, Jürg, Heller, Jörg, Sauerbruch, Tilman
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier B.V 01.10.2010; Elsevier
• Subjects: Animals; Apoptosis; Atorvastatin Calcium; Bile Ducts; Biological and medical sciences; Cell Proliferation - drug effects; Cytokines; Fibrogenesis; Gastroenterology and Hepatology; Gastroenterology. Liver. Pancreas. Abdomen; Hepatic stellate cells; Hepatic Stellate Cells - drug effects; Heptanoic Acids - pharmacology; HMG-CoA reductase inhibitor; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Ligation; Liver Cirrhosis - prevention & control; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Other diseases. Semiology; Proliferation; Pyrroles - pharmacology; Rats; Rats, Sprague-Dawley; α-smooth muscle actin; matrix metalloproteinase-2; PCNA; number of cycles; alanine aminotransferase; ALT; 3-hydroxy-3-methylglutaryl-coenzyme-A-reductase; C T -value; BDL; glyceraldehydes-3-P dehydrogenase; HMG-CoA-R; CTGF; HCl; bile duct ligation; PDGFβ-R; RT-PCR; HMG-CoA reductase inhibitor; HSC; sodium dodecyl sulfate–polyacrylamide gel electrophoresis; Fibrogenesis; hepatic stellate cells; AST; Cytokines; hydrogen chloride; real-time polymerase chain reaction; Proliferation; platelet-derived growth factor-β receptor; SDS–PAGE; PARP-1; ECM; aspartate aminotransferase; connective tissue growth factor; proliferating cell nuclear antigen; MMP-2; transforming growth factor-β; enzyme-linked immunosorbent assay; TGFβ; αSMA; poly (ADP ribose) polymerase; SEM; standard error of the mean; GAPDH; extracellular matrix; ELISA; Apoptosis; CT-value; Hepatic stellate cells; Spider cell; Biliary tract; Rat; Liver; Hepatic disease; Hypocholesterolemic agent; Gastroenterology; Turnover; Hepatic fibrosis; HMG; Enzyme; Rodentia; Cytokine; Enzyme inhibitor; Statin derivative; Vertebrata; Mammalia; Animal; Atorvastatin; Hydroxymethylglutaryl-CoA reductase; Digestive diseases; Oxidoreductases; Antilipemic agent; Reductase
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2010.04.025

Background & Aims Activation of hepatic stellate cells (HSC) and transdifferentiation to myofibroblasts following liver injury is the main culprit for hepatic fibrosis. Myofibroblasts show increased proliferation, migration, contraction, and production of extracellular matrix (ECM). In vitro , HMG-CoA reductase inhibitors (statins) inhibit proliferation and induce apoptosis of myofibroblastic HSC. To investigate the antifibrotic effects of atorvastatin in vivo we used bile duct ligated rats (BDL). Methods BDL rats were treated with atorvastatin (15 mg/kg/d) immediately after ligation (prophylactically) or in on-going fibrosis (therapeutically). Fibrosis was assessed by hydroxyproline content and Sirius-red staining. The activation of HSC was investigated by analysis of αSMA expression. mRNA levels of cytokines and procollagen were analyzed by RT-PCR, and MMP-2 activity by zymography. Proliferation was assessed by expression of cathepsins (B and D), proliferating cell nuclear antigen (PCNA), and Ki67-staining. Apoptosis was characterized by caspase-3 activity, cleavage of PARP-1, and TUNEL assay. Hepatic inflammation was investigated by serum parameters and liver histology. Results Prophylactic and early therapy with atorvastatin significantly attenuated fibrosis and HSC activation. Later therapy lacked significant effects on fibrosis but reduced profibrotic cytokine expression and led to a more quiescent state of HSC with less proliferation and apoptosis, while hepatic inflammation did not change. Conclusions This study shows that very early atorvastatin treatment inhibits HSC activation and fibrosis in the BDL model in vivo , while late treatment reduces HSC turnover and activity. Our findings underline that long-term studies in humans are warranted.