Although the precise etiological mechanism of DIAIH has not been elucidated yet, we can speculate that the variations in their developing patterns are due to the different metabolic activity and immunological reactions. We think that a wider range of drugs has the potential to cause AIH, and incidence of AIH with a drug-related Everolimus etiology is more frequent than we have previously thought. In cases of DILI, careful follow-up will be needed, keeping in mind that AIH can develop even after normalization of

liver enzymes. Furthermore, establishment of the diagnostic criteria and therapeutic strategy for DIAIH will be needed. Kazushi Sugimoto M.D., Ph.D.*, Takeshi Ito M.D., Ph.D.*, Norihiko Yamamoto M.D., Ph.D.*, Katsuya

Shiraki M.D., Ph.D.*, * Department of Gastroenterology and Hepatology, Mie University School of Medicine, Mie, Japan. “
“Liver fibrogenesis is associated with the transition of quiescent hepatocytes and I BET 762 hepatic stellate cells (HSCs) into the cell cycle. Exit from quiescence is controlled by E-type cyclins (cyclin E1 [CcnE1] and cyclin E2 [CcnE2]). Thus, the aim of the current study was to investigate the contribution of E-type cyclins for liver fibrosis in man and mice. Expression of CcnE1, but not of its homolog, CcnE2, was induced in fibrotic and cirrhotic livers from human patients with different etiologies and in murine wild-type (WT) livers after periodical administration of the profibrotic toxin, CCl4. To further evaluate the potential function of E-type cyclins for liver fibrogenesis, we repetitively treated constitutive Phosphoprotein phosphatase CcnE1−/− and CcnE2−/− knock-out mice with CCl4 to induce liver fibrosis. Interestingly, CcnE1−/− mice were protected against CCl4-mediated liver

fibrogenesis, as evidenced by reduced collagen type I α1 expression and the lack of septum formation. In contrast, CcnE2−/− mice showed accelerated fibrogenesis after CCl4 treatment. We isolated primary HSCs from WT, CcnE1−/−, and CcnE2−/− mice and analyzed their activation, proliferation, and survival in vitro. CcnE1 expression in WT HSCs was maximal when they started to proliferate, but decreased after the cells transdifferentiated into myofibroblasts. CcnE1−/− HSCs showed dramatically impaired survival, cell-cycle arrest, and strongly reduced expression of alpha smooth muscle actin, indicating deficient HSC activation. In contrast, CcnE2-deficient HSCs expressed an elevated level of CcnE1 and showed enhanced cell-cycle activity and proliferation, compared to WT cells. Conclusions: CcnE1 and CcnE2 have antagonistic roles in liver fibrosis. CcnE1 is indispensable for the activation, proliferation, and survival of HSCs and thus promotes the synthesis of extracellular matrix and liver fibrogenesis.