Portal veinous blood in NASH patients contains high levels of sugar, lipids and amino acids, and hepatic sinusoidal endothelial cells (HSECs) play as a gate-keeper to prevent hepatocyte injury. CapillaryECs have lots of caveolae on their surface where caveolin(CAV)-1 works as a signal transduction center.

The present study aimed at elucidating the functional contribution of CAV-1 and the fibrosis-relating enzymes such as MMP-1 and TGF-β to the pathophysiology of NASH. Methods: Twenty-six histologically proven NASH patients including three cases with NASH-derived HCC, and normal liver specimens obtained from 5 patients with metastatic liver cancer were enrolled. The study was approved by the ethical committees, and the written RAD001 ic50 consent was obtained from the all patients. CAV-1, MMP-1, latent form and active form of TGF-β were stained by immunohistochemistry (IHC) and immunoelectron microscopy (IEM). To discriminate cells expressing CAV-1, MMP-1, and TGF-β, dual staining with CD68, CD34, vimentin/α-SMA, and CK19 and OV-6 was used as a marker of Kupffer cells (KCs), capillary endothelial cells, hepatic stellate cells (HSC), and hepatic progenitor cells (HPCs), respectively. Results: In an early stage of NASH, co-localization of CAV-1 and MMP-1 was demonstrated by IEM predominantly in KC, HSE and HSC, suggesting activation of those cells in the progression of NASH. Consistent

with these findings, IHC revealed that expression of type I pro-collagen and the active form CHIR-99021 supplier of TGF-β were observed around the cells with ballooning injury. In contrast, IHC and IEM examination of liver specimens obtained from the advanced stage of NASH patients revealed remarkable expression of CAV-1 and MMP-1 in proliferating HPCs that were stained positive for CK19 or OV-6. Type I procollagen was selleck chemical observed at the edge of proliferating capillary endothelial cells closed to the ductular proliferation stained positive for OV-6 suggesting the formation of fibrous tissue. The sprouriting capillary ECs with MMP-1 on the caveolae along the luminal and abluminal portions of cell membrane, suggest the functional role of MMP-1 in angiogenesis.

Conclusions: In an early stage of NASH, MMP-1 expressed in KC/HSEC/HSC participates in the progression of disease. In contrast, it may contribute to the repair and regeneration of injured sinusoidal structure through the caveolae signal network in the advanced stage of NASH. Disclosures: The following people have nothing to disclose: Hiroaki Yokomori, Isao Okazaki, Masaya Oda, Wataru Ando, Yutaka Suzuki, Tsutsui Nobuhiro, Eigoro Yamanouchi, Hajime Kuroda, Soichi Kojima, Mitsuko Hara, Yutaka Inagaki Autophagy is a lysosomal degradation mechanism that has been implicated in chronic liver diseases. An association between activated autophagy and hepatic fibrogenesis has been demonstrated in mouse models. This study aimed to verify whether altered autophagy plays a role in human cirrhotic livers.