Oxidative Stress and Oval Cell Accumulation in Mice and Humans with Alcoholic and Nonalcoholic Fatty Liver Disease

Abstract

In animals, the combination of oxidative liver damage and inhibited hepatocyte proliferation increases the numbers of hepatic progenitors (oval cells). We studied different murine models of fatty liver disease and patients with nonalcoholic fatty liver disease or alcoholic liver disease to determine whether oval cells increase in fatty livers and to clarify the mechanisms for this response. To varying degrees, all mouse models exhibit excessive hepatic mitochondrial production of H 2 O 2 , a known inducer of cell-cycle inhibitors. In mice with the greatest H 2 O 2 production, mature hepatocyte proliferation is inhibited most, and the greatest number of oval cells accumulates. In rodent models for hepatocarcinogenesis, small oval cells that express both hepatocyte and cholangiocyte markers accumulate in the liver before cancerous nodules develop.

Claudin-4 differentiates biliary tract cancers from hepatocellular carcinomas

“…30,31 The identity of these cells remains controversial. It is believed that the small terminal bile ductules that form the canals of Hering constitute the primary hepatic stem cell niche.…”

Sonic hedgehog is an autocrine viability factor for myofibroblastic hepatic stellate cells

“…Cirrhotic livers also exhibit varying degrees of architectural distortion related to changes in hepatic sinusoidal structure, parenchymal nodularity, and accumulation of hepatic progenitors. These structural alterations are generally accompanied by some degree of organ dysfunction [3][4][5]. Cancers of bile ductular cells and hepatocytes also occur most often in the context of cirrhosis [6].…”

Accumulation of Hedgehog-Responsive Progenitors Parallels Alcoholic Liver Disease Severity in Mice and Humans

“…As in many other types of chronic liver disease, 3 in alcoholic liver disease, the intensity of this ductular reaction closely parallels the severity of liver injury. 4 Ductular cells, myofibroblasts, and fibrosis often extend into the hepatic parenchyma, entrap hepatocytic cells, and bridge adjacent portal tracts as fatty liver damage progresses. 5 Studies in experimental animals and humans with various types of chronic liver disease consistently demonstrate high proliferative activity in these stromal and ductular cells and show that many of them express markers of immature cells.…”