Hepatocytes in liver injury: Victim, bystander, or accomplice in progressive fibrosis?

Abstract

Chronic liver disease causes significant morbidity and mortality through progressive fibrosis, cirrhosis, and liver cancer. The classical theory of fibrogenesis has hepatic stellate cells (HSCs) as the principal and only significant source of abnormal extracellular matrix (ECM). Further, HSCs have the major role in abnormal ECM turnover. It is the death of hepatocytes, as the initial target of injury, that initiates a sequence of events including the recruitment of inflammatory cells and activation of HSCs. Following this initial response, the ongoing insult to hepatocytes is regarded as perpetuating injury, but otherwise, hepatocytes are regarded as "victims" and "bystanders" in progressive fibrosis. Recent developments, however, challenge this view and suggest the concept of the hepatocyte being an active participant in liver injury. It is clear now that hepatocytes undergo phenotypic changes, adapt to injury, and react to the altered microenvironment. In this review, we describe studies showing that hepatocytes contribute to progressive fibrosis by direct manipulation of the surrounding ECM and through signaling to effector cells, particularly HSCs and intrahepatic immune cells. Together, these findings suggest an active "accomplice" role for the hepatocyte in progressive liver fibrosis and highlight novel pathways that could be targeted for development of future anti-fibrotic therapies.

Hepatic SATB1 induces paracrine activation of hepatic stellate cells and is upregulated by HBx

“…Actually, hepatocytes actively engage in cross-talk with multiple cellular subsets, along with the release of reactive oxygen species (ROS) and pro-inflammatory signals3. Here we show that overexpresssion of SATB1 in hepatocytes led to upregulation of CTGF, IL-6 and PDGF-AA.…”

“…However, recent developments challenge the role of HSC and highlight that hepatocyte acts as an active participant in liver fibrogenesis. Several studies show that the impaired hepatocytes could contribute to progressive fibrosis by remodeling ECM and interacting with surrounding cells, particularly HSCs and intrahepatic immune cells3456. Apoptotic hepatocytes are reported to release some endogenous compounds such as damage associated molecular patterns (DAMPs) and apoptotic bodies, leading to HSC activation within the liver78.…”

Comparative transcriptomics of hepatic differentiation of human pluripotent stem cells and adult human liver tissue

“…human pluripotent stem cell; stem cell-derived hepatocytes; liver tissue; differentiation; transcriptomics LIVER DISEASE ACCOUNTS for the death of~1.7 million patients worldwide yearly (50), hereby becoming one of the leading cause of mortality in the world (34,43,49). End-stage liver disease is the condition when liver diseases lead to liver failure.…”

HBV Viral Load and Liver Enzyme Levels May Be Associated with the WildMBL2AA Genotype

“…The highest values of viral loads were found among HBV carriers with the wild-type AA genotype and mild to moderate fibrosis (F1-F2), suggesting a possible increase in liver damage repair mechanisms in the initial phase [39] and that a large number of hepatocytes could still be infected. This profile differs from that observed in cases of severe fibrosis and cirrhosis, where the presence of infected cells is decreased by the replacement of the liver parenchyma with fibrotic tissue, leading to a decrease in the viral load.…”