Targeting Cell Death and Sterile Inflammation Loop for the Treatment of Nonalcoholic Steatohepatitis

Abstract

Nonalcoholic fatty liver disease represents a wide spectrum of conditions and is currently the most common form of chronic liver disease affecting both adults and children in the United States and many other parts of the world. Great effort has been focused on the development of novel therapies for those patients with the more advanced forms of the disease, in particular those with nonalcoholic steatohepatitis (NASH) and liver fibrosis that can be associated with significant morbidity and mortality. In this review, the authors focus on the role of cell death and sterile inflammatory pathways as well as the self-perpetuating deleterious cycle they may trigger as novel therapeutic targets for the treatment of fibrotic NASH.

Fig. 1

The intrahepatic self-perpetuating noxious loop in nonalcoholic steatohepatitis (NASH). Lipid overloading of the liver may result from both intra- and extrahepatic events in distant organs such as the gut, adipose tissue, and muscle, among others. Accumulation of toxic lipids in hepatocytes may induce cellular stress triggers and lead to hepatocyte cell death by various mechanisms, including apoptosis and necrosis followed by the release of intracellular molecules that act as danger signals to communicate stress to neighboring cells. These signals impart danger-associated molecular patterns (DAMPs), and activate sterile inflammatory pathways in cells of the innate immune system, which in turn release cytokines and additional danger signals. The central consequence of this chronic injury is the activation of hepatic stellate cells that can eventually progress to fibrotic NASH.