Triggering and resolution of inflammation in NASH

Nonalcoholic steatohepatitis (NASH) is considered the progressive form of nonalcoholic fatty liver disease (NAFLD) and is characterized by liver steatosis, inflammation, hepatocellular injury and different degrees of fibrosis. A central issue in this field relates to the identification of those factors that trigger inflammation, thus fuelling the transition from nonalcoholic fatty liver to NASH. These triggers of liver inflammation might have their origins outside the liver (such as in adipose tissue or the gut) as well as inside the organ (for instance, lipotoxicity, innate immune responses, cell death pathways, mitochondrial dysfunction and endoplasmic reticulum stress), both of which contribute to NASH development. In this Review, we summarize the currently available information on the key upstream triggers of inflammation in NASH. We further delineate the mechanisms by which liver inflammation is resolved and the implications of a defective pro-resolution process. A better knowledge of these mechanisms should help to design targeted therapies able to halt or reverse disease progression. Nonalcoholic steatohepatitis is the progressive form of nonalcoholic fatty liver disease, one of the most common chronic liver diseases. In this Review, the authors comprehensively discuss the key factors that trigger hepatic inflammation, as well as the pathways involved in inflammation resolution. Key points Triggers of hepatic inflammation have their origins outside as well as inside the liver, and both pathways contribute to the transition from isolated steatosis to NASH. Adipose tissue dysfunction and the hepatic inflammatory response have a fundamental role during NASH development. Cellular and molecular response mechanisms also promote liver inflammation in the absence of a fatty liver by inducing a chronic inflammatory response that results in hepatocyte damage. System biology approaches that integrate metabolomics, proteomics and epigenetic analysis are needed to unravel the molecular signatures of NASH. Abrogation of liver inflammation could be achieved by exploiting active, physiological pro-resolving mechanisms (a ‘pushing for’ strategy) instead of the classical passive blockade of pro-inflammatory mediators (the ‘push back’ strategy).