Molecular Pathogenesis of NASH

Abstract

Nonalcoholic steatohepatitis (NASH) is the main cause of chronic liver disease in the Western world and a major health problem, owing to its close association with obesity, diabetes, and the metabolic syndrome. NASH progression results from numerous events originating within the liver, as well as from signals derived from the adipose tissue and the gastrointestinal tract. In a fraction of NASH patients, disease may progress, eventually leading to advanced fibrosis, cirrhosis and hepatocellular carcinoma. Understanding the mechanisms leading to NASH and its evolution to cirrhosis is critical to identifying effective approaches for the treatment of this condition. In this review, we focus on some of the most recent data reported on the pathogenesis of NASH and its fibrogenic progression, highlighting potential targets for treatment or identification of biomarkers of disease progression.

Keywords: chemokines; fibrosis; genetics; hepatic stellate cells; inflammation; macrophages; microbiota; nuclear receptors; pattern-recognition receptors.

Figure 1

Outline of the pathogenesis of NASH. Signals generated inside the liver as a consequence of increased lipid accumulation, together with signals derived from extrahepatic organs cooperate to induce inflammation and fibrosis. FFA, free fatty acids; PAMPs, pathogen-associated molecular patterns; ER, endoplasmic reticulum; ROS, reactive oxygen species; HSC, hepatic stellate cell.

Figure 2

Epigenetic pathways implicated in the pathogenesis of NASH. The major pathways and their main effectors are depicted.

Figure 3

Inflammasomes and the liver. In steatosis, hepatic damage leads to generation of damage-associated molecular pattern (DAMPs), while alterations in microbiota lead to increased availability of pathogen-associated molecular patterns (PAMPs). DAMPs and PAMPs act on receptors localized on liver cells leading to activation of different inflammasomes and release of cytokines implicated in NASH. NLRP3: NOD-like receptor family, pyrin domain containing 3; AIM2: Abscent in melanoma 2.