Non alcoholic steatohepatitis (NASH) is the more severe form of nonalcoholic fatty liver disease. In NASH, fatty liver, hepatic
inflammation, hepatocyte injury and fibrogenesis are associated, and this condition may eventually lead to cirrhosis. Current treatment of
NASH relies on the reduction of body weight and increase in physical activity, but there is no pharmacologic treatment approved as yet.
Emerging data indicate that NASH progression results from parallel events originating from the liver as well as from the adipose tissue,
the gut and the gastrointestinal tract. Thus, dysfunction of the adipose tissue through enhanced flow of free fatty acids and release of adipocytokines,
and alterations in the gut microbiome generate proinflammatory signals that underlie NASH progression. Additional ‘extrahepatic
hits’ include dietary factors and gastrointestinal hormones. Within the liver, hepatocyte apoptosis, ER stress and oxidative stress
are key contributors to hepatocellular injury. In addition, lipotoxic mediators and danger signals activate Kupffer cells which initiate and
perpetuate the inflammatory response by releasing inflammatory mediators that contribute to inflammatory cell recruitment and
development of fibrosis. Inflammatory and fibrogenic mediators include chemokines, the cannabinoid system, the inflammasome and
activation of pattern-recognition receptors.
Here we review the major mechanisms leading to appearance and progression of NASH, focusing on both extrahepatic signals and local
inflammatory mechanisms, in an effort to identify the most promising molecular targets for the treatment of this condition.
Keywords: Inflammation, Kupffer cells, hepatic stellate cells, adipokine, lipotoxicity, cannabinoids, cytokines, chemokines, microbiome,
toll-like receptors, oxidative stress, inflammasome.
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