Pathophysiology of NASH: Perspectives for a Targeted Treatment

Abstract

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.

Hepatocellular carcinoma is accelerated by NASH involving M2 macrophage polarization mediated by hif-1αinduced IL-10

“…23 Consistent with this, we found increased proinflammatory cytokine induction in HF-HC-HSD fed mice while it was intriguing that the levels of TNFa and MCP-1 were lower in DEN C HF-HC-HSD mice (Fig. 1D).…”

Mosapride citrate improves nonalcoholic steatohepatitis with increased fecal lactic acid bacteria and plasma glucagon-like peptide-1 level in a rodent model

“…3B). Translocation of bacterial endotoxin is considered to play an important role in the pathogenesis of NASH (24). Serum concentrations of LPS were markedly elevated in the MCD diet group as previously reported (12), whereas these levels were normalized in the MCD diet plus MC group (Fig.…”

“…Thus disruption of intestinal homeostasis and alterations of the intestinal microbiota have been considered to contribute to the pathogenesis of many disorders, including liver disease (3,10,37). In fact, several lines of evidence have suggested a role of gut microbiota in the etiology of NAFLD/NASH (1,24,28). Thus microbiota appear to be an important factor affecting the development and progression of NAFLD/NASH, possibly through several mechanisms including lipopolysaccharide (LPS) production in the gut, induction of the inflammatory cascade, modulation of insulin sensitivity, and so on (1,5,9).…”

Development of an in vitro human liver system for interrogating nonalcoholic steatohepatitis

“…Primary human hepatocytes were cocultured with primary human hepatic stellate cells (HSCs) and macrophages (MΦs) and perfused with media containing higher levels of NASH-associated risk factors (glucose, insulin, and FFA) (9). Activation of liver-resident MΦs (i.e., Kupffer cells) and HSCs significantly contribute to the pathogenesis of NASH by promoting inflammation and fibrosis locally in the liver and systemically via the secretome (10). We demonstrate that lipotoxic stress similar to that seen in NASH patients was recapitulated and we measured its impact on hepatocyte morphology and function.…”