Evolving Concepts in the Pathogenesis of NASH: Beyond Steatosis and Inflammation

Abstract

Non-alcoholic steatohepatitis (NASH) is characterised by hepatic steatosis and inflammation and, in some patients, progressive fibrosis leading to cirrhosis. An understanding of the pathogenesis of NASH is still evolving but current evidence suggests multiple metabolic factors critically disrupt homeostasis and induce an inflammatory cascade and ensuing fibrosis. The mechanisms underlying these changes and the complex inter-cellular interactions that mediate fibrogenesis are yet to be fully elucidated. Lipotoxicity, in the setting of excess free fatty acids, obesity, and insulin resistance, appears to be the central driver of cellular injury via oxidative stress. Hepatocyte apoptosis and/or senescence contribute to activation of the inflammasome via a variety of intra- and inter-cellular signalling mechanisms leading to fibrosis. Current evidence suggests that periportal components, including the ductular reaction and expansion of the hepatic progenitor cell compartment, may be involved and that the Th17 response may mediate disease progression. This review aims to provide an overview of the pathogenesis of NASH and summarises the evidence pertaining to key mechanisms implicated in the transition from steatosis and inflammation to fibrosis. Currently there are limited treatments for NASH although an increasing understanding of its pathogenesis will likely improve the development and use of interventions in the future.

Active form of vitamin D ameliorates non-alcoholic fatty liver disease by alleviating oxidative stress in a high-fat diet rat model

“…This theory posits that the first hit is lipid accumulation in the hepatocytes and the second hit is oxidative stress-induced lipotoxicity, which promotes cellular injury leading to NASH [22,23]. In the present study, body weights, liver enzymes, serum TGs, and intrahepatic TGs were significantly elevated in group HFD rats.…”

The differential effects of high-fat and high fructose diets on the liver of male albino rat and the proposed underlying mechanisms

“…In NAFLD progression, the "two-hit" theory is generally established [11]. The first hit is lipid accumulation in the hepatocytes and the second hit is oxidative stress-induced lipotoxicity, which stimulates cellular injury leading to NASH [26].…”

Nicht-alkoholische Fettlebererkrankung (NAFLD)

“…Zur hepatozellulären Schädigung tragen im Wesentlichen ▶ die Lipotoxizität, ▶ die Insulinresistenz und ▶ der oxidative Stress bei [33]. Bei 10-20 % der NASH-Patienten kommt es zu einer zunehmenden Fibrosierung bis hin zur Leberzirrhose (< 5 %) [9].…”