Since non-alcoholic steatohepatitis (NASH) became an accepted entity in 1980, its pathogenic mechanisms have remained obscure. Strong associations with central obesity, type 2 diabetes and dyslipidemia have always suggested NASH is a metabolic disorder [2,7,19,23], and by 2003 the connection to insulin resistance was securely evidence-based [6,21]. It has remained unclear, however, why only 10-25% of all those with non-alcoholic fatty liver disease (NAFLD) (25-45% of American adults) have NASH . An early suggestion was that this required a separate (second) injury/pro-inflammatory process additional to the metabolic factors linked to steatosis . While useful in its day to stimulate research, the "two hit" concept does not explain the strong links between NASH and diabetes or metabolic syndrome, a nexus which infers the more severe the "metabolic movers" the more does NAFLD manifest as NASH [6,19,21]. For this and other reasons recently reviewed [1,2,7,19,23], most now accept that hepatocyte accumulation of triglycerides (TG) leads to steatosis, but different lipid molecules mediate the pathogenesis of NASH. Such "toxic lipid species" cause hepatocellular injury and cell death [1,7,30], directly or indirectly inciting inflammatory and pro-fibrotic responses. This set of pathophysiological processes is collectively termed lipotoxicity [2,7,19,23]. Lipotoxicity is now the accepted mechanism for pancreatic beta cell injury in type 2 diabetes, intimal damage in atheroma and cardiac toxicity in metabolic syndrome. Some have even suggested re-naming NASH as "liver lipotoxicity" . To date, however, the identity of the lipid molecule(s) that cause liver lipotoxicity has remained veiled [2,7,23]. Perhaps, like the proverbial possum, the lipotoxic assasin is lying low . Enter the possum!
- non-alcoholic steatohepatitis
- Copyright © 2012, American Journal of Physiology- Gastrointestinal and Liver Physiology