Question: Pathogenesis The Pathogenesis Of NASH Is Still Unclear, However, It Is Known To Occur In The Setting Of Steatosis. Indeed, Insulin Resistance, Which Occurs In The Large Majority Of Patients With NAFLD, Is Thought To Feature Prominently In The Development Of Steatosis. Resistance To Insulin’s Nor- Mal Suppression Of Lipolysis Would Result In The Release …

Pathogenesis The pathogenesis of NASH is still unclear, however, it is known to occur in the setting of steatosis. Indeed, insulin resistance, which occurs in the large majority of patients with NAFLD, is thought to feature prominently in the development of steatosis. Resistance to insulin’s nor- mal suppression of lipolysis would result in the release of fatty acids from TAGs stored in adipocytes. The increased circulating levels of fatty acids would lead to increased influx into the liver, where TAGs are formed; this together with decreased hepatic TAG export and c- tabolism have been proposed to lead to steatosis. However, steatosis alone does not cause cel- lular injury, nor does it affect liver function, and is thus a benign condition. It has been proposed that a “second hit” is necessary for the development of NASH. Oxidative stress has been proposed to lead to the more pathogenic forms of NAFLD. Oxidative stress is generated during peroxisomal fatty acid metabolism in the form of perox- ide (see Section 22.3.4 of Biochemistry 5e), and evidence also implicates the microsomal (i.e., endoplasmic reticulum) enzyme, cytochrome P450 CYP2E1, in generating reactive oxygen species (ROS). CYP2E) is an oxidase involved in microsomal metabolism of fatty acids. Fatty acids are both inducers and substrates for this enzyme, and its level is markedly elevated in patients with NASH. Oxidative stress would then trigger lipid peroxidation, which further causes cellular damage via reactive intermediates. Evidence of lipid peroxidation has been ob- served in animal models of the disease. The products of lipid peroxidation (such as malon- dialdehyde and 4-hydroxynonenol) can induce inflammation and fibrosis, which may lead to necrosis, thus accounting for all the pathological features associated with the livers of those with NASH. Although some evidence exists for this mechanism of pathogenesis, the precise sequence of events is as yet unproven. Indeed, inflammation itself generates ROS, and thus inflammation may precede the generation of oxidative stress,