Role of Insulin Resistance and Lipotoxicity in Non-Alcoholic Steatohepatitis

It is well established that the development of NAFLD and NASH are closely linked to an excess flow of free fatty acids (FFA) arising from dysfunctional/insulin resistant adipose tissue causing ectopic fat deposition in many organs. In the liver, when chronic lipid supply surpasses the metabolic ability to adapt it will induce hepatocellular damage as FFA are redirected into harmful pathways of non-oxidative metabolism with intracellular accumulation of toxic lipid-derived metabolites. Multiple mechanisms have been implicated including mitochondrial dysfunction, endoplasmic reticulum stress, and activation of multiple inflammatory pathways. Understanding the role of insulin resistance and lipotoxicity in NASH as part of a broader metabolic disorder is likely to assist practitioners in the successful management of these challenging patients.