“Lipotoxicity” (a term coined by Unger) caused by toxic precursors of triglycerides or their metabolites and is thought to play a central role in the pathogenesis of NASH. According to the substrate-overload liver injury model of NASH pathogenesis, the liver’s capacity to handle the primary metabolic energy substrates, carbohydrates and fatty acids, is overwhelmed, leading to accumulation of toxic lipid species. NASH has been described as “the sum of injury and repair responses triggered by lipotoxicity”. Ordinarily, several regulatory mechanisms minimise the production of free fatty acid (FFA) lipotoxic metabolites.The source of hepatic FFA is adipocyte triglyceride lipolysis or hepatocyte de novo lipogenesis from excess carbohydrates and amino acids. The former normally represent 5% of FFA but can be increased 5-fold in NASH. Excessive lipolysis or FFA synthesis increases the supply of fatty acid delivery to the liver and is controlled by a number of neurologic and hormonal actions, some of which can be pharmacologically modulated. Hepatic inflammation is an important component of the process, but it is unclear whether it is a primary cause or consequence (or both) of hepatocyte injury and death.
However, lipotoxicity does not affect just the liver. Triglyceride-derived toxic lipid metabolites accumulate in ectopic tissues and lead to multiorgan dysfunction. Dysfunctional and insulin-resistant adipocytes release toxic triglycerides metabolites from the muscles, the heart, the pancreas and the liver, leading to the metabolic syndrome, T2DM, obesity and CVD. The inflammatory and immune systems, namely macrophages, are involved as well. There is a close relationship between insulin-resistant adipocytes, dysregulated immunity and steatohepatitis. Activated adipose tissue macrophages are important in adipose tissue FFA release, insulin resistance and subsequent liver fat deposition.