Oxidative stress/insulin resistance NAFLD to NASH This study published today is discussing the role of oxidative stress(Oxidative stress is caused by an imbalance between production and accumulation of oxygen reactive species a type of unstable molecule that contains oxygen and that easily reacts with other molecules in a cell. A buildup of reactive oxygen species in cells may cause cell death) /insulin resistance and liver fibrosis, they go on and talk about various antioxidant, vitamin E, diet, some drugs etc. to mitigate the cell damages. We know Tesamorelin reduces both insulin resistance and oxidative stress (two of few mechanism of actions of the drug) that is associated with decrease inflammation. Oxidative stress is per this paper is one of two “second hit” reasons for the progression of NAFLD to NASH the other one ‘first hit” is related to insulin resistance, The conditions are heterogeneous (diverse)so are the etiologies of them, that is why a drug with multiple MOAs like Tesamorelin should be considered as potential treatment of them also it is the current belief a combo therapy utilizing Tesamorelin’ s MOAs with other drugs would likely will be even more promising to treat these conditions.
“NAFLD progresses from simple steatosis to steatohepatitis, fibrosis, cirrhosis, and then to HCC due to insulin resistance, hepatic OS. Fat accumulation in more than 5% of hepatocytes (functional cells of liver) leads to impairment in the metabolism system of the liver. A “two-hit” strike theory was put forward by Day and James to provide a theoretical basis for progression from NAFLD to NASH. The “first hit” is manifested by simple hepatic steatosis. As the intake of free fatty acid increases triglyceride biosynthesis, it leads to fat accumulation in hepatocytes and increase in insulin resistance. Oxidative stress is the initiator of the “second hit.” The first blow initiates metabolic derailment in the mitochondria. ROS further aggravates lipid accumulation and promotes inflammation and fibrosis.
Oxidative Stress-Mediated Hepatocytes Apoptosis (liver cell death). High ROS levels lead to the loss of function of various intracellular organelles which can result in the activation of cell death.
ROS promotes lipid accumulation in hepatocytes through a variety of signaling pathways. The defense mechanisms in hepatocytes are unable to clear ROS and the damaged mitochondria in a timely manner.”
Antioxidants | Free Full-Text | Oxidative Stress Is a Key Modulator in the Development of Nonalcoholic Fatty Liver Disease | HTML (mdpi.com)