What is Non-Alcoholic Steatohepatitis (NASH)?

Non-Alcoholic Steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease (NAFLD), which refers to the accumulation of fat in the liver of individuals who drink little to no alcohol. In NASH, in addition to fat accumulation (steatosis), there is inflammation and liver cell damage. Over time, NASH can progress to cirrhosis, liver failure, and even liver cancer.


NASH is often associated with obesity, insulin resistance, type 2 diabetes, high cholesterol levels, and metabolic syndrome. However, not all individuals with these risk factors develop NASH, and some people with NASH do not have any known risk factors.


The exact cause of NASH is not fully understood, but it is believed to involve a complex interplay of genetic, environmental, and lifestyle factors. Insulin resistance, oxidative stress, inflammation, and mitochondrial dysfunction are thought to play key roles in the development and progression of NASH.


What is the relationship between NASH and oxidative stress?

The relationship between Non-Alcoholic Steatohepatitis (NASH) and oxidative stress is significant and plays a central role in the development and progression of the disease. Here’s how oxidative stress is implicated in NASH:


  • Fat Accumulation and Lipid Peroxidation: In NASH, there is an abnormal accumulation of fat (steatosis) in the liver. The presence of excess fat can lead to oxidative stress due to increased production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) within hepatocytes (liver cells). These ROS and RNS can damage cellular components, including lipids, through a process known as lipid peroxidation. Lipid peroxidation generates toxic byproducts that can further exacerbate liver injury and inflammation.


  • Mitochondrial Dysfunction: Mitochondria are the cellular organelles responsible for energy production, and they are particularly susceptible to oxidative damage. In NASH, mitochondrial dysfunction is commonly observed, leading to impaired energy metabolism, increased ROS production, and oxidative stress. Oxidative damage to mitochondrial DNA, proteins, and lipids can further impair mitochondrial function and exacerbate liver injury.


  • Inflammatory Response: Oxidative stress triggers an inflammatory response within the liver, characterized by the activation of immune cells such as macrophages and the release of pro-inflammatory cytokines and chemokines. Chronic inflammation is a hallmark feature of NASH and contributes to liver injury and fibrosis. In turn, inflammation can promote oxidative stress through the activation of inflammatory pathways and the recruitment of immune cells that produce ROS.


  • Insulin Resistance: Insulin resistance, a condition in which cells become less responsive to the effects of insulin, is a key factor in the development of NASH. Insulin resistance is associated with increased oxidative stress and impaired antioxidant defense mechanisms. ROS can interfere with insulin signaling pathways and exacerbate insulin resistance, leading to further lipid accumulation and liver injury.


  • Antioxidant Defense Mechanisms: To counteract the harmful effects of oxidative stress, cells have antioxidant defense mechanisms that scavenge ROS and protect against oxidative damage. However, in NASH, the balance between ROS production and antioxidant defenses is disrupted, leading to oxidative stress overload. Reduced levels of antioxidants, such as glutathione and superoxide dismutase, have been observed in individuals with NASH, further exacerbating oxidative damage and liver injury.


Overall, oxidative stress is a central mechanism in the pathogenesis of Non-Alcoholic Steatohepatitis, contributing to liver injury, inflammation, fibrosis, and disease progression.