Multiple hits, including oxidative stress, as pathogenesis and treatment target in non-alcoholic steatohepatitis (NASH)

Abstract

Multiple parallel hits, including genetic differences, insulin resistance and intestinal microbiota, account for the progression of non-alcoholic steatohepatitis (NASH). Multiple hits induce adipokine secretion, endoplasmic reticulum (ER) and oxidative stress at the cellular level that subsequently induce hepatic steatosis, inflammation and fibrosis, among which oxidative stress is considered a key contributor to progression from simple fatty liver to NASH. Although several clinical trials have shown that anti-oxidative therapy can effectively control hepatitis activities in the short term, the long-term effect remains obscure. Several trials of long-term anti-oxidant protocols aimed at treating cerebrovascular diseases or cancer development have failed to produce a benefit. This might be explained by the non-selective anti-oxidative properties of these drugs. Molecular hydrogen is an effective antioxidant that reduces only cytotoxic reactive oxygen species (ROS) and several diseases associated with oxidative stress are sensitive to hydrogen. The progress of NASH to hepatocellular carcinoma can be controlled using hydrogen-rich water. Thus, targeting mitochondrial oxidative stress might be a good candidate for NASH treatment. Long term clinical intervention is needed to control this complex lifestyle-related disease.

Figure 1

Multiple parallel hit theory. Genome-wide association studies have confirmed importance of patatin-like phospholipase 3 (PNPLA3) gene polymorphism in NAFLD. This genetic polymorphism can differentiate simple steatosis with or without minimal inflammation and fibrosis progressing to NASH. In some instances, inflammation could precede steatosis and anti-tumor necrosis factor (TNF)-α antibody improves steatosis in ob/ob mice. Obesity and diabetes induce insulin resistance, adipocyte proliferation and changes in intestinal flora. Adipokines such as IL-6 and TNF-α produced by adipocytes affect hepatocyte fat content and liver inflammatory environment. Gut-derived signals could be affected by ingested trans fatty acids, fructose, or TLR ligands. Ingested free fatty acids and free cholesterol induce ER stress and oxidative stress resulting in hepatic inflammation and fibrogenesis.

Figure 2

Mitochondria as producers of oxidative stress. High levels of plasma free fatty acids allow upregulation of hepatic free fatty acids. Long-chain fatty acids taken up into mitochondria as complexes with l-carnitine are then transferred to β-oxidation pathway. Under oxidative stress, oxidative reactions convert oxidized cofactors (NAD+ and FAD) into reduced cofactors (NADH and FADH2) and deliver electrons to respiratory chain. Imbalance between increased delivery of electrons to respiratory chain and their decreased outflow from this chain causes electrons and ROS products to accumulate. Anti-oxidant defenses such as superoxide dismutase (SOD), glutathione peroxidase (GPx) or catalase can metabolize hydrogen peroxide to non-toxic H₂O. However, the Fenton and/or Haber-Weiss reactions generate highly reactive toxic ROS, hydrogen peroxide. Hydrogen as selective cytotoxic ROS scavenger and l-carnitine as mitochondrial function supporting factor might be good candidates for controlling mitochondrial oxidative stress.