Impact of Glucoraphanin-Mediated Activation of Nrf2 on Non-Alcoholic Fatty Liver Disease with a Focus on Mitochondrial Dysfunction

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a common disease in Western nations and ranges in severity from steatosis to steatohepatitis (NASH). NAFLD is a genetic-environmental-metabolic stress-related disease of unclear pathogenesis. NAFLD is triggered by caloric overconsumption and physical inactivity, which lead to insulin resistance and oxidative stress. A growing body of evidence indicates that mitochondrial dysfunction plays a critical role in the pathogenesis of NAFLD. Mitochondrial dysfunction not only promotes fat accumulation, but also leads to generation of reactive oxygen species (ROS) and lipid peroxidation, resulting in oxidative stress in hepatocytes. Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important modulator of antioxidant signaling that serves as a primary cellular defense against the cytotoxic effects of oxidative stress. The pharmacological induction of Nrf2 ameliorates obesity-associated insulin resistance and NAFLD in a mouse model. Sulforaphane and its precursor glucoraphanin are derived from broccoli sprouts and are the most potent natural Nrf2 inducers-they may protect mitochondrial function, thus suppressing the development of NASH. In this review, we briefly describe the role of mitochondrial dysfunction in the pathogenesis of NASH and the effects of glucoraphanin on its development.

Keywords: Nrf2; chronic inflammation; glucoraphanin; insulin resistance; mitochondrial dysfunction; nonalcoholic fatty liver disease (NAFLD); sulforaphane.

Figure 1

Hypothetical mechanism of NAFLD/NASH progression. Single-nucleotide polymorphisms in several genes—including those encoding patatin-like phospholipase domain-containing 3 (PNPLA3), transmembrane 6 superfamily 2 (TM6SF2), and glucokinase regulatory protein (GCKR)—play important roles in the pathogenesis of NAFLD. Excess caloric consumption and/or physical inactivity induce hyperglycemia, hyperinsulinemia, and high levels of proinflammatory factors, leading to insulin resistance (first hit), and subsequently simple fatty liver (NAFLD). This is followed by other hits, including oxidative stress, chronic inflammation, and the activation of immune cells due to proinflammatory cytokines, the gut microbiota, and mitochondrial dysfunction. These factors cause simple fatty liver to deteriorate to steatohepatitis (NASH) and ultimately hepatic cirrhosis.

Figure 2

Role of mitochondrial dysfunction in the progression of NAFLD and NASH. De novo lipogenesis plays a critical role in the development of NASH. Acetyl-CoA is a substrate for fatty-acid synthesis, and the expression of SREBP-1c and its target genes encoding lipogenic enzymes is induced by circulating insulin. Phosphorylation of AMP-activated protein kinase (AMPK) inhibits the activity of acetyl CoA carboxylase (ACC), decreasing fat accumulation. Peroxisome proliferator-activated receptor (PPAR) α catalyzes fatty-acid β-oxidation in mitochondria. Mitochondrial dysfunction increases ROS production and lipid peroxidation, leading to a high level of oxidative stress and chronic inflammation and fibrosis of the liver.