A double-edged sword: The Kelch-like ECH-associated protein 1-nuclear factor erythroid-derived 2-related factor 2-antioxidant response element pathway targeted pharmacological modulation in nonalcoholic fatty liver disease.

Nutraceuticals activating the Kelch-like epichlorohydrin (ECH)-associated protein 1 (Keap1)-nuclear factor erythroid-derived 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway are widely used for nonalcoholic fatty liver disease (NAFLD) because no specific drugs are approved yet. The pathology of NAFLD is summarized as the 'two-hit' hypothesis. The 'first hit' includes insulin resistance and lipid accumulation. Oxidative stress, lipid peroxidation, and inflammation are regarded as the 'second hit'. Now there is controversial evidence about the roles of the Keap1-Nrf2-ARE pathway and its activators in NAFLD. When the 'first hit' occurs, the hepatocyte-specific Nrf2 deficiency reduces insulin resistance and significantly attenuates lipid accumulation. However, when the 'second hit' occurs, Nrf2 activation reduces oxidative stress and combats inflammation. We reviewed the roles of the Keap1-Nrf2-ARE pathway as a double-edged sword in the development of NAFLD, its inhibitors as a novel therapeutic approach for early NAFLD, and the nutraceutical character of its activators.