The Dual Role of Nrf2 in Nonalcoholic Fatty Liver Disease: Regulation of Antioxidant Defenses and Hepatic Lipid Metabolism

Figure 1

Activation of the Keap1-Nrf2-ARE pathway by oxidants/electrophiles. Under homeostatic conditions, Nrf2 is mainly localized in the cytoplasm through an interaction with Keap1 and the actin cytoskeleton. Keap1 is a five-domain protein consisting of an N-terminal broad complex, Tramtrack and Bric-à-brac (BTB) domain, an intervening region with cysteine (Cys) residues, a C-terminal Kelch domain with double glycine repeats (DGR), and the C-terminal domain. Keap1 homodimerizes at the BTB domain, which is also a binding site for Cullin 3 (Cul3). The Keap1 homodimer binds to a single Nrf2 molecule through the ETGE and DLG motifs of Nrf2, each binding to a DGR domain in Keap1. According to the proposed hinge and latch model [13], ETGE is a high-affinity motif (“hinge”) whereas DLG is a low-affinity one (“latch”). Keap1 functions as an adaptor protein in the Cul3-based E3 ligase complex, which results in the polyubiquitination (Ub) of the lysine residues situated between the DLG and ETGE motifs, and subsequent proteasomic degradation of Nrf2. Under stressed conditions, the modification of critical cysteine residues of Keap1 destabilizes its binding to the DLG motif of Nrf2, which blocks ubiquitination/proteasomal degradation and allows Nrf2 to escape Keap1 control and translocate into the nucleus. In the nucleus, Nrf2 heterodimerizes with small Maf proteins and promotes the expression of ARE-containing genes involved in cell stress response, drug metabolism, detoxification, and transport. Nrf2 may also be phosphorylated (P) by stress-activated kinases.