Understanding the Role of Exercise in Nonalcoholic Fatty Liver Disease: ERS-Linked Molecular Pathways

Figure 1

ERS and unfolded protein response (UPR). ATF6, IRE-1α, and PERK are the three transmembrane proteins that regulate UPR. GRP78 binds to the three sensor proteins under normal state of protein folding, resulting in UPR silencing. As the misfolded proteins accumulate, GRP78 dissociates from them and binds to the misfolded proteins. Being separated from GRP78, three proteins (ATF6, IRE-1α, and PERK) activate the downstream signaling pathway. The activated IRE-1α slices the mRNA of XBP1 to form the active transcription factor XBP1s [19]. XBP1s inhibits the expression of CHOP and activates ERAD-mediated unfolded protein degradation [15]. However, chronic ERS initiates the death pathway of IRE-1α, including RIDD, to degrade some intracellular mRNA [20]. Meanwhile, IRE-1α not only interacts with TRAF2 to activate ASK1 and Caspase12 but also triggers JNK-mediated apoptosis [21]. Activated PERK can phosphorylate eIF-2α to halt mRNA translation, leading to the reduction of the initiation complex for the temporary loss of protein synthesis. Phosphorylated eIF-2α triggers ATF4 translation, increases the expression of CHOP, and mediates apoptosis [14]. However, chronic ERS induces GADD34 expression to dephosphorylate p-eIF-2α [22]. Under ERS, ATF6 translocates from the ER to the Golgi after being dissociated from GRP78 and obtains transcriptional activity through being cleaved by the proteases S1P and S2P. Sliced ATF6 upregulates the expression of XBP1, which results in relieving ERS by enhancing ERAD or inhibiting the expression of CHOP [23]. Together, downstream effects after these signaling pathways include ERAD of misfolded proteins, inhibition of translation, induction of apoptosis or inflammation, and regulation of lipid metabolism. XBP1: X-box binding protein-1; CHOP: C/EBP homologous protein; ERAD: ER-associated degradation; RIDD: regulated IRE-1α-dependent decay; TRAF2: TNF-receptor associated factor 2; ASK1: apoptosis signal-regulating kinase; JNK: Jun N-terminal kinase; eIF-2α: eukaryotic translation initiation factor 2α; ATF4: activating transcription factor 4; GADD34: DNA damage-inducible gene 34.