ER stress aggravates NOD1-mediated inflammatory response leading to impaired nutrient metabolism in hepatoma cells.

Nucleotide-binding Oligomerization Domain 1 (NOD1) is a cytosolic pattern recognition receptor that senses specific bacterial peptidoglycan moieties, leading to the induction of inflammatory response. Besides, sensing peptidoglycan, NOD1 has been reported to sense metabolic disturbances including the ER stress-induced unfolded protein response (UPR). However, the underpinning crosstalk between the NOD1 activating microbial ligands and the metabolic cues to alter metabolic response is not yet comprehensively defined. Here, we show that underlying ER stress aggravated peptidoglycan-induced NOD1-mediated inflammatory response in hepatoma cells. The HepG2 cells, undergoing ER stress induced by thapsigargin exhibited an amplified inflammatory response induced by peptidoglycan ligand of NOD1 (i.e. iE-DAP). This aggravated inflammatory response disrupted lipid and glucose metabolism, characterized by de novo lipogenic response, and increased gluconeogenesis in HepG2 cells. Further, we characterized that the aggravation of NOD1-induced inflammatory response was dependent on inositol-requiring enzyme 1-α (IRE1-α) and protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) activation, in conjunction with calcium flux. Altogether, our findings suggest that differential UPR activation makes liver cells more sensitive towards bacterial-derived ligands to pronounce inflammatory response in a NOD1-dependent manner that impairs hepatic nutrient metabolism.