Role of toll-like receptors and their downstream molecules in the development of nonalcoholic Fatty liver disease

Abstract

Activation of innate immunity is associated with the development of liver disease, including non-alcoholic fatty liver disease (NAFLD). In the innate immune system, Toll-like receptors (TLRs) are sensors that recognize bacterial and viral components such as lipopolysaccharide, bacterial DNA, and peptidoglycan. Recent data have demonstrated that the liver is exposed to a high load of TLR ligands due to bacterial overgrowth and increased intestinal permeability in NAFLD. Upon stimulation by these TLR ligands, hepatic immune cells produce various mediators that are involved in host defense. On the other hand, these mediators alter lipid metabolism, insulin signaling, and cell survival. Indeed, some TLR-deficient mice demonstrate lesser degrees of NAFLD even though TLR ligands are increased. This paper will highlight the recent progress on the study of TLR signaling and their downstream molecules in the development of NAFLD.

Figure 1

TLRs and downstream signaling in NAFLD. Kupffer cells respond to TLR ligands such as LPS and bacterial DNA through TLR4 and TLR9, respectively. Upon TLR ligation, MyD88, an adaptor molecule, is recruited to transmit the signals that activate NF-κB and JNK. Activated Kupffer cells produce inflammatory cytokines such as TNFα and IL-1β and chemokines such as MCP-1 (CCL2). These inflammatory cytokines and chemokines induce lipid accumulation in hepatocytes and cell death. In addition, TNFα and IL-1β promote liver fibrosis by activating hepatic stellate cells. Other cells including hepatic resident cells, infiltrated cells into the liver, and adipose tissue macrophages produce various mediators in response to TLR ligands. These pathways also contribute to the development of NAFLD.