Pattern recognition receptors in the development of nonalcoholic fatty liver disease and progression to hepatocellular carcinoma: An emerging therapeutic strategy

Abstract

Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation and has become the leading chronic liver disease worldwide. NAFLD is viewed as the hepatic manifestation of metabolic syndrome, ranging from simple steatosis and nonalcoholic steatohepatitis (NASH) to advanced fibrosis, eventually leading to cirrhosis and hepatocellular carcinoma (HCC). The pathogenesis of NAFLD progression is still not clear. Pattern recognition receptor (PRR)-mediated innate immune responses play a critical role in the initiation of NAFLD and the progression of NAFLD-related HCC. Toll-like receptors (TLRs) and the cyclic GMP-AMP (cGAMP) synthase (cGAS) are the two major PRRs in hepatocytes and resident innate immune cells in the liver. Increasing evidence indicates that the overactivation of TLRs and the cGAS signaling pathways may contribute to the development of liver disorders, including NAFLD progression. However, induction of PRRs is critical for the release of type I interferons (IFN-I) and the maturation of dendritic cells (DCs), which prime systemic antitumor immunity in HCC therapy. In this review, we will summarize the emerging evidence regarding the molecular mechanisms of TLRs and cGAS in the development of NAFLD and HCC. The dysfunction of PRR-mediated innate immune response is a critical determinant of NAFLD pathology; targeting and selectively inhibiting TLRs and cGAS signaling provides therapeutic potential for treating NALF-associated diseases in humans.

Keywords: HCC; NAFLD; PRR; inflammation; innate immune signaling pathway.

Figure 1

The role of Toll-like receptors (TLRs) in the pathogenesis of NAFLD and HCC. Following excessive high-fat diet intake and liver injury, PAMPs (e.g., LPS, flagellin, lipopeptides and DNA) from microbes and DAMPs released from damaged or dying cells are accumulated in the liver. TLRs recognize PAMPs and DAMPs and initiate downstream cascades in TRIF- or MyD88-dependent manner. The activation of IKK, MAPKs and TBK1 kinases trigger dimerization and translocation of NF-κB, AP-1 and IRF3/7 respectively, then induce the expression of several cytokines, chemokines, type I interferons, and other pro-apoptotic genes. The secretion of these active factors may contribute to insulin resistance, lipid accumulation, inflammation, hepatocyte apoptosis or anti-cancer responses. Different TLRs play diverse roles in the process of NAFLD to HCC. PAMPs, pathogen-associated molecular patterns; DAMPs, damage-associated molecular patterns; TRIF, TIR-domain-containing adapter-inducing interferon β; MyD88, myeloid differentiation primary response 88; IKK, IκB kinase; MAPK, mitogen-activated protein kinase; TBK1, TANK-binding kinase 1; NF- κB, nuclear factor kappa B; AP-1, activator protein 1; IRF, interferon regulatory factor. Red, accelerative effect; Green, protective effect.

Figure 2

The cGAS-STING signaling pathway in the progression from NAFLD to HCC. A schematic detailing cytosolic dsDNA, which occurs through pathogen infection, tumor cells, death cells or cellular stress, can be recognized by cGAS. Enzymatic activation of cGAS results in the synthesis of 2′-3′ cGAMP. The binding of cGAMP enables STING translocation from ER membrane to Golgi, then recruits TBK1 and IKK complex. The phosphorylation of IRF3 and NF-κB by TBK1 and IKK enable these transcription factor dimerization and translocation to the nucleus to induce gene expression of several cytokines, type I interferons, and chemokines. Activation of cGAS-STING signaling axis could promote lipid accumulation, inflammation, or anti-cancer responses in different stage of liver disease. dsDNA, double-stranded DNA; cGAS, cyclic GMP-AMP synthase; 2′-3′ cGAMP, 2′3′ cyclic GMP-AMP; STING, stimulator of interferon genes; ER, endoplasmic reticulum; TBK1, TANK-binding kinase 1; IKK, IκB kinase; IRF3, interferon regulatory factor 3. Red, accelerative effect; Green, protective effect.