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

Chen Huang; Youlian Zhou; Jiemin Cheng; Xue Guo; Diwen Shou; Ying Quan; Hanqing Chen; Huiting Chen; Yongjian Zhou

doi:10.3389/fendo.2023.1145392

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

Front Endocrinol (Lausanne). 2023 Mar 20:14:1145392. doi: 10.3389/fendo.2023.1145392. eCollection 2023.

Authors

Chen Huang¹, Youlian Zhou^{1

2}, Jiemin Cheng^{1

2}, Xue Guo^{1

2}, Diwen Shou^{1

2}, Ying Quan^{1

2}, Hanqing Chen^{1

2}, Huiting Chen¹, Yongjian Zhou^{1

2}

Affiliations

¹ Department of Gastroenterology and Hepatology, Guangzhou Key Laboratory of Digestive Diseases, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China.
² Department of Gastroenterology and Hepatology, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, China.

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.

Publication types

Review
Research Support, Non-U.S. Gov't

MeSH terms

Carcinoma, Hepatocellular* / metabolism
Disease Progression
Fibrosis
Humans
Liver Neoplasms* / metabolism
Non-alcoholic Fatty Liver Disease* / metabolism
Toll-Like Receptors

Substances

Toll-Like Receptors

Grants and funding

This study was supported by National Natural Science Foundation of China (82170585, 82200574, 81970507 and 32171370), The Fundamental Research Funds for the Central Universities (y2eyD2220570), the Natural Science Foundation of Guangdong Province (2022A1515010415), Funding by Science and Technology Projects in Guangzhou (SL2023A04J00596), Guangzhou High Technology Project (2019GX05), The Project of Key Medical Discipline in Guangzhou (2021-2023).