NOD-like receptors in the pathogenesis of metabolic (dysfunction)-associated fatty liver disease: Therapeutic agents targeting NOD-like receptors

Shaghayegh Khanmohammadi; Bruno Ramos-Molina; Mohammad Shafi Kuchay

doi:10.1016/j.dsx.2023.102788

NOD-like receptors in the pathogenesis of metabolic (dysfunction)-associated fatty liver disease: Therapeutic agents targeting NOD-like receptors

Diabetes Metab Syndr. 2023 Jul;17(7):102788. doi: 10.1016/j.dsx.2023.102788. Epub 2023 Jun 4.

Authors

Shaghayegh Khanmohammadi¹, Bruno Ramos-Molina², Mohammad Shafi Kuchay³

Affiliations

¹ Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Science, Tehran, Iran.
² Obesity and Metabolism Laboratory, Biomedical Research Institute of Murcia (IMIB), 30120 Murcia, Spain.
³ Divison of Endocrinology and Diabetes, Medanta the Medicity Hospital, Gurugram 122001, Haryana, India. Electronic address: drshafikuchay@gmail.com.

PMID: 37302383
DOI: 10.1016/j.dsx.2023.102788

Abstract

Background and aims: In metabolic (dysfunction)-associated fatty liver disease (MAFLD), activation of inflammatory processes marks the transition of simple steatosis to steatohepatitis, which can further evolve to advanced fibrosis or hepatocellular carcinoma. Under the stress of chronic overnutrition, the innate immune system orchestrates hepatic inflammation through pattern recognition receptors (PRRs). Cytosolic PRRs that include NOD-like receptors (NLRs) are crucial for inducing inflammatory processes in the liver.

Methods: A literature search was performed with Medline (PubMed), Google Scholar and Scopus electronic databases till January 2023, using relevant keywords to extract studies describing the role of NLRs in the pathogenesis of MAFLD.

Results: Several NLRs operate through the formation of inflammasomes, which are multimolecular complexes that generate pro-inflammatory cytokines and induce pyroptotic cell death. A multitude of pharmacological agents target NLRs and improve several aspects of MAFLD. In this review, we discuss the current concepts related to the role of NLRs in the pathogenesis of MAFLD and its complications. We also discuss the latest research on MAFLD therapeutics functioning through NLRs.

Conclusions: NLRs play a significant role in the pathogenesis of MAFLD and its consequences, especially through generation of inflammasomes, such as NLRP3 inflammasomes. Lifestyle changes (exercise, coffee consumption) and therapeutic agents (GLP-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors, obeticholic acid) improve MAFLD and its complications partly through blockade of NLRP3 inflammasome activation. New studies are required to explore these inflammatory pathways fully for the treatment of MAFLD.

Keywords: Fibrosis; Inflammation; Metabolic (dysfunction)-associated fatty liver disease; NLRP3 inflammasome; NOD-Like receptors; Steatohepatitis.

Publication types

Review

MeSH terms

Humans
Inflammasomes / metabolism
NLR Family, Pyrin Domain-Containing 3 Protein
NLR Proteins
Non-alcoholic Fatty Liver Disease*
Receptors, Pattern Recognition
Sodium-Glucose Transporter 2 Inhibitors*

Substances

Inflammasomes
NLR Family, Pyrin Domain-Containing 3 Protein
NLR Proteins
Receptors, Pattern Recognition
Sodium-Glucose Transporter 2 Inhibitors