Toll-like receptor 7 affects the pathogenesis of non-alcoholic fatty liver disease

Sokho Kim,Surim Park,Bumseok Kim,Jungkee Kwon

doi:10.1038/srep27849

Abstract

Recently, a possible link between toll-like receptor 7 (TLR7) and liver disease was suggested, although it was limited to fibrosis. Based on this report, we investigated whether TLR7 has a pivotal role in non-alcoholic fatty liver disease (NAFLD). The TLR7 signaling pathway, which is activated by imiquimod (TLR7 ligand) naturally, induced autophagy and released insulin-like growth factor 1 (IGF-1) into medium from hepatocytes. Lipid accumulation induced by unsaturated fatty acid (UFA; arachidonic acid:oleic acid = 1:1) in hepatocytes, was attenuated in TLR7 and autophagy activation. Interestingly, TLR7 activation attenuated UFA-induced lipid peroxidation products, such as malondialdehyde (MDA) and 4-Hydroxy-2-Nonenal (4-HNE). To clarify a possible pathway between TLR7 and lipid peroxidation, we treated hepatocytes with MDA and 4-HNE. MDA and 4-HNE induced 2-folds lipid accumulation in UFA-treated hepatocytes via blockade of the TLR7 signaling pathway’s IGF-1 release compared to only UFA-treated hepatocytes. In vivo experiments carried out with TLR7 knockout mice produced results consistent with in vitro experiments. In conclusion, TLR7 prevents progression of NAFLD via induced autophagy and released IGF-1 from liver. These findings suggest a new therapeutic strategy for the treatment of NAFLD.

Highlights

We clarified the role of autophagy, insulin-like growth factor 1 (IGF-1), and lipid peroxidation products such as malondialdehyde (MDA) and 4-Hydroxy-2-Nonenal (4-HNE), which are associated with TLR7, at both the cellular and tissue levels under Non-alcoholic fatty liver disease (NAFLD)
TLRs play a pivotal role in innate immune responses against extrinsic pathogens such as microorganisms and it activates two independent pathways such as the MyD88 pathway for all TLRs except TLR3 and MyD88-independent for TLR3 and TLR4. These TLRs may have a crucial role in the pathogenesis of chronic liver disease[13,14,37,38]
These studies suggested that TLR4 can lead to progression of NAFLD, while TLR2 prevents NAFLD progression via uptake of diacylated lipoproteins

Summary

Introduction

Other TLR7 agonists[15]. the role of TLR7 signaling in liver fibrosis has been demonstrated[14], the role of TLR7 signaling in the progression of NAFLD has not been elucidated. The aim of the present study was to demonstrate whether TLR7 is required for progressive NAFLD. We clarified the role of autophagy, IGF-1, and lipid peroxidation products such as malondialdehyde (MDA) and 4-Hydroxy-2-Nonenal (4-HNE), which are associated with TLR7, at both the cellular and tissue levels under NAFLD. We elucidated whether MDA and 4-HNE could exert deleterious effects on TLR7 levels and clarified the possible mechanisms underlying the role of TLR7 in preventing progressive NAFLD. We confirmed these in vitro results using an in vivo mouse model of NAFLD

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Conclusion