Abstract

In Western countries, a rising incidence of obesity and type 2 diabetes correlates with an increase of non-alcoholic steatohepatitis (NASH)-a major risk factor for liver cirrhosis and hepatocellular carcinoma (HCC). NASH is associated with chronic liver injury, triggering hepatocyte death and enhanced translocation of intestinal bacteria, leading to persistent liver inflammation through activation of Toll-like receptors and their adapter protein myeloid differentiation factor 88 (MyD88). Therefore, we investigated the role of MyD88 during progression from NASH to HCC using a mouse model of chronic liver injury (hepatocyte-specific deletion of nuclear factor κB essential modulator, Nemo; NemoΔhepa). NemoΔhepa; NemoΔhepa/MyD88-/- and NemoΔhepa/MyD88Δhepa were generated and the impact on liver disease progression was investigated. Ubiquitous MyD88 ablation (NemoΔhepa/MyD88-/-) aggravated the degree of liver damage, accompanied by an overall decrease in inflammation, whereas infiltrating macrophages and natural killer cells were elevated. At a later stage, MyD88 deficiency impaired HCC formation. In contrast, hepatocyte-specific MyD88 deletion (NemoΔhepa/MyD88Δhepa) did not affect disease progression. These results suggest that signaling of Toll-like receptors through MyD88 in non-parenchymal liver cells is required for carcinogenesis during chronic liver injury. Hence, blocking MyD88 signaling may offer a therapeutic option to prevent HCC formation in patients with NASH.

Highlights

  • Primary liver cancer is the sixth most common type of cancer and the second leading cause of cancer-related deaths worldwide with almost 800 000 deaths each year [1]

  • Hepatocyte-specific myeloid differentiation factor 88 (MyD88) deletion (NemoΔhepa/MyD88Δhepa) did not affect disease progression. These results suggest that signaling of Toll-like receptors through MyD88 in non-parenchymal liver cells is required for carcinogenesis during chronic liver injury

  • To determine the importance of Toll-like receptor (TLR) signaling in liver cells during chronic liver disease (CLD), we investigated the impact of MyD88 deletion on disease progression in the NemoΔhepa model

Read more

Summary

Introduction

Primary liver cancer is the sixth most common type of cancer and the second leading cause of cancer-related deaths worldwide with almost 800 000 deaths each year [1]. During chronic liver injury, increased intestinal permeability causes translocation of bacterial products to the liver via the portal vein [4] These products are commonly termed pathogen-associated molecular patterns (PAMPS) and include lipopolysaccharide (LPS) and unmethylated CpG-containing DNA [4]. Chronic liver injury is characterized by increased occurrence of hepatocyte cell death leading to the release of various substances such as HMGB1 and mitochondrial DNA, which are collectively termed damageassociated molecular patterns (DAMPS) [5]. Both PAMPS and DAMPS trigger activation of pattern recognition receptors of the Toll-like receptor (TLR) family [6].

Objectives
Methods
Results
Conclusion

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call

Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.