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
Summary
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].
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