Inhibition of the IL-1R1 pathway in hepatocytes reduces tumor growth in a mouse model of NAFLD-associated HCC

Question Non-alcoholic fatty liver disease (NAFLD) is a relevant risk factor for developing hepatocellular carcinoma (HCC) even in the absence of advanced fibrosis or cirrhosis; however, little is known about the specific molecular mechanisms involved. Given the critical role of interleukin (IL)-1 signaling in inflammation and metabolism, we used hepatocyte-specific IL-1 receptor type 1 (IL-1R1) knockout (Il1r1 ^Hep-/-) mice to examine the contribution of this pathway in NAFLD-associated hepatocarcinogenesis.

Methods Diethylnitrosamine (DEN, 25 mg/kg) was given i.p. to 2-week-old, male Il1r1 ^Hep-/- mice and wild-type (WT) littermates. From 6 weeks of age the mice were fed either a high-fat, high-carbohydrate diet (HFD, n=8/genotype) or a control diet (CD, n=4/genotype) until sacrifice at 24 weeks of age.

Results In contrast to the DEN/CD groups with a lean phenotype, all mice treated with DEN/HFD displayed significant obesity, hyperlipidemia, and hyperglycemia; however Il1r1 ^Hep-/- mice were less susceptible to elevations of fasting glucose and HOMA-IR levels compared to WT mice. Both genotypes were similar prone to develop HFD-induced liver enlargement, elevated serum transaminases, and NAFL-histology with macrovesicular steatosis, but without significant inflammation or fibrosis. Additionally, adding HFD to DEN led to a significant increase in macroscopically visible dysplastic lesions in liver tissue compared to the CD. Despite heterogeneity, the average number and volume of tumors formed in Il1r1 ^Hep-/- livers were lower than those for WT mice, two of which developed 10mm tumor nodules. Also histopathological examination of the left lateral liver lobe revealed a 2.7-fold increase in dysplastic foci >1mm in WT compared to transgenic mice. While both DEN/HFD groups exhibited a comparable increase in circulating MCP-1 levels and relative number of GR1⁺F4/80⁺ intrahepatic cells in parallel to a slight decrease of CD4⁺ T cells, increases in serum CXCL-1 were less pronounced in Il1r1 ^Hep-/- mice compared to WT littermates.

Conclusions HFD-feeding to DEN-injected mice strongly enhances liver tumor development with an incidence rate of 100 % at already 24 weeks of age. There is early evidence that inhibition of the IL-1R1 pathway in hepatocytes leads to reduced tumor growth under these conditions. It remains to be determined whether improved insulin sensitivity and/or inflammatory processes in Il1r1 ^Hep-/- mice are critical for reduced tumor burden.

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Artikel online veröffentlicht:
04. Januar 2021