| First Author | Van Campenhout S | Year | 2020 |
| Journal | Metabolism | Volume | 107 |
| Pages | 154220 | PubMed ID | 32243868 |
| Mgi Jnum | J:293422 | Mgi Id | MGI:6452704 |
| Doi | 10.1016/j.metabol.2020.154220 | Citation | Van Campenhout S, et al. (2020) Myeloid-specific IRE1alpha deletion reduces tumour development in a diabetic, non-alcoholic steatohepatitis-induced hepatocellular carcinoma mouse model. Metabolism 107:154220 |
| abstractText | BACKGROUND AND AIMS: Obesity, diabetes and associated non-alcoholic steatohepatitis (NASH) are rising risk factors for hepatocellular carcinoma (HCC). Macrophages are important immune cells involved in inflammation and tumour development. Macrophage inositol-requiring enzyme 1 alpha (IRE1alpha), an ER-stress protein, has been shown to be involved in macrophage cytokine production, and myeloid-specific IRE1alpha knock-out (myeloid IRE1alpha-KO) mice showed reduced weight gain during high-fat diet feeding. However, the effect of myeloid IRE1alpha on NASH and subsequent HCC development has not been examined. Here, we characterized the transcriptional profile of the hepatic macrophage population in a diabetes-NASH-HCC mouse model, and investigated the effect of myeloid-specific IRE1alpha deletion on the phenotype of hepatic macrophage subsets and experimental NASH-HCC development. METHODS: Mice with non-functional myeloid IRE1alpha were created by crossing Ire1a floxed mice with Lysm-Cre mice. Two-day old myeloid IRE1alpha-KO and wild type (WT) mice were subcutaneously injected with streptozotocin (STZ), and male mice were fed a high-fat, -sucrose, -cholesterol diet (Western diet, WD) from the age of 4weeks until 21weeks. Control myeloid IRE1alpha-KO and WT mice received a PBS injection and were fed a matched control diet. These mice were evaluated for obesity, diabetes, NASH and HCC. The hepatic macrophage population was evaluated by flow cytometry and RNA sequencing on FACS-isolated macrophage subsets. RESULTS: STZ-injection and WD feeding resulted in an impaired glucose tolerance, advanced NASH with fibrosis, and HCC development. Myeloid IRE1alpha-KO STZ mice showed lower fasting glucose levels at the start of WD feeding, and an improved glucose tolerance and attenuated HCC development after 17weeks of WD feeding despite a similar degree of liver steatosis and inflammation compared to WT mice. Transcriptomic analysis of WT liver Kupffer cells, macrophages and monocytes revealed phenotypical changes in those cell subsets during NASH-HCC development. Isolated liver Kupffer cells and macrophages from mice with a myeloid IRE1alpha deletion showed downregulated pathways involved in immune system activation and metabolic pathways (only in Kupffer cells), whereas pathways involved in cell division and metabolism were upregulated in monocytes. These transcriptional differences were attenuated during NASH-HCC development. CONCLUSION: Our results show that myeloid-specific IRE1alpha deletion results in an altered transcriptional profile of hepatic macrophages and dampens diabetes-induced NASH-HCC development, possibly by attenuated diabetes induction. |
