Diabetes Accelerates Steatohepatitis in Mice
Tuerdiguli Abuduyimiti, Hisanori Goto, Kumi Kimura, Yu Oshima, Ryota Tanida, Kyoko Kamoshita, Nontaphat Leerach, Halimulati Abuduwaili, Hein Ko Oo, Qifang Li, Cynthia M. Galicia‐Medina, Hiroaki Takayama, Kiyo‐aki Ishii, Yujiro Nakano, Yumie Takeshita, Tomohiro Iba, Hisamichi Naito, Masao Honda, Kenichi Harada, Yasuhiko Yamamoto, Toshinari Takamura
Abstract
Glucose lowering independently reduces liver fibrosis in human NAFLD. We investigated the impact of diabetes on steatohepatitis and established a novel mouse model for diabetic steatohepatitis.Male C57BL/6J mice were fed a 60% high-fat diet (HFD) and injected with carbon tetrachloride (CCl4) and streptozotocin (STZ) to induce diabetes. The HFD+CCl4+STZ group displayed more severe liver steatosis, hepatocyte ballooning, and regenerative nodules compared to other groups. Diabetes upregulated inflammatory cytokine-associated genes and elevated the M1/M2 macrophage ratios in the liver. Single-cell RNA sequencing (scRNAseq) analysis of non-parenchymal cells in the liver showed that diabetes reduced the Kupffer cells and increased bone marrow-derived recruited inflammatory macrophages, such as Ly6Chi-RM. Diabetes globally reduced liver sinusoidal endothelial cells (LSECs). Furthermore, the upregulation of genes related to the receptor for advanced glycation end products (RAGE)/toll-like receptor 4 (TLR4) was observed in Ly6Chi-RM and LSECs under diabetes, suggesting a possible role of the RAGE/TLR4 signaling in the interaction between inflammatory macrophages and LSECs.The study established a novel diabetic steatohepatitis model using a combination of HFD, CCl4, and STZ. Diabetes exacerbates steatosis, hepatocyte ballooning, fibrosis, regenerative nodule formation, and the macrophage M1/M2 ratios triggered by HFD and CCl4. scRNAseq analysis indicates that diabetes activates inflammatory macrophages and impairs LSECs through the RAGE/TLR4 signaling pathway. These findings open avenues for discovering novel therapeutic targets for diabetic steatohepatitis.