LSECs promote MASH progression via IL-1R1-mediated chemokine production induced by macrophage-derived IL-1ß
In LSEC of MASH model mice, Il1r1 gene expression was elevated, and CXCL10 gene expression was upregulated compared to the normal diet group. Macrophage-derived IL-1ß, whose secretion was enhanced via autophagy impairment induced by fatty acid overload, activated JNK in LSEC, leading to increased expression of CXCL10 and CCL2. The expression levels of these chemokines positively correlated with the NAFLD activity score in MASH patients. Furthermore, spatial transcriptomic analysis of liver tissue from MASH patients revealed high expression of IL1R1, CXCL10, and CCL2 in periportal LSEC, which were in close proximity to numerous macrophages. Overall design: Western diet was used as the MASH mouse model. 6-week-old male C57BL/6J mice were fed either a normal diet (ND) (n = 2) or a Western diet (WD) (n = 1) for 12 weeks, after which they were sacrificed. The Western diet (D20092804) was custom-formulated by Research Diets, Inc. (New Brunswick, NJ, USA) to be high in fat (36.4% kcal, primarily from milk fat), cholesterol (1.21%), and sucrose-enriched carbohydrates (48.4% kcal). The mouse liver was dissociated into single cells using pronase and collagenase perfusion, followed by sample preparation for scRNA analysis.