Panoply™ Human HSD17B13 Over-expressing Stable Cell Line

The rs72613567:TA polymorphism in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) reduces the progression of steatosis to metabolic dysfunction-associated steatohepatitis (MASH). Here, researchers found that HSD17B13 can form liquid-liquid phase separations (LLPS) around lipid droplets in the livers of MASH patients. Dimerization of HSD17B13 promotes LLPS formation and enhances its enzymatic activity. HSD17B13-mediated LLPS increases platelet-activating factor (PAF) biosynthesis, thereby promoting fibrinogen synthesis and leukocyte adhesion. Blocking the PAF receptor or the STAT3 pathway inhibits fibrinogen synthesis and leukocyte adhesion. Importantly, adeno-associated virus-mediated xenogeneic expression of human HSD17B13 exacerbates high-fat diet/carbon tetrachloride-induced liver inflammation in Hsd17b13−/− mice. In summary, these findings suggest that LLPS of HSD17B13 triggers liver inflammation by promoting platelet-activating factor (PAF)-mediated leukocyte adhesion, and that targeting the HSD17B13 phase transition may be a promising therapeutic approach for treating liver inflammation in chronic liver disease.

To investigate the function of HSD17B13 LLPS in hepatocytes, researchers constructed human HSD17B13-overexpressing HepaRG cells, as HSD17B13 expression levels are low in various hepatocyte cell lines. RNA sequencing (RNA-seq) analysis revealed that expression of human HSD17B13 altered the expression of 346 genes, with 116 genes upregulated and 230 genes downregulated (Figure 1A). Gene set enrichment analysis (GSEA) showed that hemostasis-related processes were significantly enriched in the HSD17B13 overexpression group (Figure 1B). Figure 1C shows the top 28 differentially expressed genes enriched in hemostasis and cell adhesion processes. Fibrinogen promotes the aggregation of platelets and inflammatory cells at the site of vascular injury, which is crucial for initiating tissue inflammation. Researchers found that fibrinogen expression was increased in HSD17B13-overexpressing HepaRG cells, with FGG, FGA, and FGB encoding the γ, α, and β chains of fibrinogen, respectively (Figure 1D). Pearson correlation analysis showed a positive correlation between hepatic HSD17B13 and fibrinogen mRNA expression levels in MAFLD patients (Figure 1E-G). Furthermore, human HSD17B13 promoted leukocyte adhesion in vitro (Figure 1H).

Figure 1. Human HSD17B13 promotes fibrinogen expression and leukocyte adhesion. (Ye J, et al., 2024)