人类遗传学研究表明,17-β-羟基类固醇脱氢酶(HSD17β13)的功能缺失突变与非酒精性脂肪性肝炎(NASH)的保护有关。因此,正在寻求减少HSD17β13的疗法来治疗NASH。然而,对脂肪变性的影响不一致,已经在鼠Hsd17b13敲低或敲除模型中报道了炎症和纤维化发病机理。为了澄清是否小鼠Hsd17b13损失调节肝损伤和纤维化,我们表征了Hsd17b13基因敲除小鼠接受pro-NASH饮食或促炎化学诱导的肝损伤。Hsd17b13丢失对肝损伤没有影响,炎症,Gubra-AmylinNASH(GAN)饮食28周后或45%胆碱缺乏高脂肪饮食(CDAHFD)12周后的纤维化或脂质。然而,KO小鼠中AAV介导的鼠Hsd17b13的再表达增加了饲喂45%CDAHFD的两种性别的肝巨噬细胞丰度。相比之下,肝纤维化有适度减少,但不是Hsd17b13无效女性体内的脂质或炎症,但不是男性,与WT同窝动物相比,接受60%CDAHFD12周后的小鼠。在腺病毒再表达小鼠HSD17β13后,Hsd17b13KO雌性的纤维化和肝巨噬细胞的丰度增加,但这并未反映在炎症标记物中。此外,我们发现肝损伤的差异很小,脂质,或急性CCl4暴露后48小时的炎症和纤维化标志物。总之,小鼠Hsd17b13丢失对肝纤维化具有适度的饮食和性别特异性影响,这与人类遗传研究相反。这表明HSD17β13在小鼠和人类中的生物学功能之间存在脱节。
Human genetic studies show that loss of function mutations in 17-Beta hydroxysteroid dehydrogenase (HSD17β13) are associated with protection from non-alcoholic steatohepatitis (NASH). As a result, therapies which reduce HSD17β13 are being pursued for the treatment of NASH. However, inconsistent effects on steatosis, inflammation and fibrosis pathogenesis have been reported in murine Hsd17b13 knockdown or knockout models. To clarify whether murine Hsd17b13 loss regulates liver damage and fibrosis, we characterized Hsd17b13 knockout mice subjected to pro-NASH diets or pro-inflammatory chemical-induced liver injury. There were no effects of Hsd17b13 loss on liver injury, inflammation, fibrosis or lipids after 28 weeks on the Gubra-Amylin NASH (GAN) diet or 12 weeks on a 45% choline deficient high fat diet (CDAHFD). However, AAV-mediated re-expression of murine Hsd17b13 in KO mice increased liver macrophage abundance in both sexes fed the 45% CDAHFD. In contrast, there was a modest reduction in liver fibrosis, but not lipids or inflammation within Hsd17b13 null female, but not male, mice after 12 weeks of a 60% CDAHFD compared to WT littermates. Fibrosis and the abundance of liver macrophages were increased in Hsd17b13 KO females upon adenoviral re-expression of mouse HSD17β13, but this was not reflected in inflammatory markers. Additionally, we found minimal differences in liver injury, lipids, or inflammatory and fibrotic markers 48 hours after acute CCl4 exposure. In summary, murine Hsd17b13 loss has modest diet- and sex-specific effects on liver fibrosis which contrasts with human genetic studies. This suggests a disconnect between the biological function of HSD17β13 in mice and humans.