Immune modulating effects of additional supplementation of estradiol combined with testosterone in murine testosterone-deficient NAFLD model
Immune modulating effects of additional supplementation of estradiol combined with testosterone in murine testosterone-deficient NAFLD model
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DOI：
10.1152/ajpgi.00310.2019
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发表时间：
2020-06-01
影响因子：
4.5
通讯作者：
Fukui, Michiaki
中科院分区：
文献类型：
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作者：
Okamura, Takuro;Hamaguchi, Masahide;Fukui, Michiaki
非酒精性脂肪性肝病（NAFLD）与睾酮缺乏有关。然而，NAFLD患者通常对单独使用睾酮治疗没有反应。我们研究了睾酮单独、雌激素单独或睾酮和雌激素联合治疗高脂肪饮食（HFD）诱导的因睾酮缺乏引起的NAFLD的先天免疫机制。睾丸切除（OCX）雄性Rag2（-/-）小鼠作为睾酮缺乏模型。采用NAFLD活动评分（NAS）评价NAFLD严重程度。此外。采用多色流式细胞术分析免疫变化。睾酮和雌激素治疗显著降低了假小鼠/正常饮食（ND）的体重。OCX-HFD小鼠的NAS和肝纤维化明显恶化，睾酮和雌激素治疗与sham-ND小鼠相同。HFD增加了肝脏中2型和3型先天淋巴样细胞（ILC2s和ILC3s）与cd45阳性细胞的比例。单独使用睾酮治疗降低了ILC2与CD45的比值，但没有降低ilc3与CD45的比值。在治疗中添加雌激素可将ILC2-to-CD45和ILC3-to-CD45的比率降低到与假hfd小鼠相同的水平。此外，与sham-ND小鼠相比，OCX-HFD小鼠的M2巨噬细胞比例降低。单独使用睾酮治疗不能恢复M2巨噬细胞的比例；然而，雌激素和睾酮联合治疗将其增加到与假hfd小鼠相同的水平。睾酮和雌激素联合治疗可改善肝纤维化，降低ILC3，增加肝脏中M2巨噬细胞的丰度。新的和值得注意的是非酒精性脂肪性肝病（NAFLD）的进展与睾酮缺乏有关。NAFLD患者通常对单独使用睾酮治疗无反应。在动物研究中，睾酮和雌激素治疗降低了肝脏中ILC2:CD45和ILC3:CD45的比例，增加了M2巨噬细胞。我们的研究表明，基于我们的免疫学数据，雌激素和睾酮的联合治疗可能与男性更年期NAFLD患者的临床治疗相关。
Nonalcoholic fatty liver disease (NAFLD) is associated with testosterone deficiency. However, NAFLD patients generally do not respond to treatment with testosterone alone. We investigated the innate immune mechanisms underlying the effects of treatment with testosterone alone, estrogen alone, or combined testosterone and estrogen on high-fat diet (HFD)-induced NAFLD due to testosterone deficiency. Orchiectomized (OCX) male Rag2(-/-) mice were used as a model of testosterone deficiency. To assess NAFLD severity, NAFLD activity score (NAS) is adopted. Moreover. immunological change was analyzed by multicolor flow cytometry. Treatment with both testosterone and estrogen significantly decreased body weight to that of the sham mice/normal diet (ND). NAS and liver fibrosis in OCX-HFD mice were significantly deteriorated, and treatment with testosterone and estrogen improved same as sham-ND mice. HFD increased the ratio of both type 2 and 3 innate lymphoid cells (ILC2s and ILC3s) to CD45-positive cells in the liver. Treatment with testosterone alone decreased the ratio of ILC2 to CD45 but not the ILC3-to-CD45 ratio. Addition of estrogen to the treatment reduced the ratios of ILC2-to-CD45 and ILC3-to-CD45 to the same level observed in sham-HFD mice. Moreover, OCX-HFD mice had a decreased proportion of M2 macrophages compared with sham-ND mice. Treatment with testosterone alone did not restore the proportion of M2 macrophages; however, combination treatment with both estrogen and testosterone increased that to the same level as that in sham-HFD mice. Treatment with both testosterone and estrogen improves liver fibrosis and decreases ILC3 and increases M2 macrophage abundance in the liver.NEW & NOTEWORTHY The progression of nonalcoholic fatty liver disease (NAFLD) is associated with testosterone deficiency. NAFLD patients generally do not respond to treatment with testosterone alone. In animal studies, treatment with testosterone and estrogen reduced the ratios of ILC2:CD45 and ILC3:CD45 and increased M2 macrophages in liver. Our study suggests, based on our immunological data, that a combination of estrogen and testosterone may be clinically relevant for the treatment of NAFLD in patients with male menopause.