Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan.
Am J Physiol Gastrointest Liver Physiol. 2020 Jun 1;318(6):G989-G999. doi: 10.1152/ajpgi.00310.2019. Epub 2020 May 4.
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. 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.
非酒精性脂肪性肝病 (NAFLD) 与睾丸酮缺乏有关。然而，NAFLD 患者通常对单独使用睾丸酮治疗没有反应。我们研究了单独使用睾丸酮、单独使用雌激素或联合使用睾丸酮和雌激素对由于睾丸酮缺乏引起的高脂肪饮食 (HFD) 诱导的 NAFLD 的固有免疫机制。去势 (OCX) 雄性 Rag2 小鼠被用作睾丸酮缺乏的模型。为了评估 NAFLD 的严重程度，采用 NAFLD 活动评分 (NAS)。此外，通过多色流式细胞术分析免疫变化。同时使用睾丸酮和雌激素治疗可显著降低 OCX-HFD 小鼠的体重，使其与假手术-ND 组小鼠/正常饮食 (ND) 组的体重相当。OCX-HFD 小鼠的 NAS 和肝纤维化显著恶化，而同时使用睾丸酮和雌激素治疗可改善至假手术-ND 组小鼠的水平。HFD 增加了肝脏中 2 型和 3 型固有淋巴细胞 (ILC2 和 ILC3) 与 CD45 阳性细胞的比例。单独使用睾丸酮治疗可降低 ILC2 与 CD45 的比例，但不降低 ILC3 与 CD45 的比例。在治疗中加入雌激素可将 ILC2 与 CD45 和 ILC3 与 CD45 的比值降低到与假手术-HFD 组小鼠相同的水平。此外，OCX-HFD 小鼠的 M2 巨噬细胞比例与假手术-ND 组小鼠相比降低。单独使用睾丸酮治疗不能恢复 M2 巨噬细胞的比例；然而，联合使用雌激素和睾丸酮可将其增加到与假手术-HFD 组小鼠相同的水平。同时使用睾丸酮和雌激素可改善肝纤维化，减少肝脏中 ILC3 并增加 M2 巨噬细胞的丰度。非酒精性脂肪性肝病 (NAFLD) 的进展与睾丸酮缺乏有关。NAFLD 患者通常对单独使用睾丸酮治疗没有反应。在动物研究中，睾丸酮和雌激素联合治疗可降低 ILC2:CD45 和 ILC3:CD45 的比值，并增加肝脏中的 M2 巨噬细胞。基于我们的免疫学数据，我们的研究表明，雌激素和睾丸酮的联合治疗可能对男性更年期患者的 NAFLD 治疗具有临床意义。
