Background

Although the impact of hepatic androgen receptor (AR) pathway on liver pathogenesis was documented, its physiological function in normal liver is remained unclear. This study aims to investigate if hepatic AR acts on metabolism, the major liver function, using a hepatic-specific AR-transgenic (H-ARTG) mouse model.

Methods

We established the albumin promoter driven H-ARTG mice and included wild type (WT) and H-ARKO mice for study. The body weight, specific metabolic parameters and results from various tolerance tests were compared in different groups of mice fed a chow diet, from 2 to 18 months of age. Glucose feeding and insulin treatment were used to study the expression and zonal distribution pattern of AR and related genes in liver at different prandial stages.

Results

The body weight of H-ARTG mice fed a chow diet was 15 % lower than that of wild-type mice, preceded by lower blood glucose and liver triglyceride levels caused by AR reduced hepatic gluconeogenesis. The opposite phenotypes identified in H-ARKO and castrated H-ARTG mice support the critical role of activated AR in decreasing gluconeogenesis and triglyceride levels in liver. Hepatic AR acting by enhancing the expression of cytosolic glycerol-3-phosphate dehydrogenase (cGPDH), a key of glycerophosphate shuttle, was identified as one mechanism to decrease gluconeogenesis from glycerol. We further found AR normally expressed in zone 3 of hepatic lobules. Its level fluctuates dependent on the demand of glucose, decreased by fasting but increased by glucose uptake or insulin stimulation.

Conclusion

AR is a newly identified zone 3 hepatic gene with function in reducing blood glucose and body weight in mice. It suggests that stabilization of hepatic AR is a new direction to prevent hyperglycemia, obesity and nonalcoholic fatty liver disease (NAFLD) in males.

中文翻译：

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雄激素受体在中枢周围肝细胞中发挥作用，以减少雄性小鼠的糖异生并避免高血糖和肥胖

背景

虽然肝脏雄激素受体 (AR) 通路对肝脏发病机制的影响已有文献记载，但其在正常肝脏中的生理功能仍不清楚。本研究旨在使用肝脏特异性 AR 转基因 (H-ARTG) 小鼠模型研究肝脏 AR 是否作用于主要肝功能的代谢。

方法

我们建立了白蛋白启动子驱动的 H-ARTG 小鼠，并包括野生型 (WT) 和 H-ARKO 小鼠进行研究。比较了 2 至 18 个月大的不同组小鼠的体重、特定代谢参数和各种耐受性测试的结果。采用葡萄糖喂养和胰岛素治疗研究不同膳食阶段肝脏中AR及相关基因的表达及带状分布模式。

结果

喂食食物的 H-ARTG 小鼠的体重比野生型小鼠低 15%，之前由于 AR 减少了肝脏糖异生，导致血糖和肝脏甘油三酯水平降低。在 H-ARKO 和去势的 H-ARTG 小鼠中发现的相反表型支持激活的 AR 在降低肝脏糖异生和甘油三酯水平中的关键作用。通过增强细胞溶质 3-磷酸甘油脱氢酶 (cGPDH)（甘油磷酸穿梭的关键）的表达而发挥作用的肝 AR 被确定为减少甘油糖异生的一种机制。我们进一步发现 AR 通常在肝小叶 3 区表达。其水平随对葡萄糖的需求而波动，在禁食时降低，但在葡萄糖摄取或胰岛素刺激时升高。

结论

AR是一种新发现的3区肝基因，具有降低小鼠血糖和体重的功能。这表明稳定肝脏AR是预防男性高血糖、肥胖和非酒精性脂肪肝（NAFLD）的新方向。