Redox regulation in the hepatostat

摘要/摘要 已知：肝脏与身体的质量比因一种叫做“恒肝器”的现象而保持恒定[1]。 当肝脏受损时，随之而来的全身性肝功能不全状态会导致再生增殖。一个 调节轴已经被发现依赖于循环胆汁酸(BA)的水平，这两者都是 由肝细胞合成和回收。从肠道中回收的BAS进入循环，激活 肠细胞(小鼠)或其他细胞(人)的法尼基-X受体(FXR)。这诱导了FGF15/19的分泌 进入肠-肝循环[2-4]。在肝脏，肝细胞中的FGFR信号反馈调节BA 通过抑制细胞色素P7A1的表达而产生[5]，并调节生物能量途径[6]。在一个不那么好的地方 了解的过程，bas和FGF15/19也协调调节促进和反对再生活动在 肝脏。这些活动的平衡决定了肝细胞是否增殖[7-9]。 新的见解：越来越多的人认识到氧化还原信号参与了许多生理过程 功能。我们最近报道，肝细胞既缺乏硫氧还蛋白还原酶-1又缺乏硫氧还蛋白还原酶-1的小鼠的肝脏 谷胱甘肽还原酶(TR/GR-Null)--两个主要的胞质抗氧化剂系统的入口点--是2.1- 比正常的倍数大[10]，这表明这些小鼠有一个错误校准的恒肝器。这些老鼠也有 BA水平升高。然而，令人惊讶的是，无论是无胆固醇饮食还是抑制胆固醇合成 限制BA前体，也不用氯苯乙胺治疗以增加粪便BA排泄，使循环正常化 巴斯。这表明，除了有缺陷的恒肝器中有促再生活动外， 在tr/gr缺失的小鼠中，BA合成的系统反馈调节主要被扰乱。 建议：由于TR/GR零状态仅限于肝细胞，我们预测FXR- 肠上皮细胞诱导产生FGF15是正常的。我们假设恒肝-和BA反馈- 信号受氧化还原调节，因此在TR/GR缺失的肝细胞中受到干扰。为了检验这一假设，我们 提出两个具体目标：目标1，评估肠细胞FGF15的产生和FGF15的肝细胞活性。 诱导信号在WT或TR/GR-Null肝脏中级联。目的2，评估蛋白质-半胱氨酸的修饰 这些肝脏中依赖于FGFR4的通路的组成，并决定其中哪些影响信号转导 以及调节恒肝器的基因表达结果。 预期结果和价值：BAS在脂肪消化、毒素排泄和肝脏稳定器中起作用。在……里面 反过来，脂质分解代谢、毒素暴露和再生都与氧化应激增加有关。在……里面 在这个探索性项目中，我们假设存在以前未被识别的氧化还原调节成分 在BA/恒肝轴上，确保这些活动与细胞氧化还原的适当协调 状态。调节这一点可能有助于治疗肝脏损伤或中毒暴露。

Summary/Abstract What is known: Liver-to-body mass-ratio is held constant by a phenomenon named the “hepatostat” [1]. When liver is damaged, an ensuing state of systemic hepatic insufficiency induces regenerative proliferation. A regulatory axis has been uncovered that is dependent on levels of circulating bile acids (BA), which are both synthesized and recycled by hepatocytes. BAs reclaimed from the gut enter the circulation and activate the farnesyl-X-receptor (FXR) in enterocytes (mice) or other cells (human). This induces secretion of FGF15/19 into the enterohepatic circulation [2-4]. At the liver, FGFR-signaling in hepatocytes feedback-regulates BA production by repressing CYP7A1 expression [5] and modulates bioenergetic pathways [6]. In a less-well understood process, BAs and FGF15/19 also coordinately regulate pro- and anti-regeneration activities in the liver. The balance of these activities determines whether the hepatocytes proliferate [7-9]. New insights: It is becoming increasingly recognized that redox signaling participates in many physiological functions. We recently reported that livers of mice in which hepatocytes lack both thioredoxin reductase-1 and glutathione reductase (TR/GR-null) - the entry points to the two major cytosolic antioxidant systems - are 2.1- fold larger than normal [10], suggesting these mice have a mis-calibrated hepatostat. These mice also have elevated BA levels. Surprisingly however, neither cholesterol-free diets nor inhibition of cholesterol synthesis to limit BA precursors, nor treatment with cholestyramine to increase fecal BA excretion, normalize circulating BAs. This suggests that, along with having a defective hepatostat in which pro-regeneration activities predominate, systemic feedback regulation of BA synthesis is disrupted in mice with TR/GR-null livers. What is proposed: Because the TR/GR-null condition is restricted to hepatocytes, we predict that FXR- induced production of FGF15 in enterocytes is normal. We hypothesize that hepatostat- and BA feedback- signals are redox-regulated and therefore disrupted in TR/GR-null hepatocytes. To test this hypothesis, we propose two specific aims: Aim 1, to assess enterocytic FGF15 production and hepatocytic activity of FGF15- induced signaling cascades in WT or TR/GR-null livers. Aim 2, to assess protein-Cys modifications on components of the FGFR4-dependent pathways in these livers and determine which of these affect signaling and gene expression outcomes that regulate the hepatostat. Anticipated outcomes and value: BAs function in lipid digestion, toxin-excretion, and the hepatostat. In turn, lipid catabolism, toxin exposure, and regeneration are each associated with increased oxidative stress. In this Exploratory Project, we hypothesize that there are previously unrecognized redox-regulated components on the BA/hepatostat axis that ensure appropriate coordination of these activities with the cellular redox status. Modulation of this could be helpful in therapies addressing liver injuries or toxic exposures.