Redox regulation in the hepatostat

总结/摘要 已知情况：肝脏与身体的质量比通过一种名为“hepatostat”的现象保持恒定[1]。 当肝脏受损时，随后的全身性肝功能不全状态诱导再生增殖。一 调节轴已被发现，这是依赖于循环胆汁酸（BA）的水平，这两者都是 由肝细胞合成和回收。从肠道回收的BA进入循环并激活 法尼基-X-受体（FXR）在肠细胞（小鼠）或其他细胞（人）。这诱导FGF 15/19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CYP7A1表达[5]和调节生物能量途径[6]来生产。在一个不太好的 在已知的过程中，BAs和FGF 15/19还协调调节细胞中的促再生和抗再生活性。 肝脏这些活性的平衡决定了肝细胞是否增殖[7 - 9]。 新的见解：人们越来越认识到氧化还原信号参与许多生理 功能协调发展的我们最近报道，肝细胞缺乏硫氧还蛋白还原酶-1和 谷胱甘肽还原酶（TR/GR-无效）-两个主要的胞质抗氧化系统的入口点-是2.1 - 2.5。 比正常值大1倍[10]，表明这些小鼠具有错误校准的肝脏稳定器。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，也不使用消胆胺治疗以增加粪便BA排泄，使循环正常化 bas.这表明，沿着有缺陷的肝细胞，其中促再生活性 在TR/GR缺失肝脏的小鼠中，BA合成的系统反馈调节被破坏。 由于TR/GR-无效条件仅限于肝细胞，我们预测FXR- 在肠细胞中诱导产生FGF 15是正常的。我们假设肝脏稳定剂和BA反馈- 信号是氧化还原调节的，因此在TR/GR缺失的肝细胞中被破坏。为了验证这个假设，我们 提出了两个具体目标：目标1，评估肠细胞FGF 15的产生和FGF 15的肝细胞活性， 在WT或TR/GR缺失的肝脏中诱导信号级联。目的2，评估蛋白质-Cys修饰对 这些肝脏中FGFR4依赖性通路的组分，并确定其中哪些影响信号传导 和调节肝细胞的基因表达结果。 预期结果和价值：BA在脂肪消化，毒素排泄和肝脏稳定中发挥作用。在 反过来，脂质代谢、毒素暴露和再生各自与增加的氧化应激有关。在 在这个探索性项目中，我们假设存在以前未被认识到的氧化还原调节组分， 在BA/hepatostat轴上，确保这些活动与细胞氧化还原的适当协调 status.调节这一点可能有助于解决肝损伤或毒性暴露的治疗。

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.