Metabolic Crosstalk During Hepatic Insulin Resistance

2型糖尿病（T2 DM）是一种以肝脏和外周胰岛素抵抗为特征的危及生命的疾病，其失调的组织间代谢通量和通讯促进高血糖和血脂异常。胰岛素受体底物蛋白IRS 1和IRS 2介导全身的胰岛素信号传导。在肝脏内，胰岛素主要通过IRS依赖性抑制转录因子FoxO 1来调节基因表达和代谢。这种更新是建立在一个惊人的观察基础上的，即“LDKO”小鼠的肝脏胰岛素抵抗--肝脏中缺乏Irs 1和Irs 2--将胰岛素抵抗传播到骨骼肌和白色和棕色脂肪组织（WAT和BAT）。糖尿病期间的过度肝葡萄糖生成（HGP）至少部分归因于肝脏胰岛素抵抗和FoxO 1激活的促胰岛素生成基因。然而，在肝FoxO 1失活/缺失后，HGP在LDKO小鼠中正常化（即，“LTKO”小鼠），这表明肝脏分泌的未知FoxO 1依赖性因子（“肝细胞因子”）可促进外周组织的胰岛素抵抗。这种竞争性更新的重点是LDKO肝脏中失调的肝细胞因子，以揭示外周代谢疾病如何依赖于FoxO 1-而不是肝脏胰岛素信号传导本身。这是对单一组织或途径研究的创新性偏离，而且可以揭示肝抵抗单独引起小鼠T2 DM许多特征的机制。稳健的初步数据使我们能够关注在LDKO肝脏中升高或降低但在LTKO肝脏中正常化的功能重要的肝因子。除了心血管疾病风险增加外，T2 DM还与非酒精性脂肪性肝病（NAFLD）相关，NAFLD可进展为非酒精性脂肪性肝炎（NASH）并最终发展为肝细胞癌（HCC）;我们进一步确定了这种进展在LTKO小鼠中减弱。使用删除floxed hepatokine等位基因或嗜肝性AAV（腺相关病毒）敲低或过度表达hepatokine基因，我们采用LDKO和LTKO小鼠揭示（并证实）失调的FoxO 1依赖性hepatokines对全身营养平衡和肝病进展的影响。

Type 2 diabetes (T2DM) is a life-threatening disease characterized by hepatic and peripheral insulin resistance, which dysregulate inter-tissue metabolic flux and communication to promote hyperglycemia and dyslipidemia. Insulin signaling throughout the body is mediated by the insulin receptor substrate proteins IRS1 and IRS2. Within the liver, insulin regulates gene expression and metabolism largely via the IRS-dependent inhibition of transcription factor FoxO1. This renewal is founded on the striking observation that hepatic insulin resistance in ‘LDKO’ mice—which lack Irs1 and Irs2 in liver—propagates insulin resistance to the skeletal muscle and white and brown adipose tissues (WAT and BAT). Excessive hepatic glucose production (HGP) during diabetes owes, at least in part, to hepatic insulin resistance and activation of gluconeogenic genes by FoxO1. However, HGP is normalized in LDKO-mice upon inactivation/deletion of hepatic FoxO1 (i.e., ‘LTKO’ mice), suggesting that unknown, FoxO1-dependent factors secreted by the liver (‘hepatokines’) act to promote insulin resistance in peripheral tissues. This competitive renewal focuses upon the dysregulated hepatokines in LDKO liver to reveal how peripheral metabolic disease depends upon FoxO1—rather than hepatic insulin signaling per se. This is an innovative departure from the study of a single tissue or pathway that can, moreover, reveal the mechanisms by which hepatic resistance alone gives rise to many of the features of T2DM in mice. Robust preliminary data allow us to focus upon functionally important hepatokines that are elevated or decreased in LDKO liver, but normalized in LTKO liver. In addition to increased cardiovascular disease risk, T2DM is associated with non-alcoholic fatty liver disease (NAFLD) that can progress to non-alcoholic steatohepatitis (NASH) and eventual hepatocellular carcinoma (HCC); we have further established that this progression is attenuated in LTKO mice. Using deletion of floxed hepatokine alleles—or hepatotropic AAV (adeno-associated virus) to knock-down or over-express hepatokine genes—we employ both LDKO and LTKO mice to reveal (and corroborate) the effects of dysregulated FoxO1-dependent hepatokines upon systemic nutrient homeostasis and the progression of liver disease.