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，其特征是组织间代谢流动和通讯失调，从而促进高血糖和血脂异常。体内的胰岛素信号是由胰岛素受体底物蛋白IRS1和IRS2介导的。在肝脏内，胰岛素主要通过依赖IRS抑制转录因子FoxO1来调节基因的表达和代谢。这一更新建立在一个惊人的观察结果之上，即‘LDKO’小鼠的肝脏胰岛素抵抗--肝脏中缺乏IRS1和IRS2--会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)。糖尿病时肝脏葡萄糖产生过多(HGP)，至少部分原因是肝脏胰岛素抵抗和FoxO1激活糖异生基因。然而，在肝脏FoxO1失活/缺失的LDKO小鼠(即‘LTKO’小鼠)中，HGP是正常的，这表明未知的、肝脏分泌的FoxO1依赖因子(‘肝因子’)促进了外周组织的胰岛素抵抗。这一竞争性更新集中在LDKO肝脏中调节失调的肝素，以揭示外周代谢性疾病如何依赖于FoxO1-而不是肝脏胰岛素信号本身。这是对单一组织或途径研究的创新，该研究可以揭示肝脏抵抗单独导致小鼠T2 DM许多特征的机制。可靠的初步数据使我们能够专注于在LDKO肝脏中升高或降低，但在LTKO肝脏中正常化的具有重要功能的肝素。除了增加心血管疾病的风险，T2 DM还与非酒精性脂肪性肝病(NAFLD)相关，后者可以进展为非酒精性脂肪性肝炎(NASH)和最终的肝细胞癌(HCC)；我们进一步证实，在LTKO小鼠中，这种进展是减弱的。我们使用LDKO和LTKO两种小鼠，通过缺失游离的肝细胞因子等位基因或嗜肝AAV(腺相关病毒)来下调或过度表达肝细胞因子基因，以揭示(并证实)失调的FOXO1依赖的肝细胞因子对系统营养动态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.