Dysfunctional adipose tissue's role in hepatic metabolic disease

过多的脂肪组织(肥胖)已被确定为发展为脂肪肝的主要危险因素 2型糖尿病。矛盾的是，明显缺乏脂肪组织(脂肪营养不良)也会导致这些 合并症。这些观察表明，脂肪功能而不是数量对全身新陈代谢至关重要。 监管。健康脂肪组织的主要功能是调节脂肪的储存，当营养物质 当营养缺乏时，游离脂肪酸和甘油的丰富和动员，但它们的功能障碍 这些过程导致肝脏中异位的脂肪储存，从而导致代谢性疾病。Dogma暗示过度 游离脂肪酸从内脏脂肪输出到门静脉，压倒肝脏代谢主导 肝脏脂肪变性。肥胖患者在脂肪组织中储存脂肪酸的能力降低， 失调的脂肪分解。然而，最近的研究表明，~40%的肝脂是由肝脂得来的。 新的脂肪生成(DNL)，碳水化合物在肝脏内转化为脂肪。肝脏DNL受以下因素调节 营养感受型AMP蛋白激酶(AMPK)抑制多种DNL的活性和表达 酵素。这个为期3年的项目的目标是建立脂肪组织功能障碍之间的机制联系。 和肝脏DNL调节失调。在脂肪细胞中，甘油三酯是通过甘油-3-磷酸生成的 路径。倒数第二步是通过磷脂酸生成甘油二酯 脂蛋白1(LPIN1)的磷酸水解酶活性。我们的初步数据显示，在人类脂肪中， LPIN1表达与胰岛素敏感性呈正相关，与肝DNL呈负相关。排队 有了这一点，我们产生了脂肪组织中缺乏脂类1的小鼠，这些小鼠表现出精瘦，但在代谢上 不健康的表型，包括肝脏脂肪变性和胰岛素抵抗。重要的是，这些老鼠也有 AMPK通常抑制的肝脏DNL率和DNL酶的表达增加。同舟共济 这些数据表明，抑制脂肪组织甘油三酯的合成可以激活肝脏的新脂肪合成。 来自替代碳源。我们假设功能失调的脂肪组织减少了肝脏的营养 通过慢性AMPK失活驱动DNL和肝脏脂肪变性的感知能力。我们还假设 肝脏AMPK的重新激活将恢复肝脏的营养感知，从而降低DNL和肝脂 储藏室。由于肥胖是一种获得性疾病，我们将使用一个成人发病的脂肪功能障碍的模型， 诱导脂肪特异性脂蛋白1KO模型。我们将使用全面的代谢测试结合 磷酸化蛋白质组学评估肝DNL的AMPK活性。我们将过度表达结构性活跃的AMPK 在我们的脂肪功能障碍模型的肝脏中，通过抑制DNL来挽救肝脏代谢。我们还将使用 同一腹部手术患者的多器官活检证实LPIN1的表达 与肝脏AMPK活性呈负相关，并发现其他新的分子关系 用多组学方法研究脂肪组织功能障碍与肝病进展。

Excess adipose tissue (obesity) has been identified as a leading risk factor for developing fatty liver disease and type 2 diabetes. Paradoxically, the marked absence of adipose tissue (lipodystrophy) also leads to these comorbidities. These observations suggest that adipose function, not quantity, is critical for systemic metabolic regulation. The primary function of healthy adipose tissue is the regulated storage of lipids when nutrients are abundant and mobilization of free fatty acids and glycerol when nutrients are scarce, but dysfunction of these processes leads to ectopic lipid storage in the liver, which drives metabolic disease. Dogma suggests excessive free fatty acid export from visceral adipose dumps into the portal vein, overwhelming hepatic metabolism leading to hepatic steatosis. Obese patients have a reduced capacity to store fatty acids in adipose tissue and dysregulated lipolysis. However, recent studies suggest that ~40 % of hepatic lipids are derived by hepatic de novo lipogenesis (DNL), the conversion of carbohydrates to lipids within the liver. Hepatic DNL is regulated by the nutrient-sensing AMP Protein Kinase (AMPK), which suppresses the activity and expression of many DNL enzymes. The goal of this 3-year project is to establish the mechanistic links between adipose tissue dysfunction and dysregulated hepatic DNL. In adipocytes, triglycerides are generated through the glycerol-3-phosphate pathway. The penultimate step is the generation of diacylglycerol through the phosphatidic acid phosphohydrolase activity of lipin 1 (gene name Lpin1). Our preliminary data shows that in humans adipose, LPIN1 expression positively correlates with insulin sensitivity and negatively corelates to hepatic DNL. In line with this, we have generated mice lacking lipin 1 in adipose tissue, which display a lean, yet metabolically unhealthy phenotype that includes hepatic steatosis and insulin resistance. Importantly, these mice also have increased rates of hepatic DNL and expression of DNL enzymes that AMPK normally suppresses. Together these data suggest that inhibiting adipose tissue triglyceride synthesis activates de novo hepatic lipid synthesis from alternative carbon sources. We hypothesize that dysfunctional adipose tissue reduces hepatic nutrient sensing capacity through chronic AMPK inactivation driving DNL and hepatic steatosis. We also hypothesize that re-activation of hepatic AMPK will restore hepatic nutrient sensing serving to lower DNL and hepatic lipid storage. Because obesity is an acquired disease, we will use a model of adult-onset adipose dysfunction, an inducible adipose specific lipin 1 KO model. We will use comprehensive metabolic testing combined with phospho-proteomics to assess AMPK activation of hepatic DNL. We will overexpress constitutively active AMPK in livers of our adipose dysfunction models to rescue hepatic metabolism by suppressing DNL. We will also use multi-organ biopsies from the same patients undergoing abdominal surgery to confirm that LPIN1 expression inversely correlates with hepatic AMPK activation and identify additional novel molecular relationships between adipose tissue dysfunction and hepatic disease progression using a multi-omic approach.