Dysfunctional adipose tissue's role in hepatic metabolic disease

功能失调的脂肪组织在肝脏代谢疾病中的作用

• 批准号: 11013535
• 负责人: Andrew Lutkewitte
• 金额: $ 23.25万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-12-15 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/11013535
• 关键词: Dysfunctional; adipose; tissue; role; hepatic

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.

过量的脂肪组织（肥胖）已被确定为发展脂肪肝疾病的主要危险因素， 2型糖尿病奇怪的是，脂肪组织的明显缺乏（脂肪营养不良）也导致这些 合并症。这些观察结果表明，脂肪的功能，而不是数量，是至关重要的全身代谢 调控健康脂肪组织的主要功能是在营养素缺乏时调节脂质储存。 当营养素缺乏时，游离脂肪酸和甘油的丰富和动员，但这些功能障碍 这一过程导致肝脏中的异位脂质储存，从而导致代谢疾病。Dogma暗示过度 游离脂肪酸从内脏脂肪输出进入门静脉，压倒性的肝脏代谢导致 肝脂肪变性肥胖患者在脂肪组织中储存脂肪酸的能力降低， 脂解失调然而，最近的研究表明，约40%的肝脏脂质是由肝脏脂质代谢产生的。 新生脂肪生成（DNL），即肝脏内碳水化合物向脂质的转化。肝脏DNL受以下因素调节： 营养敏感AMP蛋白激酶（AMPK），它抑制许多DNL的活性和表达， 内切酶这个为期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DNL失调。在脂肪细胞中，甘油三酯是通过甘油-3-磷酸 通路倒数第二步是通过磷脂酸生成甘油二酯 Lipin 1（基因名称Lpin 1）的磷酸水解酶活性。我们的初步数据显示，在人类脂肪， LPIN 1表达与胰岛素敏感性呈正相关，与肝DNL呈负相关。一致 有了这个，我们已经产生了脂肪组织中缺乏lipin 1的小鼠，这些小鼠显示出瘦，但代谢 不健康的表型，包括肝脂肪变性和胰岛素抵抗。重要的是，这些小鼠还具有 AMPK通常抑制的肝DNL和DNL酶表达速率增加。一起 这些数据表明，抑制脂肪组织甘油三酯的合成激活了肝脏脂质的重新合成 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和肝脂肪变性的传感能力。我们还假设 肝AMPK的再激活将恢复肝营养物感知，从而降低DNL和肝脂质 存储.由于肥胖是一种获得性疾病，我们将使用成人发病的脂肪功能障碍模型， 诱导型脂肪特异性脂蛋白1 KO模型。我们将使用全面的代谢测试，结合 磷酸化蛋白质组学以评估肝DNL的AMPK活化。我们将过度表达组成型活性AMPK 在我们的脂肪功能障碍模型的肝脏中，通过抑制DNL来拯救肝脏代谢。我们还将使用 多器官活检来自同一患者接受腹部手术，以确认LPIN 1表达 与肝脏AMPK活化呈负相关，并确定了与肝脏AMPK活化之间的其他新的分子关系。 脂肪组织功能障碍和肝脏疾病进展。