棕榈油酸通过调控SIRT3来抑制肝脏糖异生的机制研究

Hepatic gluconeogenesis is a crucial process to maintain glucose level during starvation. But unabated glucose production in diabetic patients is a major contributor to hyperglycemia. Palmitoleic acid or palmitoleate is a monounsaturated fatty acid (16:1n7) that is available from dietary sources，mainly from marine products. Palmitoleic acid exhibits health beneficial effects in diabetes, insulin resistance, inflammation and metabolic syndrome. However, the mechanism of how palmitoleic acid reduces blood glucose is still unclear. SIRT3 is a key metabolism-regulating protein deacetylase. It is known that fasting elevates the expression of SIRT3 in the liver and it regulates many aspects of liver’s response to nutrient deprivation, such as fatty acid oxidation and ketone body formation. However, it is unknown whether SIRT3 also regulates gluconeogenesis. We have collected preliminary data indicating that palmitoleic acid inhibits hepatic gluconeogenesis and enhances systemic insulin sensitivity. Over expression of SIRT3 in primary hepatocytes increases hepatic gluconeogenesis. SIRT3 also deacetylates and actives enzymes in hepatic gluconeogenesis. Therefore, in our study, we will investigate how palmitoleic acid regulates hepatic gluconeogenesis and the mechanism of palmitoleic acid regulating hepatic gluconeogenesis through “gain-of-function” or “loss-of-function” of hepatic SIRT3.

肝脏糖异生是在饥饿条件下维持血糖水平的一个重要过程。在糖尿病患者中，不减弱的肝脏葡萄糖的合成是高血糖症的主要原因。棕榈油酸是一种单不饱和脂肪酸（16:1n7），主要来源于海产油脂。棕榈油酸在糖尿病、胰岛素抵抗、炎症和代谢综合症中具有积极的防治作用。然而，棕榈油酸是如何控制血糖的机制还没有完全清楚。SIRT3是一种调控代谢的去乙酰化酶。已有研究表明禁食能够增加肝脏中SIRT3的表达。在营养素丧失时，SIRT3与肝脏的很多应对反应相关，例如脂肪酸氧化和酮体的形成。然而SIRT3是否调控肝脏的糖异生还不被人们所知。此研究的前期结果发现棕榈油酸能够降低肝脏的糖异生和提高系统胰岛素敏感度。在原代肝细胞中过表达SIRT3能够增加肝脏的糖异生。SIRT3能够去乙酰化并激活肝脏糖异生的关键酶。因此，此项目将上调或下调肝脏SIRT3的表达来探索棕榈油酸对肝脏糖异生的调控和其中的相关机制。

肝脏糖异生是饥饿时维持血糖水平的关键过程。糖尿病患者肝脏释放的葡萄糖不减弱是高血糖的主要原因。棕榈油酸是一种单不饱和脂肪酸(16:1n7)，可从饮食来源获得，主要来自海产品。棕榈油酸对糖尿病、胰岛素抵抗、炎症和代谢综合征具有有益的健康作用。然而，棕榈油酸降低血糖的机制尚不清楚。SIRT3是一种关键的代谢调节NAD+依赖的蛋白去乙酰化酶。众所周知，禁食提高了肝脏中SIRT3的表达，并调节了肝脏对营养剥夺的许多方面的反应，如脂肪酸氧化和酮体的形成。然而，SIRT3是否也调控糖异生尚不清楚。我们的研究发现棕榈油酸降低了高脂肪饮食条件下肝脏糖异生和SIRT3的表达。SIRT3在肝脏和肝细胞中的过表达促进了糖异生。进一步的研究表明，SIRT3可与PEPCK、PCX和MDH2等糖异生酶结合，并可能通过去乙酰作用增强酶的活性。因此，我们的研究表明，在高脂肪饮食下，棕榈油酸通过降低SIRT3的表达来降低糖异生，SIRT3参与糖异生相关的乙酰化状态和酶活性。