PUFA Synthesis and the Control of Hepatic Metabolism

PUFA合成和肝脏代谢的控制

• 批准号: 8312010
• 负责人: DONALD B JUMP
• 金额: $ 31.27万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8312010
• 关键词: Acetylation; Adipocytes; Affect; Antioxidants; Applications Grants; Attenuated; Biochemical; Blood; Blood Glucose; Body Weight; Body Weight Changes; Boxing; Cell physiology; Complications of Diabetes Mellitus; Desire for food; Diabetes Mellitus; Diabetic mouse; Diet; Dietary Essential Fatty Acid; Enzymes; Fasting; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Gene Expression; Genes; Gluconeogenesis; Health; Hepatic; Hepatocyte; Human; Hydrolysis; Hyperglycemia; Individual; Insulin Resistance; Ketone Bodies; Lead; Link; Lipase; Liver; Liver diseases; MAPK14 gene; Mediator of activation protein; Metabolic syndrome; Metabolism; Methods; Molecular; Mus; NADH; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Obese Mice; Obesity; Outcome; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Patients; Phosphoenolpyruvate Carboxylase; Phosphoric Monoester Hydrolases; Phosphorylation; Plasma; Play; Polyunsaturated Fatty Acids; Protein Phosphatase 2A Regulatory Subunit PR53; Proteins; Reactive Oxygen Species; Recombinants; Relative (related person); Reporting; Role; Stress; System; Testing; Triglycerides; acylcarnitine; base; comparative; desaturase; diabetic; fatty acid elongases; fatty acid metabolism; fatty acid oxidation; glucose production; glucose-6-phosphatase; heme oxygenase-1; insight; non-alcoholic fatty liver; novel; novel strategies; oxidant stress; response; restoration; small molecule; transcription factor

DESCRIPTION (provided by applicant): Dietary polyunsaturated fatty acids (PUFA) are generally regarded as beneficial to human health. Obese humans with diabetes (NIDDM), metabolic syndrome (MetS) or non-alcoholic fatty liver disease (NAFLD), however, have low a low ratio of 20:4w6 relative to 18:2w6 in plasma and liver when compared to healthy individuals. This outcome implicates a problem with PUFA metabolism. While the linkage between PUFA metabolism and diabetic complications in humans is unclear, recent studies with diet-induced obese-diabetic mice have established a link between PUFA synthesis and diabetic complications. We reported that the activity of hepatic fatty acid elongase-5 (Elovl5), a key enzyme involved in PUFA synthesis, was suppressed in livers of diet-induced obese-diabetic C57BL/6J mice. Restoration of hepatic Elovl5 activity abrogated high fat diet-induced hyperglycemia, insulin resistance, and fatty liver in 4 days without changing body weight or appetite. The mechanism for the control of blood glucose was linked to the suppression of hepatic nuclear content of forkhead box O1 (FoxO1), a major transcription factor controlling gluconeogenesis (GNG). Elevated Elovl5 activity increased the phosphorylation and acetylation status of FoxO1 and attenuated the expression of genes involved in GNG, e.g., phosphoenolpyruvate carboxykinase and glucose-6 phosphatase. Preliminary studies show that Elovl5 controls FoxO1 phosphorylation through the mTorc2 (rictor)-Akt2 pathway. Moreover, elevated Elovl5 activity induced adipocyte triglyceride lipase (ATGL), comparative gene identification-58 (CGI58, ATGL co-activator) and short & long chain acylcarnitines in livers of obese mice. This outcome suggests Elovl5 activity controls hepatic triglyceride (TAG) by regulating TAG hydrolysis and fatty acid oxidation (FAO). Finally, elevated hepatic Elovl5 activity attenuated stress pathways ([ER-stress, XBP1 and ATF6]; NFkB, Jnk & p38) and induced the anti-oxidant enzyme, i.e., hemeoxygenase-1 (HMOX1). Both ER- and oxidant stress control FoxO1 and GNG. This grant proposal will provide additional mechanistic insight to explain how hepatic PUFA synthesis controls FoxO1, GNG, TAG metabolism and stress pathways. Using cultured hepatocytes and obese-diabetic mice, Aim 1 will define how endogenously generated and exogenously supplied PUFA control hepatic FoxO1, GNG, TAG and stress pathways. Aim 2 will establish the requirement for ATGL and CGI58 in the Elovl5 control of hepatic TAG & FoxO1, GNG and anti-oxidant-response pathways (HMOX1). Aim 3 will establish the requirement for HMOX1 and other anti-oxidant enzymes in the Elovl5 control of FoxO1, GNG, ATGL, CGI58 and TAG. Defining the mechanistic linkage between PUFA synthesis, TAG hydrolysis, FoxO1, GNG & stress pathways will identify novel methods to manage diabetic complications, like hyperglycemia & fatty liver. PUBLIC HEALTH RELEVANCE: Dietary polyunsaturated fatty acids (PUFA) are generally regarded as beneficial to human health and well being. Obese humans with diabetes, metabolic syndrome or non-alcoholic fatty liver disease have impaired PUFA metabolism. We have linked hepatic PUFA synthesis to the control of hepatic triglycerides and stress pathways that impact fasting blood glucose. Further study of this novel mechanism will lead to better methods to control hepatic metabolism and diabetic complications.

描述（由申请人提供）：膳食多不饱和脂肪酸（PUFA）通常被认为对人体健康有益。然而，与健康人相比，患有糖尿病（NIDDM）、代谢综合征（MetS）或非酒精性脂肪性肝病（NAFLD）的肥胖者血浆和肝脏中w6的比例较低，为20:4w6相对于18:2w6。这一结果暗示了PUFA代谢的问题。虽然PUFA代谢与人类糖尿病并发症之间的联系尚不清楚，但最近对饮食诱导的肥胖糖尿病小鼠的研究已经建立了PUFA合成与糖尿病并发症之间的联系。我们报道了在饮食诱导的肥胖糖尿病C57BL/6J小鼠肝脏中，参与PUFA合成的关键酶肝脂肪酸延长酶-5 （Elovl5）的活性被抑制。肝脏Elovl5活性的恢复在4天内消除了高脂饮食引起的高血糖、胰岛素抵抗和脂肪肝，而没有改变体重或食欲。血糖控制的机制与抑制叉头盒O1 （FoxO1）的肝核含量有关，叉头盒O1是控制糖异生（GNG）的主要转录因子。Elovl5活性的升高增加了FoxO1的磷酸化和乙酰化状态，并减弱了与GNG相关的基因，如磷酸烯醇丙酮酸羧激酶和葡萄糖-6磷酸酶的表达。初步研究表明，Elovl5通过mTorc2 (rictor)-Akt2途径控制FoxO1磷酸化。此外，Elovl5活性升高可诱导肥胖小鼠肝脏中脂肪细胞甘油三酯脂肪酶（ATGL）、比较基因鉴定-58 （CGI58， ATGL共激活剂）和短链和长链酰基肉碱。这一结果表明Elovl5活性通过调节TAG水解和脂肪酸氧化（FAO）来控制肝甘油三酯（TAG）。最后，升高的肝脏Elovl5活性减弱应激途径（[er应激，XBP1和ATF6]； NFkB， Jnk和p38）并诱导抗氧化酶，即血红素加氧酶-1 （HMOX1）。ER应激和氧化应激均可控制FoxO1和GNG。这项拨款提案将为解释肝脏PUFA合成如何控制fox01、GNG、TAG代谢和应激途径提供额外的机制见解。利用培养的肝细胞和肥胖糖尿病小鼠，Aim 1将确定内源性和外源性PUFA如何控制肝脏fox01、GNG、TAG和应激途径。目的2将确定ATGL和CGI58在Elovl5控制肝脏TAG和FoxO1、GNG和抗氧化反应途径（HMOX1）中的需求。Aim 3将确定Elovl5控制FoxO1、GNG、ATGL、CGI58和TAG对HMOX1和其他抗氧化酶的需求。明确PUFA合成、TAG水解、FoxO1、GNG和应激途径之间的机制联系，将找到治疗糖尿病并发症（如高血糖和脂肪肝）的新方法。