PUFA Synthesis and the Control of Hepatic Metabolism

PUFA合成和肝脏代谢的控制

基本信息

批准号：
8434823
负责人：
DONALD B JUMP
金额：
$ 30.1万
依托单位：
OREGON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
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/8434823
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

项目摘要

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.

描述（由申请人提供）：膳食多不饱和脂肪酸（PUFA）通常被认为对人类健康有益。然而，与健康个体相比，患有糖尿病 (NIDDM)、代谢综合征 (MetS) 或非酒精性脂肪肝病 (NAFLD) 的肥胖人群血浆和肝脏中的比例较低，为 20:4w6 与 18:2w6。这一结果表明 PUFA 代谢存在问题。虽然人类多不饱和脂肪酸代谢与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确定了多不饱和脂肪酸合成与糖尿病并发症之间的联系。我们报道，在饮食诱导的肥胖糖尿病 C57BL/6J 小鼠的肝脏中，肝脂肪酸延长酶 5 (Elovl5)（一种参与 PUFA 合成的关键酶）的活性受到抑制。恢复肝脏 Elovl5 活性可在 4 天内消除高脂肪饮食引起的高血糖、胰岛素抵抗和脂肪肝，而不会改变体重或食欲。控制血糖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 活性升高会增加 FoxO1 的磷酸化和乙酰化状态，并减弱参与 GNG 的基因的表达，例如磷酸烯醇丙酮酸羧激酶和葡萄糖 6 磷酸酶。初步研究表明，Elovl5 通过 mTorc2 (rictor)-Akt2 途径控制 FoxO1 磷酸化。此外，Elovl5 活性升高会诱导肥胖小鼠肝脏中的脂肪细胞甘油三酯脂肪酶 (ATGL)、比较基因识别 58（CGI58、ATGL 共激活剂）以及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，肝脏 Elovl5 活性升高会减弱应激途径（[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-和氧化应激均控制 FoxO1 和 GNG。该资助提案将提供额外的机制见解，以解释肝脏 PUFA 合成如何控制 FoxO1、GNG、TAG 代谢和应激途径。使用培养的肝细胞和肥胖糖尿病小鼠，目标 1 将定义内源性生成和外源性供应的 PUFA 如何控制肝脏 FoxO1、GNG、TAG 和应激途径。目标 2 将确定 Elovl5 控制肝脏 TAG 和 FoxO1、GNG 和抗氧化反应途径 (HMOX1) 中 ATGL 和 CGI58 的要求。目标 3 将确定 FoxO1、GNG、ATGL、CGI58 和 TAG 的 Elovl5 对照中对 HMOX1 和其他抗氧化酶的要求。定义 PUFA 合成、TAG 水解、FoxO1、GNG 和应激途径之间的机制联系将确定治疗糖尿病并发症（如高血糖和脂肪肝）的新方法。