权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Role of Liver Stearoyl-CoA Desaturase-1 in the Regulation of Metabolism

肝脏硬脂酰辅酶 A 去饱和酶 1 在代谢调节中的作用

基本信息

批准号：
9975004
负责人：
JAMES M. NTAMBI
金额：
$ 36.98万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9975004
关键词：
Actins Address Adipocytes Adipose tissue Biochemical Pathway Brown Fat CRISPR/Cas technology Carbohydrates Cardiovascular Diseases Cells ChIP-seq Coenzyme A Development Diabetes Mellitus Diet Disease Energy Metabolism Exhibits FGF21 gene FGFR1 gene Fatty Acids Fatty Liver Fatty acid glycerol esters Female Gene Expression Gluconeogenesis Glucose Goals Health Hepatic Hepatocyte Homeostasis Hormones Human Hyperglycemia Incidence Insulin Resistance Knock-out Knockout Mice Link Lipids Liver Liver diseases Malignant neoplasm of liver Mediating Mediator of activation protein Metabolic Metabolic Diseases Metabolism Monounsaturated Fatty Acids Mus Non-Insulin-Dependent Diabetes Mellitus Obesity Oleates Palmitoyl Coenzyme A Phenotype Physiological Plasma Proteins Reducing diet Regulation Rodent Role SLC2A1 gene Saturated Fatty Acids Serum Signal Transduction Skin Stearoyl-CoA Desaturase Stimulus Testing Tissues Triglycerides Triolein Variant Very low density lipoprotein adipokines adiponectin blood glucose regulation desaturase detection of nutrient fatty acid metabolism feeding fibroblast growth factor 21 glucose metabolism glucose uptake insulin sensitizing drugs lipid biosynthesis lipid metabolism liver metabolism male mouse model novel oxidation recombinase-mediated cassette exchange response stearoyl-coenzyme A sugar targeted treatment transcription factor

项目摘要

The increased incidence of obesity with its complications - such as insulin resistance, type 2 diabetes, cardiovascular disease, liver steatosis or cancer - poses one of the predominant health threats worldwide. The increased diet induced adiposity is mainly due to hepatic de novo lipogenesis followed by very low-density lipoprotein (VLDL)-mediated transport of the triglycerides to white adipose tissue (WAT) for storage. Stearoyl-CoA desaturase (SCD) is a critical regulator of lipogenesis and catalyzes the synthesis of monounsaturated fatty acids (MUFA), mainly oleoyl- (18:1n9) and palmitoleoyl-CoA (16:1n7), from saturated fatty acids (SFA), stearoyl-CoA (18:0) and palmitoyl-CoA (16:0), respectively. Variations in 18:1n9 levels in many metabolic diseases indicate a prominent role of SCD in health and disease. We have shown in several studies that the global and skin-specific SCD1 deficiency increased energy expenditure and protected mice against high fat and high carbohydrate diet-induced adiposity, hepatic steatosis and hyperglycemia but the mechanisms of how SCD1 deficiency can result in such protective and beneficial phenotypes has eluded us for some. Using a liver specific SCD1 knockout (LKO) mouse model fed a high carbohydrate diet (HCD), we now show that hepatic SCD1 deficiency enhances tissue glucose uptake and is correlated with dramatic increases in the expression and plasma levels of the fibroblast growth factor 21 (FGF21), a liver derived insulin-sensitizing hormone and adiponectin an adipocyte derived adipokine that are known to regulate whole body lipid and glucose homeostasis. Feeding both male and female LKO mice with triolein, but not tristearin, supplemented HCD reduced FGF21 expression and restored plasma glucose levels. Inhibition of SCD activity in primary hepatocytes induced FGF21 expression which was repressed by treatment with oleate but not stearate. Lipogenic gene expression was reduced when the primary hepatocytes were treated with serum isolated from LKO mice previously fed with HCD while in adipocytes Glut-4 and adiponectin gene expression was increased. We hypothesize that hepatic oleate regulates systemic glucose and lipid metabolism either directly or through the modulation of FGF21 and adiponectin expression. We propose two specific aims. In aim 1, we will define the role of SCD1 deficiency in regulating FGF21 expression in the liver. In aim 2, we will determine whether SCD1 deficiency mediated decrease in hepatic de novo fatty acid synthesis, steatosis, gluconeogenesis, and adiposity is dependent on FGF21 stimulated adiponectin-mediated liver-adipose tissue axis. Establishment of FGF21 and adiponectin as major mediators of systemic metabolic benefits of SCD1 deficiency is significant because SCD1 itself, FGF21 and adiponectin are attractive drug targets for the treatment of human obesity, diabetes and other metabolic diseases.

肥胖及其并发症（如胰岛素抵抗、2型糖尿病、心血管疾病、肝脂肪变性或癌症）发病率的增加，是全世界主要的健康威胁之一。饮食引起的肥胖增加主要是由于肝脏新生脂肪生成，然后是极低密度脂蛋白（VLDL）介导的甘油三酯转运到白色脂肪组织（WAT）储存。硬脂酰辅酶a去饱和酶（SCD）是脂肪生成的关键调节因子，并催化从饱和脂肪酸（SFA）、硬脂酰辅酶a（18:0）和棕榈酰辅酶a （16:1n7）中合成单不饱和脂肪酸（MUFA），主要是油酰-(18:19)和棕榈酰辅酶a（16:0）。许多代谢性疾病中18:19 . 9水平的变化表明SCD在健康和疾病中的重要作用。我们已经在几项研究中表明，全球和皮肤特异性SCD1缺乏增加了能量消耗，并保护小鼠免受高脂肪和高碳水化合物饮食诱导的肥胖、肝脂肪变性和高血糖症的影响，但SCD1缺乏如何导致这种保护性和有益表型的机制尚不清楚。通过高碳水化合物饮食（HCD）的肝脏特异性SCD1敲除（LKO）小鼠模型，我们现在发现肝脏SCD1缺乏增强了组织葡萄糖摄取，并与成纤维细胞生长因子21 （FGF21）的表达和血浆水平的急剧增加相关，FGF21是一种肝源性胰岛素敏感激素和脂联素（脂肪细胞源性脂肪因子），已知可调节全身脂质和葡萄糖稳态。给雄性和雌性LKO小鼠喂食三油酸（而不是三硬脂酸）后，添加HCD可以降低FGF21的表达，恢复血糖水平。抑制原代肝细胞SCD活性诱导FGF21表达，油酸盐处理抑制FGF21表达，而硬脂酸盐不抑制FGF21表达。原代肝细胞用HCD喂养的LKO小鼠分离的血清处理后，脂质基因表达降低，而脂肪细胞中Glut-4和脂联素基因表达增加。我们假设肝油酸直接或通过调节FGF21和脂联素表达调节全身葡萄糖和脂质代谢。我们提出两个具体目标。在目的1中，我们将确定SCD1缺乏在调节肝脏中FGF21表达中的作用。在目的2中，我们将确定SCD1缺乏介导的肝脏新生脂肪酸合成、脂肪变性、糖异生和肥胖的减少是否依赖于FGF21刺激的脂联素介导的肝-脂肪组织轴。FGF21和脂联素作为SCD1缺乏症全身代谢益处的主要介质的确立意义重大，因为SCD1本身、FGF21和脂联素是治疗人类肥胖、糖尿病和其他代谢疾病的有吸引力的药物靶点。