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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.

肥胖症及其并发症的发病率增加----如胰岛素抵抗、2型糖尿病、心血管疾病、脂肪肝或癌症----是全球主要的健康威胁之一。饮食诱导的肥胖增加主要是由于肝脏新生脂肪生成，随后是极低密度脂蛋白（VLDL）介导的甘油三酯转运至白色脂肪组织（WAT）储存。硬脂酰辅酶A去饱和酶（SCD）是脂肪生成的关键调节剂，催化饱和脂肪酸（SFA）、硬脂酰辅酶A（18：0）和棕榈酰辅酶A（16：0）分别合成单不饱和脂肪酸（MUFA），主要是油酰辅酶A（18：1 n9）和棕榈油酰辅酶A（16：1 n7）。许多代谢疾病中18：1 n9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，整体和皮肤特异性SCD 1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SCD 1缺乏如何导致这种保护性和有益表型的机制一直困扰着我们。使用肝脏特异性SCD 1敲除（LKO）小鼠模型，喂食高碳水化合物饮食（HCD），我们现在表明肝脏SCD 1缺乏增强组织葡萄糖摄取，并与成纤维细胞生长因子21（FGF 21）的表达和血浆水平的显著增加相关，肝源性胰岛素，增敏激素和脂联素，脂联素是已知调节全身脂质和葡萄糖稳态的脂肪细胞衍生的脂肪因子。用三油酸甘油酯而不是三硬脂酸甘油酯喂养雄性和雌性LKO小鼠，补充HCD降低FGF 21表达并恢复血浆葡萄糖水平。抑制原代肝细胞中的SCD活性诱导FGF 21表达，其通过用油酸酯而非硬脂酸酯处理而被抑制。当原代肝细胞用从先前喂食HCD的LKO小鼠分离的血清处理时，脂肪生成基因表达减少，而脂肪细胞中Glut-4和脂联素基因表达增加。我们推测肝油酸酯直接或通过调节FGF 21和脂联素表达来调节全身葡萄糖和脂质代谢。我们提出两个具体目标。在目标1中，我们将定义SCD 1缺陷在调节肝脏中FGF 21表达中的作用。在目标2中，我们将确定SCD 1缺陷介导的肝脏从头脂肪酸合成、脂肪变性、脂肪变性和肥胖的减少是否依赖于FGF 21刺激的脂联素介导的肝脏脂肪组织轴。FGF 21和脂联素作为SCD 1缺乏的全身代谢益处的主要介质的确立是重要的，因为SCD 1本身、FGF 21和脂联素是用于治疗人类肥胖、糖尿病和其它代谢疾病的有吸引力的药物靶标。