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.

肥胖症的发生率增加了，其并发症（例如胰岛素抵抗，2型糖尿病，心血管疾病，肝脏脂肪变性或癌症）在全球范围内带来了主要的健康威胁之一。饮食诱导的肥胖量增加主要是由于从头脂肪生成，然后是非常低密度的脂蛋白（VLDL）介导的甘油三酸酯向白脂肪组织（WAT）的转运以存储。 stearoyl-COA去饱和酶（SCD）是脂肪生成的关键调节剂，并催化单不饱和脂肪酸（MUFA）的合成，主要是Oleoyl-（18：1n9）（18：1N9）和棕榈酰 - COA（16：1N7）（16：1N7），来自饱和脂肪酸（SFA）（SFA），Stear-COA（Smit），palyl-coA（18：18：18：18：18：18：18：18：18：18：18：18：18：18：18：18：18：18：18：18：18：18：18：18：18：（16：0）。许多代谢疾病中18：1N9水平的变化表明SCD在健康和疾病中的重要作用。我们在几项研究中表明，全球和皮肤特异性的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性，肝脂肪变性和高血糖症的影响，但是SCD1缺乏症的机制如何导致我们的这种保护性和有益的表型为某些人而言。 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衍生的脂肪因子已知可以调节全身脂质和葡萄糖稳态。用三利果蛋白（而非三脂蛋白）喂养雄性和雌性LKO小鼠，补充了HCD，可降低FGF21的表达并恢复血浆葡萄糖水平。原发性肝细胞中SCD活性的抑制作用诱导的FGF21表达，该表达受到Oleate的治疗而不是硬化酸酯的抑制作用。当原发性肝细胞用从先前用HCD喂食的LKO小鼠分离的血清处理时，在脂肪细胞GLUT-4和脂联素基因表达增加时，将脂肪生成基因表达降低。我们假设肝脏的油裂调节系统性葡萄糖和脂质代谢直接或通过FGF21和脂联素表达的调节。我们提出了两个具体目标。在AIM 1中，我们将定义SCD1缺乏在调节肝脏中FGF21表达中的作用。在AIM 2中，我们将确定SCD1缺乏介导的从头脂肪酸合成，脂肪酸，糖异生和脂肪的减少是否取决于FGF21刺激的脂联素介导的脂肪介导的肝磷脂组织轴。建立FGF21和脂联素作为SCD1缺乏症的全身代谢益处的主要介质，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标。