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

肥胖及其并发症--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--发病率的增加，构成了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，其次是极低密度脂蛋白(VLDL)介导的甘油三酯运输到白色脂肪组织(WAT)储存。硬脂酰辅酶A脱饱和酶(SCD)是脂肪合成的关键调节因子，它催化由饱和脂肪酸(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(18：1n9)和棕榈酰辅酶A(16：1n7)。在许多代谢性疾病中，18：1N9水平的变化表明SCD在健康和疾病中具有突出的作用。我们在几项研究中表明，全球性和皮肤特异性的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、肝脏脂肪变性和高血糖，但对于SCD1缺乏如何导致这些保护性和有益的表型的机制，我们对一些人还不清楚。使用高碳水化合物饮食(HCD)喂养的肝脏特异性SCD1基因敲除(LKO)小鼠模型，我们现在发现，肝脏SCD1缺乏增加了组织对葡萄糖的摄取，并与肝脏来源的胰岛素敏感激素成纤维细胞生长因子21(FGF21)和脂肪细胞来源的脂肪因子脂联素(Adiponectin)的表达和血浆水平显著增加有关，脂联素是已知调节全身脂肪和葡萄糖稳态的脂肪细胞来源的脂肪因子。给雄性和雌性LKO小鼠喂食三油酸甘油酯，但不喂甘油三酯，补充HCD可降低FGF21的表达，并恢复血糖水平。抑制原代肝细胞SCD活性可诱导FGF21的表达，油酸可抑制FGF21的表达，但硬脂酸不能抑制FGF21的表达。原代肝细胞经HCD处理后，成脂基因表达降低，而脂肪细胞GLUT-4和脂联素基因表达增加。我们假设，肝脏油酸直接或通过调节FGF21和脂联素的表达来调节全身的糖和脂代谢。我们提出了两个具体目标。在目标1中，我们将确定SCD1缺陷在调节肝脏FGF21表达中的作用。在目标2中，我们将确定SCD1缺陷是否导致肝脏新生脂肪酸合成减少、脂肪变性、糖异生和肥胖依赖于FGF21刺激的脂联素介导的肝脏-脂肪组织轴。建立FGF21和脂联素作为SCD1缺乏症全身代谢益处的主要介体具有重要意义，因为SCD1本身、FGF21和脂联素是治疗人类肥胖、糖尿病和其他代谢性疾病的有吸引力的药物靶点。

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.