Fatty Acid Regulation of Liver Lipoprotein Production

肝脏脂蛋白产生的脂肪酸调节

• 批准号: 7525895
• 负责人: HENRY N GINSBERG
• 金额: $ 40.08万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7525895
• 关键词: ADD-1 protein; Acids; Affect; Albumins; Apolipoprotein A-I; Apolipoproteins B; Apoptosis; Area; Autophagocytosis; Binding; CCAAT-Enhancer-Binding Proteins; Characteristics; Chemicals; Cholesterol Esters; Complex; Condition; Cultured Cells; Data; Development; Disease; Dose; Endoplasmic Reticulum; Exposure to; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Funding; Goals; Grant; Hepatic; Hepatocyte; Human; Hydrolase; In Vitro; Insulin; Insulin Resistance; Insulin Signaling Pathway; Investigation; Knockout Mice; Knowledge; Laboratories; Leptin; Link; Lipase; Lipid Binding; Lipids; Lipoproteins; Liver; Measures; Metabolic syndrome; Modeling; Molecular; Molecular Chaperones; Molecular Weight; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Receptors; Numbers; Oleic Acid; Oleic Acids; PTEN gene; Palmitic Acids; Pathway interactions; Play; Production; Protein Biosynthesis; Protein Secretion; Proteins; Public Health; Rate; Regulation; Role; Series; Signal Transduction; Source; Stress; Surveys; System; TGFA gene; Testing; Transforming Growth Factor alpha; Translation Initiation; Translations; Triglycerides; Tunicamycin; Week; Work; apolipoprotein B-48; base; density; fatty acid metabolism; hepatoma cell; in vivo; interest; lipid biosynthesis; lipid metabolism; mouse model; novel; protein structure; receptor; research study; response; size; uptake

DESCRIPTION (provided by applicant): The combination of increased secretion of triglyceride (TG)-rich apolipoprotein B (apoB) lipoproteins (Lps) and hepatic steatosis, are characteristic concomitants of insulin resistance, the metabolic syndrome, and type 2 diabetes mellitus. The basis for increased secretion of apoB-Lps is complex, and includes altered regulation of apoB synthesis and transport in hepatocytes, increased delivery of fatty acids (FA) to the liver, and increased de novo hepatic lipogenesis (DNHL). Increased hepatic uptake of FA and increased DNHL are also critical for the development of hepatic steatosis. However, recent evidence from our laboratory, and others, indicate that endoplasmic reticulum (ER) stress and aberrant hepatic expression of PPAR32 may both play important roles in apoB-Lp secretion and the development of hepatic steatosis. The studies proposed in this application focus mainly on our very recent and exciting findings linking disordered FA metabolism to both ER stress and hepatic expression of PPAR32. Specifically, we have demonstrated that oleic acid (OA)-loading of cultured hepatoma cells can induce ER stress that can have, at lower doses of FA for shorter durations, a "selective" effect on apoB100 secretion without affecting total protein synthesis or secretion of albumin or apoA-I. We have comparable in vivo data in mice. Higher doses or longer exposure to OA cause "global" ER stress with inhibition of secretion of several proteins and reduced total protein synthesis. We propose a series of experiments to extend, in detail, these exciting findings. We will compare ER stress effects on apoB by OA and tunicamycin, characterize the pathways by which apoB is degraded during ER stress, examine the effects of palmitic acid (PA) and docosahexanoic acid (DHA), extend our investigations regarding the particular sensitivity of apoB100 to ER stress, demonstrate in vivo that inhibition of ER stress results in increased secretion of VLDL and reversal of steatosis, and examine the important link between ER stress and increased lipogenesis. In a parallel series of studies we will extend observations related to the role of aberrant hepatic expression of PPAR32 in steatosis. In particular, we will determine the role of C/EBPs in the expression of PPAR32 in liver, investigate the signaling pathways for insulin stimulation of PPAR32 expression, and compare the effects of different FAs. We will extend initial studies indicating that hepatic expression of PPAR32 may both increase DNHL and, by suppressing a neutral TG lipase, TGH2, reduce the incorporation of hepatic TG into apoB-containing Lps. Finally, we will assess recent data suggesting that PPAR32 expression in liver can be a response to ER stress, possibly via increased expression of C/EBP. Overall, our proposed studies should provide the basis for a unified model to explain the common association of increased (but not maximal) apoB secretion, increased hepatic DNHL, and steatosis in mice and people with insulin resistance. The combination of increased secretion of triglycerides and apolipoprotein B (apoB), and hepatic steatosis (fatty liver), are characteristic concomitants of insulin resistance, the metabolic syndrome, and type 2 diabetes mellitus. Recent evidence from our laboratory indicate that endoplasmic reticulum (ER) stress and aberrant hepatic expression of the nuclear receptor, PPAR2, which is typically found in fat, may both play important roles in the increased secretion of triglycerides and apoB, and in the development of hepatic steatosis. PUBLIC HEALTH RELEVANCE: The studies proposed in this application will focus on these new discoveries and extend our knowledge about the roles of ER stress and PPAR2 in the regulation of hepatic lipid metabolism. We will use cell culture models and mice, conducting in vitro and in vivo studies. Overall, our proposed studies should provide evidence for a unified model to explain the common association of increased apoB secretion, increased hepatic DNHL, and steatosis in mice and people with insulin resistance.

描述（由申请人提供）：甘油三酸酯（TG）的分泌增加的组合 - 富脂蛋白B（APOB）脂蛋白（LPS）（LPS）和肝脂肪变性，是胰岛素抵抗，代谢综合征和2型糖尿病的特征伴侣。 APOB-LPS分泌增加的基础是复杂的，包括肝细胞中APOB合成和转运的调控，脂肪酸（FA）向肝脏的递送增加，并增加了从头肝脂肪生成（DNHL）。 FA的肝癌摄取增加和DNHL的增加对于肝脂肪变性的发展也至关重要。但是，我们实验室和其他实验室的最新证据表明，PPAR32的内质网应力（ER）压力和异常的肝表达可能在APOB-LP分泌和肝脂肪变性的发展中起重要作用。该应用中提出的研究主要集中在我们最近令人兴奋的发现，将无序的FA代谢与PPAR32的ER应激和肝表达联系起来。具体而言，我们已经证明了培养的肝癌细胞的油酸（OA）载荷可以诱导ER应力，而在较短持续时间内，可以在较低剂量的FA时对APOB100分泌产生“选择性”影响，而不会影响总蛋白质合成或白蛋白或APOA-I的分泌。我们在小鼠中具有可比的体内数据。较高的剂量或更长的OA暴露会导致“全球” ER应激，并抑制几种蛋白质的分泌并减少总蛋白质合成。我们提出了一系列实验，以详细扩展这些令人兴奋的发现。 We will compare ER stress effects on apoB by OA and tunicamycin, characterize the pathways by which apoB is degraded during ER stress, examine the effects of palmitic acid (PA) and docosahexanoic acid (DHA), extend our investigations regarding the particular sensitivity of apoB100 to ER stress, demonstrate in vivo that inhibition of ER stress results in increased secretion of VLDL and reversal of steatosis, and examine the important ER应激与脂肪生成增加之间的联系。在一系列平行的研究中，我们将扩展与PPAR32异常表达在脂肪变性中的作用相关的观察结果。特别是，我们将确定C/EBP在PPAR32表达中的作用，研究PPAR32表达胰岛素刺激的信号传导途径，并比较不同FAS的作用。我们将扩展初始研究，表明PPAR32的肝表达可能会增加DNHL，并且通过抑制中性TG脂肪酶TGH2，TGH2降低了肝TG掺入含APOB的LPS中。最后，我们将评估最新数据，表明肝脏中的PPAR32表达可能是对ER应力的反应，这可能是通过增加C/EBP的表达来反应。总体而言，我们提出的研究应该为统一模型提供基础，以解释APOB分泌增加（但不是最大）的共同关联，增加的肝DNHL以及小鼠和胰岛素抵抗的人的脂肪变性。甘油三酸酯和载脂蛋白B（APOB）和肝脂肪变性（脂肪肝）的分泌增加的组合是胰岛素抵抗，代谢综合征和2型糖尿病的特征伴侣。我们实验室的最新证据表明，核受体的内质网应力（ER）应激和异常的肝表达PPAR2（通常在脂肪中发现）都可能在甘油三酸酯和APOB的增加以及肝steatosis的发育中起重要作用。公共卫生相关性：本申请中提出的研究将集中在这些新发现上，并扩展我们对ER压力和PPAR2在肝脂质代谢调节中的作用的了解。我们将使用细胞培养模型和小鼠进行体外和体内研究。总体而言，我们提出的研究应为统一模型提供证据，以解释APOB分泌增加，肝DNHL增加以及胰岛素抵抗的人的共同关联。