NPC1L1 and Metabolic Diseases

NPC1L1 与代谢疾病

基本信息

批准号：
8587678
负责人：
Liqing Yu
金额：
$ 0.07万
依托单位：
UNIV OF MARYLAND, COLLEGE PARK
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8587678
关键词：
ASBT protein Address Adipose tissue Affect Age Animals Bile Acids Biliary Biochemical Biochemistry Blood Body Size Body Weight Brain Brown Fat Catabolism Cholesterol Cholesterol Homeostasis Data Development Diet Disease Dyslipidemias Eating Energy Metabolism Enterocytes Enterohepatic Circulation Enzymes Etiology Excretory function FDA approved Fasting Fatty Liver Fatty acid glycerol esters Feces Gatekeeping Gender Gene Expression Genes Genetic Glucose Goals Heart Homeostasis Hormones Human Inflammation Insulin Resistance Intestines Iodothyronine Deiodinase Knock-out Knockout Mice Link Lipids Liver Liver diseases Measures Messenger RNA Metabolic Metabolic Diseases Metabolism Molecular Molecular Probes Morbidity - disease rate Mus Muscle Non-Insulin-Dependent Diabetes Mellitus Nutrient Obesity Organ Pathway interactions Phenotype Physical activity Pilot Projects Prevention Proteins Public Health Relative (related person)Reproduction Research Resistance Risk Factors Role Signaling Molecule Skeletal Muscle Small Intestines Societies Testing Thyroid Hormones Tissues Transgenic Mice Weight Gain Wild Type Mouse base cholesterol absorption cholesterol biosynthesis clinically relevant cytokine dietary excess ezetimibe feeding gene function global health glucose metabolism human tissue ileum inhibitor/antagonist insight insulin sensitivity lipid metabolism mortality non-alcoholic fatty liver novel novel strategies obesity treatment prevent public health relevance uptake

项目摘要

DESCRIPTION (provided by applicant): Niemann-Pick C1-Like 1 (NPC1L1) was originally identified as an essential protein for intestinal cholesterol absorption. It is the target of ezetmibe, a cholesterol absorption inhibitor that is widely used to lower blood cholesterol in humans. Surprisingly, genetic inactivation or ezetimibe inhibition of NPC1L1 in mice was recently found to protect against high fat diet (HFD)-induced obesity (DIO) and associated metabolic disorders. The molecular mechanisms underlying these novel findings remain unknown. The overall goal of the proposed studies is to define how NPC1L1 deficiency affects DIO. In preliminary studies, we found that food intake was identical between wild-type (WT) and NPC1L1 knockout (L1KO) mice, yet L1KO mice were protected against DIO and fatty liver, which was associated with increased expression of genes promoting energy expenditure in brown adipose tissue (BAT) and skeletal muscle. Thus, we hypothesize that NPC1L1 deficiency protects mice from DIO by increasing energy expenditure. We will directly measure energy expenditure, and molecularly define how NPC1L1 deficiency stimulates energy dissipation by measuring metabolic changes at biochemical and gene expression levels in WT and L1KO mice under dietary excess, ezetimibe treatment or fasting conditions. In mice, NPC1L1 is highly expressed in small intestine and only low levels of NPC1L1 mRNA can be detected in non-intestinal tissues. We hypothesize that loss of intestinal NPC1L1 is responsible for resistance to DIO. To directly test this hypothesis, we will cross our newly-created transgenic mice specifically expressing human NPC1L1 in small intestine to L1KO mice, thereby re-establishing intestinal NPC1L1 expression, and determine if this will rescue weight gain in L1KO mice. We will also determine if NPC1L1 deficiency requires a thyroid hormone activating enzyme type 2 iodothyronine deiodinase (D2) to prevent DIO since we found that D2 expression was substantially elevated in BAT and muscle in L1KO mice, and D2 activation is known to promote energy expenditure. To probe the molecular link between NPC1L1 deficiency and D2 activation, we will examine if bile acid metabolism differs between WT and L1KO mice on HFD because we found that many bile acid sensitive genes were upregulated in the ileum of L1KO mice and bile acids can function as signaling molecules to stimulate energy expenditure via a D2- dependent mechanism. Taken together, these studies will provide important new insight into the role of NPC1L1 in metabolic diseases, and have the potential to reveal new approaches for the prevention and treatment of obesity and associated metabolic risk factors, which contribute substantially to disease morbidity and mortality.

描述（由申请人提供）：Niemann-Pick C1-Like 1 (NPC1L1) 最初被鉴定为肠道胆固醇吸收的必需蛋白质。它是依泽米贝（ezetmibe）的目标，依泽米贝是一种胆固醇吸收抑制剂，广泛用于降低人类血液胆固醇。令人惊讶的是，最近发现小鼠中 NPC1L1 的基因失活或依折麦布抑制可以预防高脂饮食 (HFD) 诱导的肥胖 (DIO) 和相关代谢紊乱。这些新发现背后的分子机制仍然未知。拟议研究的总体目标是确定 NPC1L1 缺陷如何影响 DIO。在初步研究中，我们发现野生型 (WT) 和 NPC1L1 敲除 (L1KO) 小鼠的食物摄入量相同，但 L1KO 小鼠可以免受 DIO 和脂肪肝的侵害，这与棕色小鼠中促进能量消耗的基因表达增加有关。脂肪组织（BAT）和骨骼肌。因此，我们假设 NPC1L1 缺陷通过增加能量消耗来保护小鼠免受 DIO 的侵害。我们将直接测量能量消耗，并通过测量 WT 和 L1KO 小鼠在饮食过量、依折麦布治疗或禁食条件下生化和基因表达水平的代谢变化，从分子角度定义 NPC1L1 缺陷如何刺激能量耗散。在小鼠中，NPC1L1 在小肠中高表达，在非肠组织中仅检测到低水平的 NPC1L1 mRNA。我们假设肠道 NPC1L1 的缺失导致了对 DIO 的耐药性。为了直接检验这一假设，我们将新创建的在小肠中特异性表达人 NPC1L1 的转基因小鼠与 L1KO 小鼠杂交，从而重新建立肠道 NPC1L1 表达，并确定这是否会挽救 L1KO 小鼠的体重增加。我们还将确定 NPC1L1 缺陷是否需要甲状腺激素激活酶 2 型碘甲状腺氨酸脱碘酶 (D2) 来预防 DIO，因为我们发现 L1KO 小鼠的 BAT 和肌肉中 D2 表达显着升高，并且已知 D2 激活会促进能量消耗。为了探究 NPC1L1 缺陷和 D2 激活之间的分子联系，我们将检查 WT 和 L1KO 小鼠在 HFD 上的胆汁酸代谢是否存在差异，因为我们发现 L1KO 小鼠的回肠中许多胆汁酸敏感基因上调，并且胆汁酸可以作为信号分子通过 D2 依赖性机制刺激能量消耗。总而言之，这些研究将为 NPC1L1 在代谢疾病中的作用提供重要的新见解，并有可能揭示预防和治疗肥胖及相关代谢危险因素的新方法，这些因素对疾病发病率和死亡率有重大影响。