NPC1L1 and Metabolic Diseases

NPC1L1 与代谢疾病

• 批准号: 7768744
• 负责人: Liqing Yu
• 金额: $ 37万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 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/7768744
• 关键词: ASBT protein; Address; Adipose tissue; Affect; Age; Animals; Bile Acids; Biliary; Biochemical; Biochemistry; Blood; Body Size; Brain; Brown Fat; Catabolism; Cholesterol; Cholesterol Homeostasis; Complement component C1s; 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; Small Intestines; Societies; Testing; Thyroid Hormones; Tissues; Transgenic Mice; Weight; Weight Gain; Wild Type Mouse; base; cholesterol absorption; cholesterol biosynthesis; clinically relevant; cytokine; dietary excess; ezetimibe; feeding; gene function; global health; human tissue; ileum; inhibitor/antagonist; insight; insulin sensitivity; lipid metabolism; mortality; non-alcoholic fatty liver; novel; novel strategies; obesity treatment; prevent; public health relevance; skeletal; uptake

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. PUBLIC HEALTH RELEVANCE: The overall goal of this proposal is to define how genetic inactivation or pharmacologic inhibition of intestinal NPC1L1 influences the development of obesity induced by a high fat diet. Findings from proposed studies hold the promise of revealing new approaches for the prevention and treatment of metabolic diseases such as obesity, type 2 diabetes and nonalcoholic fatty liver diseases. Given that NPC1L1 is the target of ezetimibe, an FDA-approved intestinal cholesterol absorption inhibitor that is widely used to lower blood cholesterol in humans, these studies have enormous translational potential.

描述（由申请人提供）：Niemann-Pick类似C1样1（NPC1L1）最初被鉴定为肠道胆固醇吸收的必需蛋白质。它是Ezetmibe的靶标，Ezetmibe是一种胆固醇吸收抑制剂，可广泛用于降低人类的血液胆固醇。令人惊讶的是，最近发现，NPC1L1的遗传灭活或ezetimibe抑制了小鼠，可预防高脂肪饮食（HFD）诱导的肥胖症（DIO）和相关的代谢障碍。这些新发现的分子机制仍然未知。拟议的研究的总体目标是定义NPC1L1缺乏对DIO的影响。在初步研究中，我们发现野生型（WT）和NPC1L1基因敲除（L1KO）小鼠之间的食物摄入相同，但是L1KO小鼠受到DIO和FATTY肝脏的保护，这与促进棕色脂肪组织（BAT）和骨骼肌肉促进基因表达的表达增加有关。因此，我们假设NPC1L1缺乏通过增加能量消耗来保护小鼠免受DIO的影响。我们将直接测量能量消耗，并分子定义NPC1L1缺乏症如何通过测量WT和L1KO小鼠在饮食过量，Ezetimibe治疗或禁食条件下的生物化学和基因表达水平的代谢变化来刺激能量耗散。在小鼠中，NPC1L1在小肠中高度表达，并且在非智能组织中只能检测到低水平的NPC1L1 mRNA。我们假设肠道NPC1L1的损失是对DIO的抗性。为了直接检验该假设，我们将跨越新创建的转基因小鼠，该小鼠在小肠中特异性表达人NPC1L1至L1KO小鼠，从而重新建立肠NPC1L1表达，并确定这是否会挽救L1KO小鼠中的体重增加。我们还将确定NPC1L1缺乏症是否需要甲状腺激素激活2型碘甲醇脱碘酶（D2）来防止DIO，因为我们发现D2表达在L1KO小鼠的BAT和肌肉中显着升高，并且已知D2激活已知可以促进能量支出。为了探测NPC1L1缺乏症与D2激活之间的分子联系，我们将检查HFD上WT和L1KO小鼠之间的胆汁酸代谢是否有所不同，因为我们发现许多胆汁酸敏感的基因在L1KO小鼠的卵巢中被上调在L1KO小鼠和胆汁酸的卵巢中可以通过刺激分子的信号来刺激了Engientient，从而通过a刺激了a d2 expient for a d2 exportion a d2 exportion a d2 exend exende n d2 d2。综上所述，这些研究将为NPC1L1在代谢性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和相关代谢危险因素的新方法，这对疾病的发病率和死亡率产生了重大影响。 公共卫生相关性：该提案的总体目标是确定肠道NPC1L1的遗传灭活或药物抑制如何影响高脂肪饮食引起的肥胖的发展。拟议研究的发现有望揭示预防和治疗代谢疾病的新方法，例如肥胖，2型糖尿病和非酒精性脂肪肝疾病。鉴于NPC1L1是Ezetimibe的靶标，Ezetimibe是FDA批准的肠道胆固醇吸收抑制剂，该抑制剂被广泛用于降低人类的血液胆固醇，因此这些研究具有巨大的转化潜力。