Molecular mechanisms underlying the genetic association between PPP1R3B and hepatic steatosis

PPP1R3B与肝脂肪变性遗传关联的分子机制

• 批准号: 10224175
• 负责人: Joseph A. Baur
• 金额: $ 54.11万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10224175
• 关键词: Adipocytes; Adipose tissue; Affect; Agreement; Alkaline Phosphatase; Alleles; Allelic Imbalance; American; Apolipoprotein E; Apolipoproteins B; Automobile Driving; Biological; Biological Assay; Blood Glucose; CSPG3 gene; Carbohydrates; Cell Culture Techniques; Cholesterol; Cholesterol Homeostasis; Chromatin; Chromosomes; Data; Defect; Diet; Disease Progression; Distant; Dyslipidemias; Elements; Esterification; European; Fasting; Fatty Liver; Fatty acid glycerol esters; Functional disorder; Generations; Genes; Genotype; Glucose; Glycogen; Haplogroup; Health; Hepatic; High Density Lipoprotein Cholesterol; High Density Lipoproteins; High Fat Diet; Human; Human Genetics; Hydrolysis; Hypoglycemia; Insulin; Ketone Bodies; Knockout Mice; LDL Cholesterol Lipoproteins; Lead; Link; Lipids; Lipolysis; Lipoproteins; Liver; Liver Glycogen; Low-Density Lipoproteins; Luciferases; Maps; Measures; Mediating; Messenger RNA; Metabolic; Metabolic Diseases; Minor; Molecular; Mus; Names; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Olive oil preparation; Oxides; Pathway interactions; Peripheral; Phenotype; Phosphorylation; Plasma; Prevalence; Promoter Regions; Protein phosphatase; Proteins; Public Health; Quantitative Trait Loci; RNA; Regulator Genes; Reporter; Role; Secondary to; Signal Transduction; TNKS gene; Testing; Tissues; Triglycerides; Untranslated RNA; Variant; alkalinity; carbohydrate metabolism; causal variant; chromosome conformation capture; experimental study; falls; fasting glucose; fasting plasma glucose; genetic approach; genetic association; genetic regulatory protein; genetic variant; genome wide association study; genome-wide; glycogen metabolism; lipid biosynthesis; lipid metabolism; mRNA Expression; mouse model; non-alcoholic fatty liver disease; novel; overexpression; particle; promoter; trait; uptake

PROJECT SUMMARY Non-alcoholic fatty liver disease (NAFLD) is a major public health issue that affects millions of Americans, and that is increasing in prevalence with the global rise in obesity. Cutting edge human genetic approaches have identified natural human genetic variants associated with liver fat. Of these, associations with two genes: PNPLA3, and PPP1R3B, have been replicated in multiple studies. We have developed unique new mouse models to help us understand how increased PPP1R3B protects against fatty liver. PPP1R3B encodes a protein known to regulate liver glycogen, but which has only been connected to liver fat by genetic association: in other words, the role of PPP1R3B in liver fat metabolism is unknown. Interestingly, PPP1R3B is also genetically associated with multiple traits relevant to human metabolic health, including fasting insulin and glucose, plasma lactate, alkaline phosphatase, and plasma cholesterol (total, LDL and HDL cholesterol). All of these association signals map quite far from the end of the PPP1R3B gene, to a long non-coding RNA (lncRNA) of unknown function, LOC157273. Despite the considerable physical distance, genetic variants were found to correlate with increased liver PPP1R3B RNA. The minor allele (occurring in ~9% of Europeans) is associated with increased hepatic PPP1R3B mRNA expression and reduced liver and plasma lipids. Our preliminary data in mice strongly suggest that PPP1R3B is the causal gene: liver-specific PPP1R3B knockout mice (Ppp1r3bΔhep) have increased hepatic and plasma lipids, whereas increasing Ppp1r3b levels in liver reduces hepatic and plasma lipids. We propose to elucidate the mechanisms by which hepatic PPP1R3B influences hepatic fat and plasma cholesterol, and to determine how the natural variants increase expression of the PPP1R3B gene. !

项目摘要 非酒精性脂肪肝病（NAFLD）是影响数百万美国人和的主要公共卫生问题 随着肥胖症的全球兴起，这一流行率正在增加。尖端人类遗传方法具有 确定了与肝脂肪相关的自然人遗传变异。其中，与两个基因的关联： PNPLA3和PPP1R3B在多个研究中已复制。我们已经开发了独特的新鼠标 模型以帮助我们了解增加的PPP1R3B如何预防脂肪肝。 PPP1R3B编码a 已知可以调节肝糖原的蛋白质，但仅通过遗传关联将其与肝脂肪联系在一起： 换句话说，PPP1R3B在肝脂肪代谢中的作用尚不清楚。 有趣的是，PPP1R3B也与与人类代谢健康有关的多种特征相关， 包括禁食胰岛素和葡萄糖，血浆乳酸，醇磷酸酶和血浆胆固醇（总LDL） 和HDL胆固醇）。所有这些关联信号都远离PPP1R3B基因的末端的映射到A 未知功能的长无编码RNA（LNCRNA），LOC157273。尽管身体距离很大， 发现遗传变异与肝脏PPP1R3B RNA的增加相关。小等位基因（发生在 〜9％的欧洲人）与肝ppp1r3b mRNA表达增加并降低肝脏有关 血浆脂质。我们在小鼠中的初步数据强烈表明PPP1R3B是因果基因：肝特异性 PPP1R3B敲除小鼠（PPP1R3BΔHEP）的肝脂质和血浆脂质增加，而增加 肝脏中的PPP1R3B水平降低了肝脂质和血浆脂质。我们建议阐明其机制 肝PPP1R3B影响肝脂肪和血浆胆固醇，并确定自然变体如何 增加PPP1R3B基因的表达。 呢