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. !

项目概要 非酒精性脂肪肝（NAFLD）是影响数百万美国人的主要公共卫生问题， 随着全球肥胖率的上升，这种疾病的患病率也在不断增加。 确定了与肝脏脂肪相关的自然人类遗传变异，其中与两个基因相关： PNPLA3 和 PPP1R3B 已在多项研究中得到复制，我们开发了独特的新型小鼠。 模型帮助我们了解增加的 PPP1R3B 如何预防脂肪肝。 已知可调节肝糖原的蛋白质，但仅通过遗传关联与肝脏脂肪相关： 换句话说，PPP1R3B在肝脏脂肪代谢中的作用尚不清楚。 这表明，PPP1R3B 还与人类代谢健康相关的多种特征存在遗传相关性， 包括空腹胰岛素和葡萄糖、血浆乳酸、碱性磷酸酶和血浆胆固醇（总胆固醇、低密度脂蛋白胆固醇） 所有这些关联信号都映射到距 PPP1R3B 基因末端很远的地方。 功能未知的长非编码 RNA (lncRNA)，LOC157273，尽管物理距离相当远， 发现遗传变异与肝脏 PPP1R3B RNA 的增加相关（发生于。 ~9% 的欧洲人）与肝脏 PPP1R3B mRNA 表达增加以及肝脏和肝脏功能减少相关。 我们在小鼠中的初步数据强烈表明 PPP1R3B 是致病基因：肝脏特异性。 PPP1R3B 敲除小鼠 (Ppp1r3bΔhep) 的肝脏和血浆脂质增加，而 肝脏中的 Ppp1r3b 水平降低肝脏和血浆脂质。我们建议阐明其机制。 肝 PPP1R3B 影响肝脂肪和血浆胆固醇，并确定自然变异如何 增加 PPP1R3B 基因的表达。 ！