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Regulation of de novo lipogenesis through BAD-dependent glucose signaling

通过 BAD 依赖性葡萄糖信号传导调节从头脂肪生成

基本信息

批准号：
9244778
负责人：
Elizabeth Lane
金额：
$ 3.15万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9244778
关键词：
Acetates Acetylation Active Sites Acute Affect Amphipathic Alpha Helix BCL2 gene BH3 Domain Bad protein Binding Binding Proteins Biochemical Carbohydrates Cardiovascular Diseases Cells Charge Cues DNA Binding Data Disease Enzymes Equilibrium Fasting Fatty acid glycerol esters Fructose Gene Expression Genes Genetic Genetic Transcription Glucokinase Gluconeogenesis Glucose Glucose-6-Phosphate Glycogen Glycolysis Hepatic Hepatocyte Hormonal Lead Learning Link Lipids Liver Measurement Mediating Metabolic Modification Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Nuclear Translocation Nutrient Obesity Organ Pathway interactions Pharmacology Phosphorylation Post-Translational Protein Processing Production Protein Family Proteins Regulation Response Elements Role Serine Signal Transduction Testing Transcription Alteration activating transcription factor blood glucose regulation extracellular glucose metabolism glucose production inorganic phosphate insight lipid biosynthesis liquid chromatography mass spectrometry new therapeutic target programs protein activation public health relevance reaction rate response small hairpin RNA transcription factor

项目摘要

DESCRIPTION (provided by applicant): Regulation of de novo lipogenesis through BAD-dependent glucose signaling The homeostatic balance between hepatic utilization, storage, and production of glucose and fat in fed and fasted states is exquisitely controlled by hormonal and nutrient cues. In the fed state, the liver stores excess glucose first as glycogen then as fat through de novo lipogenesis. How the liver senses glucose to determine its utilization and storage is not fully understood at the molecular level. Emerging evidence indicates that glucose-derived metabolites, including the activity of glucokinase (GK), which catalyzes the first step of hepatic glycolysis, influence de novo lipogenesis by both providing metabolic precursors for lipid synthesis as well as triggering the expression of lipogenic genes. Glucose regulation of de novo lipogenesis is dependent, at least in part, on the Carbohydrate Response Element Binding Protein (ChREBP), a transcription factor that is activated by certain glucose-derived metabolites. My proposed studies test the role of the BCL-2 family protein BAD as an upstream regulator of hepatic glucose signaling and de novo lipogenesis through ChREBP. BAD's modulation of glucose metabolism is mediated by phosphorylation of Ser155, which leads to direct activation of GK. The functional relevance of this interaction is evident from the observations that BAD deficiency or interference with its phosphorylation is associated with reduced hepatic GK activity and glycolysis. I have found that glucose induction of ChREBP activity and lipogenic gene expression is diminished in Bad -/- hepatocytes. These data, together with the known capacity of BAD to activate GK and GK's relevance in ChREBP activation, give rise to the hypothesis that BAD modulates hepatic ChREBP activity and de novo lipogenesis through its ability to regulate GK activity. I will test this hypothesis through the following specific aims: Aim 1 will interrogate the acute and cell autonomous effect of BAD modifications in primary hepatocytes and the attendant changes in GK on stimulation of ChREBP transcriptional activity by glucose. Aim 2 will determine the functional and metabolic correlates of BAD-dependent changes in lipogenic gene expression by biochemical measurement of de novo lipogenesis and glucose-dependent changes in lipid profiles in primary hepatocytes following genetic or pharmacologic modification of BAD. Aim 3 will dissect the mechanistic link between BAD modifications and ChREBP activity by examining alterations in defined post translational modifications of ChREBP in response to glucose, including phosphorylation and acetylation known to modulate ChREBP transcriptional activity. In the fullness of time, these studies will provide an integrated picture of the pathway connecting BAD and GK- dependent glucose metabolism with ChREBP activity and the lipogenic program. Understanding this pathway should yield useful molecular insights into hepatic glucose sensing, nutrient utilization and storage.