Role of Multi-enzyme Complex in ApoBCL Secretion

多酶复合物在 ApoBCL 分泌中的作用

• 批准号: 10332597
• 负责人: JAY D. HORTON
• 金额: $ 57.4万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10332597
• 关键词: ADD-1 protein; ATP Citrate (pro-S)-Lyase; Acetyl-CoA Carboxylase; Acyltransferase; Apolipoproteins B; Cardiovascular system; Complement; Complex; Coronary heart disease; Cytoplasm; Cytosol; Data; Development; Dyslipidemias; Endoplasmic Reticulum; Enzymes; Event; Fatty-acid synthase; Genes; Genetic Transcription; Genetic study; Goals; Hepatic; Hepatocyte; Hypertriglyceridemia; In Vitro; Individual; LDL Cholesterol Lipoproteins; Lead; Lipids; Lipoproteins; Liver; Location; Metabolic; Metabolism; Mitochondria; Molecular; Multienzyme Complexes; Mus; New Agents; Organelles; Outcome; Palmitates; Physiological; Plasma; Production; Program Research Project Grants; Proteins; Regulation; Research Project Grants; Residual state; Risk; Role; Series; Signal Transduction; Structural Protein; Triglycerides; Very low density lipoprotein; alpha-glycerophosphoric acid; cardiovascular risk factor; density; enzyme activity; gene function; gene synthesis; heart disease risk; hormonal signals; in vivo; inhibitor; insight; lipid metabolism; mitochondrial membrane; novel strategies; polymerization; protein protein interaction; stem; transcription factor

Project 2. Role of Multi-Enzyme Complexes in ApoBCL Secretion SUMMARY/ABSTRACT Although statins and PCSK9 inhibitors decrease LDL-Cholesterol (LDL-C) levels and reduce cardiovascular events, significant residual risk of CHD remains even in maximally treated individuals with low plasma levels of LDL-C. Multiple lines of evidence support the contention that elevated plasma levels of triglyceride (TG)-rich ApoB-Containing Lipoproteins (ApoBCLs) contribute significantly to this residual risk. Previously, we have shown that the transcription factor, SREBP-1c, leads to activation of all genes encoding the enzymes involved in FA synthesis. Excessive activation of SREBP-1c in liver results in high levels of FA and TG synthesis, VLDL secretion, and ultimately hypertriglyceridemia. The studies in this project will characterize a new post- translational regulatory mechanism that modulates FA and TG synthesis as well as VLDL production. The three enzymes that synthesize palmitate (C16:0) — ATP-citrate lyase (ACL), acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) — reside in the cytoplasm. The two enzymes that elongate and/or desaturate palmitate, ELOVL6 and SCD1, are located in the ER, and the first enzyme in the synthesis of glycerolipids, glycerol-3-phosphate acyltransferase 1 (GPAM), is located in the mitochondrial membrane. The distinct subcellular locations of these enzymes produce a unique spatial challenge for the efficient synthesis of FAs and TGs since the product of one enzyme is the substrate for the next. Our preliminary data suggest that the cytosolic FA synthesis enzymes form a complex. This discovery stemmed from the characterization of a SREBP-1c-regulated gene designated MIG12. We found that MIG12 bound directly to ACCs, facilitated ACC polymerization, and increased overall rates of FA synthesis in liver. MIG12 is structurally similar to another small protein designated S14. Our subsequent studies have shown that S14 co-immunoprecipitated MIG12, ACC, and FAS suggesting that these proteins form a complex in the cytosol. Here, we will identify and characterize all proteins in the FA synthesis complex and determine how these proteins associate with each other and with the ER and/or mitochondria. Next, we will determine whether the formation and disassociation of the FA synthesis complex is regulated by hormonal signals in vitro and in vivo. Finally, we will characterize the physiological function of lipogenic complex in vivo through a series of studies in mice that lack the key proteins required for the formation of the FA synthesis complex. Combined, these studies will provide important new insights into how the cytosolic lipogenic complex ultimately provides FAs to the ER for further elongation and/or desaturation as well as to GPAM for TG synthesis and VLDL secretion.

项目2。多酶复合物在载脂蛋白cl分泌中的作用