The role of NADPH production in regulating endoplasmic reticulum function and the progression of non-alcoholic steatohepatitis

NADPH产生在调节内质网功能和非酒精性脂肪性肝炎进展中的作用

• 批准号: 10386489
• 负责人: Erica Gansemer
• 金额: $ 1.51万
• 依托单位: UNIVERSITY OF IOWA
• 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 2022-05-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10386489
• 关键词: Affect; Animals; Attenuated; Budgets; Cell physiology; Cells; Cessation of life; Cholesterol; Chronic; Citric Acid Cycle; Communication; Confocal Microscopy; Data; Development; Diet; Disease; Endoplasmic Reticulum; Environment; Equilibrium; Fatty acid glycerol esters; Fructose; Genetic Transcription; Glutathione; Glutathione Disulfide; Glutathione Reductase; Goals; Health; Hepatic; Hepatocyte; Homeostasis; Individual; Inflammation; Isocitrate Dehydrogenase; Isoenzymes; Knockout Mice; Lead; Link; Lipids; Liver; Mediating; Metabolic; Metabolic Diseases; Metabolism; Mitochondria; Mitochondrial Matrix; Molecular; Molecular and Cellular Biology; Mus; NADP; Nutrient; Obesity; Organelles; Organism; Outcome; Oxidation-Reduction; Oxides; Pathway interactions; Physiological; Predisposition; Process; Production; Proteins; Research; Role; Signal Transduction; Source; Stable Isotope Labeling; Stress; System; Testing; Tissues; Training; Translations; Tricarboxylic Acids; Work; base; endoplasmic reticulum stress; experience; experimental study; glutathione peroxidase; in vivo; lipid metabolism; liver injury; mitochondrial dysfunction; mitochondrial metabolism; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel therapeutics; nutrient deprivation; oxidative damage; premature; protein folding; proteostasis; pyruvate carrier; ratiometric; sensor

Project Summary Cellular homeostasis is critical not only for the health of individual cells, but for an organism as a whole. Dysregulation of cellular processes, such as metabolism, contribute to the development of numerous diseases that have been difficult to fully characterize and treat thus far. Difficulty with treatment arises in part from the intricacy of cellular metabolism. The mitochondria are the primary metabolic organelles, and they cooperate with other organelles, including the endoplasmic reticulum (ER). The ER is responsible for lipid packaging and oxidative protein folding, and is sensitive to perturbations that disrupt these processes. Perturbations to ER function, better known as ER stress, result in activation of an adaptive pathway that coordinates transcription, translation, and metabolism to return the cell to homeostasis. However, chronic ER stress often leads to disease, including metabolic diseases such as non-alcoholic steatohepatitis (NASH). To date, NASH research has focused on either the mitochondria or ER, but not both. I recently showed that flux through the mitochondrial tricarboxylic acid (TCA) cycle impacts ER homeostasis through cellular redox signaling via NADPH and glutathione. This observation led to the hypothesis that TCA flux could communicate nutrient availability to the ER through NADPH and glutathione in an effort to balance the cellular redox budget and prime the ER for an influx of proteins or lipids. This also led to the hypothesis that redox communication between the ER and mitochondria results in ER stress-induced NASH. These two hypotheses are not mutually exclusive; it is possible that this redox mechanism is responsible for communicating nutrient status to the ER, but that it has no impact on NASH progression. Testing these hypotheses has the potential to uncover a novel mechanism for NASH progression. In this proposal, I will rigorously test the hypothesis that NADPH and glutathione redox lead to ER stress- induced NASH when nutrients are abundant. I will utilize animals lacking the TCA isozyme, isocitrate dehydrogenase (Idh2), which generates NADPH in the mitochondrial matrix. I will assess the susceptibility of these animals to ER stress and a NASH-promoting diet, while also determining how nutrient availability regulates pathway-specific NADPH production. Additionally, I will test the hypothesis that redox signals are communicated from the mitochondria to the ER by assessing compartment-specific levels of NADPH and glutathione under varied nutrient conditions. The broad goal of this proposal is to clarify the role of NADPH and glutathione in regulating ER function based on nutrient status. Successful completion of this proposal has the potential to spur research to develop new therapeutics for NASH, and may also be applied to other metabolic diseases and metabolically active tissues.

项目总结