PKCbeta mediates dietary fat/cholesterol-induced cholesterol homeostasis

PKCbeta 介导膳食脂肪/胆固醇诱导的胆固醇稳态

• 批准号: 9368518
• 负责人: KAMAL D MEHTA
• 金额: $ 38.75万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-15 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9368518
• 关键词: American diet; Anabolism; Animal Sources; Atherosclerosis; Bile Acid Biosynthesis Pathway; Bile Acids; Biochemical; Calories; Catabolism; Cell physiology; Cholesterol; Cholesterol Homeostasis; Defense Mechanisms; Development; Diet; Dietary Cholesterol; Dietary Fats; Disease; Event; Fatty Acids; Fatty acid glycerol esters; Gene Expression; Gene Expression Regulation; Genetic Transcription; Goals; Hepatic; Hepatocyte; Impairment; Individual; Intake; Investigation; Knowledge; Laboratories; Lead; Life; Ligands; Link; Liver; Liver diseases; Mediating; Messenger RNA; Modification; Molecular; Mus; Nature; Nuclear; Pathology; Pathway interactions; Phosphorylation; Physiological; Plasma; Protein Isoforms; Risk Factors; Role; Signal Pathway; Signal Transduction; Sterols; Stress; Testing; Tissues; Transcriptional Regulation; base; body sense; cholesterol biosynthesis; ileum; liver metabolism; liver-specific protein; mouse model; novel; promoter; protein kinase C beta; response; saturated fat; sensor; transcription factor; uptake; western diet

ABSTRACT The Western diet is an established risk factor for atherosclerosis due to substantial impact of saturated fat and cholesterol intake on the body's cholesterol homeostasis. An average American diet contains 37% of calories from fat and 385 mg/day of cholesterol, predominantly derived from animal sources. Significant advances have been made in defining transcription factors responding to either fatty acids or cholesterol, but whether there is a separate sensing mechanism in the body for detecting both fat and cholesterol is unknown. In particular, the nature and timing of dietary signals that can sense, integrate and synchronize cholesterol regulatory network in response to a high-fat/cholesterol load have not been studied. In view of recent demonstrations that dietary fat and dietary cholesterol act synergistically to impair cholesterol homeostasis, assessing the impact of both on dysregulated cholesterol homeostasis, rather than an individual component alone, is more physiologically relevant. We propose that the body has a separate sensor to detect both fat and cholesterol and utilize a distinct strategy for adaptation to high-fat/cholesterol load to minimize its detrimental impact on cholesterol homeostasis. Emerging evidence from our laboratory indicates that diet-sensitive PKC is a critical link between high-fat/cholesterol intake and hepatic adaptiveness of cholesterol homeostasis. Consistent with this function, a high-fat/cholesterol diet dramatically induced PKC expression in the liver, while a systemic PKC deficiency elevated liver and plasma cholesterol content in response to high-fat/cholesterol diet. We suggested a molecular mechanism by which liver PKC signaling, with or without ileum PKC, converges on the liver Erk- 1/2 to differentially regulate critical transcription factors of cholesterol homeostasis. These observations are exciting in that they not only represent first demonstration of the role of a specific PKC isoform in cholesterol metabolism but may also provide a missing signaling and regulatory link between dietary lipids and cholesterol homeostasis. Based on the above results, we propose a novel hypothesis that PKC is a “fat/cholesterol sensor” whose activation in the liver represents a potent defense mechanism to cope with dietary high- fat/cholesterol insult by promoting cholesterol catabolism and concurrently downregulating cholesterol biosynthesis and uptake with the primary aim of avoiding over-accumulation of toxic cholesterol in the liver. PKC thus represents a unique hub within the cholesterol homeostatic network. To test this hypothesis, we plan to use newly generated tissue-specific PKC deficient mice to determine the impact of a liver-specific PKC deficiency on diet-induced cholesterol homeostasis. After establishing its role, we plan to define the signaling and transcriptional mechanisms operating during diet-dependent liver PKC induction. Finally, we propose to delineate the mechanism for requirement of PKC in sterol-sensitive Srebp-2 processing. Establishing PKC as a crucial checkpoint will provide novel targets for treating cholesterol diseases by unlocking this evolutionary developed endogenous mechanism to restore cholesterol homeostasis.

抽象的 西方饮食是由于饱和脂肪和 人体胆固醇稳态的胆固醇摄入量。美国平均饮食中含有37％的卡路里 来自脂肪和385 mg/天的胆固醇，主要源自动物来源。取得了重大进展 是在定义响应脂肪酸或胆固醇的转录因子时做出的，但是是否存在 体内一种单独的感应机制检测脂肪和胆固醇是未知的。特别是 饮食信号的性质和时机可以感知，整合和同步胆固醇调节网络 对高脂/胆固醇负荷的反应尚未研究。鉴于最近的饮食脂肪的演示 和饮食胆固醇的作用协同作用，以损害胆固醇的稳态，评估两者的影响 胆固醇稳态失调，而不是单独的成分，在身体上是更大的 相关的。我们建议身体有一个单独的传感器来检测脂肪和胆固醇，并利用 适应高脂/胆固醇负荷的独特策略，以最大程度地减少其对胆固醇的不利影响 稳态。我们实验室的新兴证据表明，对饮食敏感的PKC是关键的联系 在胆固醇稳态的高脂/胆固醇摄入和肝适应性之间。与此一致 功能，高脂/胆固醇饮食在肝脏中急剧诱导的PKC表达，而全身PKC 响应高脂/胆固醇饮食的缺乏升高肝脏和血浆胆固醇含量。我们建议 一种分子机制，肝脏PKC信号传导或不带回肠PKC，在肝脏Erk-上收敛 1/2差异调节胆固醇稳态的关键转录因子。这些观察是 令人兴奋的是，它们不仅代表了特定PKC同工型在胆固醇中的作用的首次演示 代谢，但也可能提供饮食脂质与胆固醇之间缺失的信号传导和调节性联系 稳态。基于上述结果，我们提出了一个新的假设，即PKC是“脂肪/胆固醇 传感器”的激活在肝脏中代表了一种潜在的防御机制，以应对饮食高的饮食 通过促进胆固醇分解代谢和同时下调胆固醇，脂肪/胆固醇侮辱 生物合成和摄取的主要目的是避免过度积累肝脏中有毒胆固醇。 因此，PKC代表胆固醇稳态网络中的独特枢纽。为了检验这一假设，我们 计划使用新生成的组织特异性PKC缺乏小鼠来确定肝脏特异性的影响 饮食诱导的胆固醇稳态缺乏症。确定其角色后，我们计划定义 在饮食依赖性肝PKC诱导过程中运行的信号传导和转录机制。最后，我们 提议描述PKC在固醇敏感的SREBP-2处理中的要求机制。 建立PKC作为关键检查点将提供新的靶标，以治疗胆固醇疾病 解锁这种进化发展的内源性机制可以恢复胆固醇稳态。