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.

摘要 西方饮食是动脉粥样硬化的一个既定的危险因素，因为饱和脂肪和 胆固醇摄入量对人体胆固醇稳态的影响。美国人的平均饮食含有37%的卡路里 从脂肪和385毫克/天的胆固醇，主要来自动物来源。了重大进展 在定义对脂肪酸或胆固醇有反应的转录因子方面， 体内用于检测脂肪和胆固醇的单独的传感机制是未知的。特别是 饮食信号的性质和时间，可以感知，整合和同步胆固醇调节网络， 尚未研究对高脂肪/胆固醇负荷的反应。鉴于最近的证据表明， 和膳食胆固醇协同作用损害胆固醇稳态，评估两者对胆固醇的影响 胆固醇体内平衡失调，而不是单独的一个组成部分， 相关的我们建议，人体有一个单独的传感器来检测脂肪和胆固醇，并利用一个 适应高脂肪/胆固醇负荷的独特策略，以最大限度地减少其对胆固醇的不利影响 体内平衡我们实验室的新证据表明，饮食敏感的PKC β是一个关键环节， 高脂肪/胆固醇摄入与胆固醇稳态的肝脏适应性之间的关系。符合本 功能，高脂肪/胆固醇饮食显着诱导PKC β在肝脏中的表达，而系统性PKC β表达， 缺乏升高肝脏和血浆胆固醇含量响应于高脂肪/胆固醇饮食。我们建议 一种分子机制，通过该机制，肝PKC β信号传导（有或没有回肠PKC β）会聚在肝Erk上， 1/2差异调节胆固醇稳态的关键转录因子。这些观察结果 令人兴奋的是，它们不仅首次证明了一种特定的PKC亚型在胆固醇中的作用， 但也可能提供饮食脂质和胆固醇之间缺失的信号传导和调节联系 体内平衡基于上述结果，我们提出了一个新的假说，即PKC β是一种“脂肪/胆固醇 传感器”，其在肝脏中的激活代表了一种有效的防御机制，以科普饮食中的高- 通过促进胆固醇代谢并同时下调胆固醇来损害脂肪/胆固醇 胆固醇是胆固醇生物合成和摄取的主要途径，其主要目的是避免毒性胆固醇在肝脏中的过度积累。 因此，PKC β代表胆固醇稳态网络中的独特枢纽。为了验证这个假设，我们 计划使用新产生的组织特异性PKC β 2缺陷小鼠来确定肝脏特异性 PKC β缺乏对饮食诱导的胆固醇稳态的影响在确定其作用后，我们计划定义 在饮食依赖性肝脏PKC β诱导过程中的信号传导和转录机制。最后我们 拟阐明在固醇敏感的Srebp-2加工中需要PKC β的机制。 将PKC β作为一个关键的检查点，将为治疗胆固醇疾病提供新的靶点， 解锁这种进化发展的内源性机制以恢复胆固醇稳态。