Modulation of Hepatic Protein Kinase Cβ Expression in Metabolic Adaptation to a Lithogenic Diet.
Modulation of Hepatic Protein Kinase Cβ Expression in Metabolic Adaptation to a Lithogenic Diet.
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DOI：
10.1016/j.jcmgh.2015.05.008
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发表时间：
2015-07
影响因子：
7.2
通讯作者：
Mehta KD
中科院分区：
文献类型：
--
作者：
Huang W;Mehta KD
饮食因素可能是胆结石发展的重要决定因素，难以适应致石饮食可能使个体易于形成胆结石。识别关键的早期饮食依赖的代谢适应性标志物是迫切需要防止胆结石的发展。我们关注饮食和基因之间的相互作用，以及由此产生的通过饮食改变影响胆结石风险的可能性。测定致石性饮食小鼠肝脏蛋白激酶C（PKC）亚型的表达水平，分析肝脏胆固醇含量与PKCβ表达的关系，以及肝脏PKCβ过表达对细胞内信号通路的影响。致石饲料喂养导致肝脏PKCβ和PKCδ mRNA和蛋白水平的显著诱导，这先于胆汁胆固醇晶体的出现。与PKCβ缺乏不同的是，整体PKCδ缺乏并不影响致石性饮食诱导的胆石形成。有趣的是，载脂蛋白E的缺乏消除了饮食诱导的肝脏PKCβ表达，而肝脏X受体-α的缺乏进一步增强了诱导作用，这表明肝脏PKCβ诱导程度与细胞内胆固醇含量之间存在潜在联系。此外，我们的研究结果表明，PKCβ是回肠基底成纤维细胞生长因子15（FGF 15）表达和肝原癌基因丝氨酸/苏氨酸蛋白激酶Raf-1/丝裂原活化蛋白激酶（MAP激酶激酶）/细胞外信号调节激酶1/2活性的生理性阻遏物（Raf-1/MEK/ERK 1/2）级联蛋白，并且这些途径之间的复杂相互作用可决定肝ERK 1/2活化的程度，胆固醇7α-羟化酶和甾醇12α-羟化酶表达的有效抑制剂。我们发现PKCβ通过调节抑制性Raf-1 Ser 259磷酸化来调节Raf-1活性。我们的研究结果表明，肝脏PKCβ/Raf-1调节轴和回肠PKCβ/FGF 15/ERK轴之间存在一种新的相互作用，这种相互作用可以调节饮食脂质的胆汁成石性。所提供的数据与肠道和肝脏PKCβ信号传导会聚于肝脏ERK 1/2通路以控制肝脏对致石饮食的适应性反应的双管齐下的机制一致。阐明PKCβ作用的影响和潜在机制可以帮助我们了解不同类型的膳食脂肪如何改变胆结石形成的风险，这些信息可以帮助确定对抗这种疾病的治疗方法的新靶点。
Dietary factors are likely an important determinant of gallstone development, and difficulty in adapting to lithogenic diets may predispose individuals to gallstone formation. Identification of the critical early diet-dependent metabolic markers of adaptability is urgently needed to prevent gallstone development. We focus on the interaction between diet and genes, and the resulting potential to influence gallstone risk by dietary modification. Expression levels of hepatic protein kinase C (PKC) isoforms were determined in lithogenic diet-fed mice, and the relationship of hepatic cholesterol content and PKCβ expression and the effect of hepatic PKCβ overexpression on intracellular signaling pathways were analyzed. Lithogenic diet feeding resulted in a striking induction of hepatic PKCβ and PKCδ mRNA and protein levels, which preceded the appearance of biliary cholesterol crystals. Unlike PKCβ deficiency, global PKCδ deficiency did not influence lithogenic diet-induced gallstone formation. Interestingly, a deficiency of apolipoprotein E abrogated the diet-induced hepatic PKCβ expression, whereas a deficiency of liver X receptor-α further potentiated the induction, suggesting a potential link between the degree of hepatic PKCβ induction and the intracellular cholesterol content. Furthermore, our results suggest that PKCβ is a physiologic repressor of ileum basal fibroblast growth factor 15 (FGF15) expression and activity of hepatic proto-oncogene serine/threonine-protein kinase Raf-1/mitogen-activated protein (MAP) kinase kinase/extracellular signal-regulated kinases 1/2 (Raf-1/MEK/ERK1/2) cascade proteins, and the complex interactions between these pathways may determine the degree of hepatic ERK1/2 activation, a potent suppressor of cholesterol 7α-hydroxylase and sterol 12α-hydroxylase expression. We found that PKCβ regulated Raf-1 activity by modulating the inhibitory Raf-1Ser259 phosphorylation. Our results demonstrate a novel interaction between the hepatic PKCβ/Raf-1 regulatory axis and ileum PKCβ/FGF15/ERK axis, which could modulate the bile lithogenecity of dietary lipids. The data presented are consistent with a two-pronged mechanism by which intestine and liver PKCβ signaling converges on the liver ERK1/2 pathway to control the hepatic adaptive response to a lithogenic diet. Elucidating the impact and the underlying mechanism(s) of PKCβ action could help us understand how different types of dietary fat modify the risk of gallstone formation, information that could help to identify novel targets for therapeutic approaches to combat this disease.