Investigations on the reasons of stress of the endoplasmic reticulum (ER stress) in the liver of dairy cows in early lactation and the role of ER stress in the development of fatty liver syndrome and ketosis

对于高产奶牛来说，围产卵期是一种应激状态，与高代谢需求和各种代谢疾病的风险增加有关。在代谢性疾病中，脂肪肝综合征和酮症最为相关。这些疾病也具有特别的相关性，因为它们与其他几种疾病的发展和生育能力的损害有关。因此，预防脂肪肝和酮症具有高度的优先性。由于这些疾病的发病机制仅部分得到澄清，因此需要更好地了解脂肪肝和酮症发展的生化原因。基于我们自己的初步研究，本申请项目旨在研究一种假设，即内质网应激（ER应激）在脂肪肝和酮症的发展中起核心作用（假设I），这是我们最近在泌乳早期高产奶牛肝脏中发现的一种现象。由于肝脏内质网应激发展的原因尚未被揭示，该项目进一步旨在研究内质网应激是由以下假设引起的：(I)血浆中高水平的非酯化脂肪酸（NEFA）， （II）肝脏炎症过程的发生，（III）氧化应激，（IV）血浆中高浓度的脂多糖（LPS）（假设II）。为了验证这些假设，可以使用50头荷斯坦奶牛在产前2周、产后1周、产后4周和产后7周采集的肝脏活检样本和血浆样本。为了验证假设1，将测定肝脏样品中内质网应激的各种标志物与肝脏样品中甘油三酯浓度或ß-羟基丁酸盐浓度之间的相关性。为了验证假设二，将计算(I)血浆NEFA浓度、（II）肝脏炎症标志物、（III）血浆氧化应激参数、（IV）血浆LPS浓度与肝脏内质网应激标志物之间的相关性。我们希望通过这些研究，能够更好地理解泌乳早期奶牛肝脏内质网应激的原因，以及内质网应激在脂肪肝和酮症发展中的作用。证明内质网应激在脂肪肝和酮症发展中的核心作用将为奶牛预防这些疾病提供新的视角。

For high yielding dairy cows, the periparturient phase represents a stressful condition which is associated with a high metabolic demand and an increased risk of various metabolic diseases. Among metabolic diseases, fatty liver syndrome and ketosis are most relevant. These diseases are also of particular relevance as they are associated with the development of several other diseases and an impairment of fertility. Therefore, the prevention of fatty liver and ketosis has high priority. Because pathogenesis of these diseases has been clarified only in part, a better understanding of biochemical reasons underlying the development of fatty liver and ketosis is required. Based on our own preliminary studies, the applied project aims to investigate the hypothesis that stress of the endoplasmic reticulum (ER stress), a phenomenon we could recently demonstrate to occur in the liver of high-yielding cows in early lactation, plays a central role in the development of fatty liver and ketosis (hypothesis I). As the reasons underlying the development of ER stress in the liver have not yet been unraveled, the project further aims to investigate the hypothesis that ER stress is caused by (I) high levels of non-esterified fatty acids (NEFA) in Plasma, (II) the occurrence of an inflammation process in the liver, (III) oxidative stress, (IV) high concentrations of lipopolysaccharides (LPS) in plasma (hypothesis II). For investigating these hypotheses, liver biopsy samples and plasma samples which were collected from 50 Holstein cows at 2 weeks ante partum, 1 week post partum, 4 weeks post partum and 7 weeks post partum can be used. In order to investigate hypothesis I, correlations between various markers of ER stress in liver samples and concentrations of triglycerides in liver samples or concentrations of ß-hydroxy butyrate will be determined. In order to investigate hypothesis II, correlations between (I) plasma NEFA concentrations, (II) inflammatory markers in the liver, (III) parameters of oxidative stress in plasma (IV) plasma concentrations of LPS and markers of ER stress in the liver will be calculated. We expect from these investigations that they will provide a better understanding of the reasons underlying ER stress in the liver of dairy cows in early lactation and the role of ER stress in the development of fatty liver and ketosis. Proving a central role of ER stress in the development of fatty liver and ketosis would offer new perspectives in the prevention of these diseases in dairy cows.