Molecular insights into the mechanisms of liver‐associated diseases in early‐lactating dairy cows: hypothetical role of endoplasmic reticulum stress

The transition period represents the most critical period in the productive life of high‐yielding dairy cows due to both metabolic and inflammatory stimuli, which challenge the liver and predispose dairy cows to develop liver‐associated diseases such as fatty liver and ketosis. Despite the fact that all high‐yielding dairy cows are affected by marked metabolic stress due to a severe negative energy balance (NEB) during early lactation, not all cows develop liver‐associated diseases. Although the reason for this is largely unknown, this indicates that the capacity of the liver to cope with metabolic and inflammatory challenges varies between individual high‐yielding dairy cows. Convincing evidence exists that endoplasmic reticulum (ER) stress plays a key role in the development of fatty liver, and it has been recently shown that ER stress occurs in the liver of high‐yielding dairy cows. This indicates that ER stress may be involved in the development of liver‐associated diseases in dairy cows. The present review shows that the liver of dairy cows during early lactation is exposed to several metabolic and inflammatory challenges, such as non‐esterified fatty acids, tumour necrosis factor α, interleukin‐1β, reactive oxygen species and lipopolysaccharides, which are known inducers of ER stress. Thus, ER stress may represent a molecular basis for fatty liver development and account for the frequent occurrence of fatty liver and ketosis in high‐yielding dairy cows. Interindividual differences between dairy cows in the activation of hepatic stress response pathways, such as nuclear factor E2‐related factor 2, which is activated during ER stress and reduces the sensitivity of tissues to oxidative and inflammatory damage, might provide an explanation at the molecular level for differences in the capacity to cope with pathological inflammatory challenges during early lactation and the susceptibility to develop liver‐associated diseases between early‐lactating dairy cows with similar NEB and milk yield.     

反刍动物围产期能量负平衡的调控研究进展

在奶牛围产期,许多奶牛因能量负平衡(NEB)无法适应代谢、内分泌和生理的巨大变化,引发酮病和脂肪肝,影响奶牛产后恢复,造成严重的经济损失.奶牛分娩、产犊的应激性大,产奶量增长迅速,采食量降低,饲养中能量供应不足是此阶段存在的主要问题.为获得更高品质的肉制品以及更高的养殖收益,文章针对调控围产期NEB展开综述,以期为生产...     

Relationship between overfeeding and overconditioning in the dry period and the problems of high producing dairy cows during the postparturient period

Summary

In dairy cows, overfeeding during the dry period leads to overcondition at calving and to depression of appetite after calving. As a consequence, at calving overconditioned high‐producing dairy cows inevitably go into a more severe negative energy balance (NEB) postpartum than cows that have a normal appetite. During the period of NEB, the energy requirements of the cow are satisfied by lipolysis and proteolysis. Lipolysis results in an increased concentration of non esterified fatty acids (NEFA) in the blood. In the liver, these NEFA are predominantly esterified to triacylglycerols (TAG) that are secreted in very low density lipoproteins (VLDL). In early lactation in cows with a severe NEB, the capacity of the liver to maintain the export of the TAG in the form of VLDL in balance with the hepatic TAG production is not always adequate. As a result, the excess amount of TAG accumulates in the liver, leading to fatty infiltration of the liver (hepatic lipidosis or fatty liver). The NEB and/or fatty liver postpartum are frequently associated with postparturient problems. In general, a severe NEB induces changes in biochemical, endocrinological, and metabolic pathways that are responsible for production, maintenance of health, and reproduction of the postparturient dairy cow. These changes include a decrease in blood glucose and insulin concentrations, and an increase in blood NEFA concentrations. High NEFA concentrations caused by intensive lipolysis are accompanied by impairment of the immune system, making the cows more vulnerable to infections. Metabolic diseases such as ketosis, milk fever, and displaced abomasum are related to overcondition at calving. The changes in biochemical, endocrinological, and metabolic pathways are associated with delay of the first visible signs of oestrus, an increase in the interval from calving to first ovulation, a decrease in conception rate, and a prolonged calving interval. It is possible that the increased blood NEFA concentration directly impairs ovarian function.     

泌乳奶牛脂肪肝早期诊断的研究

为了寻找泌乳奶牛脂肪肝早期诊断方法,本研究从某千头奶牛场随机选取了30头乳酮阳性的奶牛,其中临床酮病牛10头,亚临床酮病牛20头,测定其肝脂含量以及血中代谢指标和肝功指标。试验结果表明,脂肪肝的奶牛存在能量负平衡现象,机体呈现高游离脂肪酸血症、高酮血症,肝脂浸润越重,能量代谢障碍越严重;乳酮阳性出现时间的早晚与脂肪肝的严重程度密切相关,乳酮阳性产后出现的越早,乳酮阳性越明显,肝脂浸润越重;随肝脂浸润程度的加重,肝功多个指标会出现异常,重度的脂肪肝会引发肝功能不全。本试验证明,酮粉法可以作为早期诊断奶牛脂肪肝的初选方法,肝功指标异常可作为诊断脂肪肝的辅助方法,两者结合可作为奶牛脂肪肝的实用、有效和准确的早期诊断方法,准确率可达80%。     

Relationship between overfeeding and overconditioning in the dry period and the problems of high producing dairy cows during the postparturient period.

In dairy cows, overfeeding during the dry period leads to overcondition at calving and to depression of appetite after calving. As a consequence, at calving overconditioned high-producing dairy cows inevitably go into a more severe negative energy balance (NEB) postpartum than cows that have a normal appetite. During the period of NEB, the energy requirements of the cow are satisfied by lipolysis and proteolysis. Lipolysis results in an increased concentration of non esterified fatty acids (NEFA) in the blood. In the liver, these NEFA are predominantly esterified to triacylglycerols (TAG) that are secreted in very low density lipoproteins (VLDL). In early lactation in cows with a severe NEB, the capacity of the liver to maintain the export of the TAG in the form of VLDL in balance with the hepatic TAG production is not always adequate. As a result, the excess amount of TAG accumulates in the liver, leading to fatty infiltration of the liver (hepatic lipidosis or fatty liver). The NEB and/or fatty liver postpartum are frequently associated with postparturient problems. In general, a severe NEB induces changes in biochemical, endocrinological, and metabolic pathways that are responsible for production, maintenance of health, and reproduction of the postparturient dairy cow. These changes include a decrease in blood glucose and insulin concentrations, and an increase in blood NEFA concentrations. High NEFA concentrations caused by intensive lipolysis are accompanied by impairment of the immune system, making the cows more vulnerable to infections. Metabolic diseases such as ketosis, milk fever, and displaced abomasum are related to overcondition at calving. The changes in biochemical, endocrinological, and metabolic pathways are associated with delay of the first visible signs of oestrus, an increase in the interval from calving to first ovulation, a decrease in conception rate, and a prolonged calving interval. It is possible that the increased blood NEFA concentration directly impairs ovarian function.     

围产期奶牛NEFA的营养调控研究进展

非酯化脂肪酸（NEFA）升高是围产期奶牛能量负平衡的标志，也是导致奶牛发生脂肪肝和酮病的直接原因。在过去的30余年里人们对围产期奶牛NEFA营养调控的方法和机制进行了大量研究，文章就该方面的研究进展作一综述。     

过瘤胃胆碱在围产期奶牛的应用研究进展

奶牛养殖过程中,围产期被认为是最重要的时期之一,在该时期奶牛从干奶状态转为泌乳状态,生理上所受的应激造成奶牛泌乳早期采食量降低,易发生能量负平衡.此外,奶牛生产性能和繁殖性能也会降低,并常常伴有一些围产期疾病的发生,如脂肪肝、酮症、乳房炎等.胆碱能影响奶牛的生产与繁殖性能,参与奶牛的脂肪代谢,可降低脂肪肝发生率,提高免疫性能.对围产期奶牛饲喂过瘤胃保护胆碱(rumen protected choline,RPC),可改善奶牛机体代谢,增加小肠胆碱供应,进而提高奶产量、改善乳成分、缓解脂肪肝、减少围产期疾病的发生.本文综述了RPC对围产期奶牛干物质采食量、生产性能、乳成分以及健康状况的影响,旨在为围产期奶牛的养殖提供理论参考依据.     

Relevance of apolipoproteins in the development of fatty liver and fatty liver-related peripartum diseases in dairy cows

Most metabolic diseases in dairy cows occur during the peripartum period and are suggested to be derived from fatty liver initially developed during the nonlactating stage. Fatty liver is induced by hepatic uptake of nonesterified fatty acids that are released in excess by adipose tissues attributable to negative energy balance. The fatty accumulation leads to impairment of lipoprotein metabolism in the liver, and the impairment in turn influences other metabolic pathways in extrahepatic tissues such as the steroid hormone production by the corpus luteum. Detailed understanding of the impaired lipoprotein metabolism is crucial for elucidation of the mechanistic bases of the development of fatty liver and fatty liver-related peripartum diseases. This review summarizes results on evaluation of lipoprotein lipid and protein concentrations and enzyme activity in cows with fatty liver and those with ketosis, left displacement of the abomasum, milk fever, downer syndrome and retained placenta. Obtained data strongly suggest that decreases in serum concentrations of apolipoprotein B-100, apolipoprotein A-I and apolipoprotein C-III, a reduction in activity of lecithin:cholesterol acyltransferase and induction of haptoglobin and serum amyloid A are intimately related to the development of fatty liver and fatty liver-related diseases. Moreover, determination of the apolipoprotein concentrations and enzyme activity during the peripartum period is useful for early diagnoses of these diseases.     

腺苷酸活化蛋白激酶在奶牛疾病中的作用研究进展

随着奶牛养殖规模化、集约化程度的不断提高，奶牛养殖过程中乳腺炎、酮病和脂肪肝等疾病的发病率也逐年增加。腺苷酸活化蛋白激酶（AMP-activated protein kinase，AMPK）作为一种能量感受器可以反映细胞能量状态。AMPK在葡萄糖、脂质和蛋白质代谢以及线粒体生物发生和自噬等过程中发挥重要调控作用。AMPK被认为是多种疾病潜在的干预或治疗靶点，在奶牛代谢性疾病中的研究也较为广泛。综述了AMPK在奶牛乳腺炎、酮病、脂肪肝中的调控作用研究进展，以期为这些疾病的靶向治疗提供参考。     

The Role of Exogenous Insulin in the Complex of Hepatic Lipidosis and Ketosis Associated with Insulin Resistance Phenomenon in Postpartum Dairy Cattle

As a result of a marked decline in dry matter intake (DMI) prior to parturition and a slow rate of increase in DMI relative to milk production after parturition, dairy cattle experience a negative energy balance. Changes in nutritional and metabolic status during the periparturient period predispose dairy cattle to develop hepatic lipidosis and ketosis. The metabolic profile during early lactation includes low concentrations of serum insulin, plasma glucose, and liver glycogen and high concentrations of serum glucagon, adrenaline, growth hormone, plasma β-hydroxybutyrate and non-esterified fatty acids, and liver triglyceride. Moreover, during late gestation and early lactation, flow of nutrients to fetus and mammary tissues are accorded a high degree of metabolic priority. This priority coincides with lowered responsiveness and sensitivity of extrahepatic tissues to insulin, which presumably plays a key role in development of hepatic lipidosis and ketosis. Hepatic lipidosis and ketosis compromise production, immune function, and fertility. Cows with hepatic lipidosis and ketosis have low tissue responsiveness to insulin owing to ketoacidosis. Insulin has numerous roles in metabolism of carbohydrates, lipids and proteins. Insulin is an anabolic hormone and acts to preserve nutrients as well as being a potent feed intake regulator. In addition to the major replacement therapy to alleviate severity of negative energy balance, administration of insulin with concomitant delivery of dextrose increases efficiency of treatment for hepatic lipidosis and ketosis. However, data on use of insulin to prevent these lipid-related metabolic disorders are limited and it should be investigated.     

Metabolic changes in cows with or without retained fetal membranes in transition period

The purpose of the study was to evaluate the effect of retained fetal membranes (RFM) on serum minerals and energy- and protein-related metabolites in dairy cows at a herd with a recent history of fatty liver syndrome. Forty-seven multiparous Holstein cows were selected during transition period. Nine cows had RFM longer than 24 h after calving. Blood samples were obtained on prepartum days 21 and 7 and postpartum days 7 and 21. We used repeated measure procedure of anova to evaluate the effect of RFM on serum metabolites. Cows with RFM had significantly higher concentrations of beta-hydroxybutyrate, non-esterified fatty acids and triglycerides after calving, but had lower concentrations of cholesterol during transition period. The concentrations of serum albumin and blood urea nitrogen were also significantly lower in RFM-affected cows than non-affected ones after parturition. Our results suggested that negative energy balance (NEB) postpartum was associated with RFM in dairy cattle. However, our findings did not reveal a cause and effect relationship with respect to the role of NEB as a possible risk factor for RFM.     

Glucagon as a potential therapy for ketosis and fatty liver.

An experiment demonstrating the usefulness of glucagon as a treatment for fatty liver and ketosis in early-lactation dairy cows has been described. This is the first report of the ability of glucagon, or any agent, to promote clearance of lipid from livers of animals suffering hepatic lipidosis. The development and use of glucagon as a therapeutic agent for the fatty-liver complex in dairy cows may provide a powerful management tool to enhance the profitability of the high-producing dairy cow.     

奶牛脂肪肝的发病机理及防制措施

高产奶牛在分娩期易患脂肪肝。脂肪肝的发病机理尚不完全清楚 ,采食量下降并导致体脂动员是脂肪肝发生的直接原因 ,更深入的机制涉及奶牛肝脂代谢的特殊性。防制脂肪肝的思路包括降低体脂的动员、减少肝脂合成量和提高肝脂的输出量。本文对脂肪肝的发病特点、可能机制和预防措施作了讨论     

Nutritional factors that regulate ovulation of the dominant follicle during the first follicular wave postpartum in high-producing dairy cows

During recent decades, milk production per cow has increased drastically due to improved management, nutrition, and genetic selection; however, the reproductive performance of high-producing dairy cows has been declining. One of the factors responsible for this low reproductive performance is negative energy balance (NEB). NEB affects the onset of first ovulation in early postpartum cows. It is generally accepted that early first ovulation positively relates to the resumption of normal ovarian function, first service, and conception rate in dairy cows. Hence, delayed first ovulation has a negative impact on subsequent fertility. The metabolic condition of cows in NEB shifts to catabolic metabolism, which in turn causes increased plasma growth hormone and non-esterified fatty acid concentrations and decreased plasma insulin-like growth factor-1, insulin, and glucose concentrations. On the other hand, plasma β-carotene concentrations decrease throughout the dry period and reach their nadir in about the first week postpartum, and this change reflects energy balance during the peripartum period. β-Carotene plays a role independently of vitamin A in the reproductive performance of dairy cows, and the positive relationship between supplemental β-carotene and reproductive function has been demonstrated in many studies during the past decades. However, β-carotene content in corn silage, which is a popular main feed in high-producing dairy cows, is very low. This review describes nutritional factors related to ovulation during the first follicular wave postpartum in dairy cows.     

Fatty acid profiles in relation to triglyceride level in the liver of dairy cows

To elucidate possible relationships between triglyceride (TG) levels and fatty acid composition in bovine liver, hepatic TG and seven individual fatty acids were measured in 23 Holstein dairy cows, of them 6 are healthy. Liver TG level was greater than 3 % in 12 cows which were ruled fatty liver. Palmitic and oleic acid proportions were significantly higher in fatty liver cows than in the healthy cows, while stearic acid was lower in fatty liver cows. With increased liver TG, stearic acid proportions decreased dramatically. Results indicate that hepatic lipidosis markedly alters the proportions of the various fatty acids in the liver of dairy cows.     

脂多糖致奶牛糖脂代谢异常研究进展

脂多糖（LPS）是革兰阴性菌细胞壁的主要成分,广泛存在于环境中,可诱导机体炎症反应,与奶牛的多种疾病相关。环境和疾病等因素引起机体LPS水平升高,LPS与巨噬细胞、中性粒细胞和上皮细胞等作用,激活NF-κB和MAPKs信号通路,释放炎症因子,改变机体糖脂代谢相关激素和脂肪因子水平,进而影响糖脂代谢,造成奶牛2型糖尿病、酮病、脂肪肝和肥胖等代谢性疾病。本文综述了LPS与炎症反应和糖脂代谢相互作用关系及其导致糖脂代谢异常作用机制,为LPS致奶牛糖脂代谢异常机理研究提供参考。     

Nutritional and management strategies for the prevention of fatty liver in dairy cattle

Fatty liver occurs in dairy cattle during periods of elevated blood non-esterified fatty acids (NEFAs). Elevated blood NEFAs are associated with hormonal changes at parturition and negative energy balance. Approaches for preventing fatty liver include inhibition of fatty acid mobilization from adipose tissues and altering hepatic metabolism to enhance fatty acid oxidation or export as a constituent of very low-density lipoproteins (VLDL). Nutritional and management strategies to implement these approaches have been examined. Increasing energy density of diet, either by increasing non-fiber carbohydrate or fat, has failed to prevent fatty liver. Two nutritional supplements, ruminally-protected choline and propylene glycol, have proven effective at preventing fatty liver. Choline probably enhances hepatic VLDL secretion. Propylene glycol most likely reduces fatty acid mobilization from adipose tissue. Shortening or eliminating the dry period is a management strategy that reduces the magnitude of negative energy balance after calving and triglyceride accumulation in the liver.     

Therapy of diseases of ruminant intermediary metabolism.

Diseases of intermediary metabolism include ketosis and fatty liver of dairy cattle and pregnancy toxemia of ewes. These conditions occur when there is a failure of the homeostatic mechanisms regulating the mobilization of fats and the conservation of carbohydrates. The therapeutic approach is to reestablish the normal homeostatic patterns of fuel utilization. Suppression of excessive ketogenesis is the most important factor in reestablishing homeostasis. Ketogenesis can be suppressed by a number of therapeutic agents that act either by suppressing the mobilization of fatty acids or by inhibiting the transport of fatty acids into the hepatic mitochondria, the site at which fatty acids are converted to ketone bodies. Useful therapies include bolus glucose infusions, glucose precursors, and glucocorticoids.     

Blood parameters in Swedish dairy herds with high or low incidence of displaced abomasum or ketosis

Sixty dairy herds were studied to investigate the association between long-term incidence of displaced abomasum and clinical ketosis and body condition score and blood profiles, including parameters estimating energy metabolism and hepatic lipidosis in the periparturient period and early lactation. Blood samples were taken around parturition and in early lactation from cows without apparent clinical symptoms of metabolic disorders. A difference in metabolism between high and low incidence herds was shown post-partum by a lower metabolic index (the revised Quantitative Insulin Sensitivity Check Index, RQUICKI), and tendencies for higher concentrations of glucose, insulin and non-esterified fatty acids in the high incidence herds. High incidence herds had more cows and produced on average 1400kg energy-corrected milk per cow per year more than the low incidence herds. No differences were found in parameters reflecting liver cell damage. In the first 3weeks post-partum the RQUICKI was a more sensitive marker of herds with a high incidence of displaced abomasum and clinical ketosis than any of the individual parameters, but further research is needed before practical applications of the RQUICKI can be foreseen.     

过瘤胃氯化胆碱在奶牛上的应用研究进展

高产奶牛在产后泌乳初期体内常出现能量供应负平衡状态,继而引发如脂肪肝、酮病等一系列营养代谢性疾病。在产后奶牛日粮中外源适量添加过瘤胃氯化胆碱(rumen-protected choline, PRC)能改善血液生化指标,提高奶牛生产性能。作者综合了过瘤胃氯化胆碱的有关文章和试验,简要综述了其在奶牛上应用的研究进展。