Effects of nutrition, disease, and body condition score during the transition period on dairy cattle liver gene expression
Transcriptomics and the introduction of bioinformatics approaches over the last couple of decades have had a large impact on the current revolutions in dairy welfare and the economics and structure of dairy industries. The etiology of disease e.g. endomeritits, metabolic dis-comforts and optimal calving BCS are major challenges for future advances in dairy cow management. The current research conducted five different studies to investigate the effects of nutrition, infection, disease and different calving BCS on cows’ hepatic transcriptomes and metabolic profiles using mRNA gene expression profiles, biochemical parameters, and the latest bioinformatics tools. The first study investigated the expression and regulatory mechanism of FGF21 under early postpartal ketosis, L-carnitine infusion, a prepartal high energy diet and inflammatory mediators. Ketosis increased the expression and serum level of FGF2; however, a high plasma concentration of carnitine decreased hepatic expression of FGF21. Prepartal high energy diet increased FGF21 expression and intra mammary LPS challenge further increased hepatic expression of FGF21. The decrease in hepatic KLB expression may suggest adipose as a target tissue for FGF21 in these cows. The findings from this study revealed that, like rodents and other mammals, bovine hepatic FGF21 is also regulated by changes in nutrition, metabolism, and inflammatory conditions through different mechanisms. This study will help to clarify the role of FGF21 as a nutrition adaptation factor in dairy cows (For details see chapter 2). The liver has a precise role in lipid metabolism; any change in dietary lipid supplementation can affect hepatic cell function through modulating the expression of an array of genes from different networks. The second project uncovered the change in phospholipids (PL) and triacylglycerol (TAG) LCFA profiles and expression of genes associated PPARα signaling, metabolism, growth, energy and immune responses in transitional cows supplemented with saturated fatty acids or polyunsaturated fatty acids (PUFA). Preliminary findings revealed that both diets affected the LCFA profile of hepatic LP and TAG. However, saturated fatty acids were more effective than PUFA in eliciting hepatic transcriptional changes; PUFA showed a greater decrease in fatty acid oxidation, gluconeogenesis, intraocular energy and inflammation (For details see chapter 3). In the third set of experiments, bovine specific microarray and related bioinformatics tools were used to study the transcriptomic changes of peripheral tissues in response to sub clinical endometritis (SCE). Milk production, blood metabolites, and disease biomarkers did not differ greatly between healthy and SCE cows. However, transcriptomic analysis of hepatic and subcutaneous adipocytes from cows with SCE revealed a marked effect on the complement and coagulation cascade, steroid hormone biosynthesis, apoptosis, inflammation and oxidative stress. Other effects included the hepatic inhibition of vitamin B3 and B6 metabolism in cows with SCE. The findings from this study uncovered that SCE in dairy cattle during early lactation induces molecular alterations in liver and adipose tissues, indicative of immune activation and cellular stress. (For details see chapter 4). Calving body condition score (BCS) management is a key contributing factor to cow welfare subsequent to calving. The fourth and fifth sets of experiments aimed to investigate the metabolic and molecular changes induced by change in BCS using blood biomarkers, hepatic TAG concentrations, and hepatic gene expression profiling. For this purpose, a group of cows with mixed ages and breeds managed from the second half of the previous lactation to achieve mean group BCS that were high (H, 5.5 BCS), medium (M, 4.5 BCS), or low (L, 3.5 BCS) BCS (10-point scale). In the fourth study, blood and hepatic biomarkers as well as gene expression data revealed that both high and medium BCS at calving benefit milk production. However, high BCS cows may be more prone to accumulating fat in the liver. All cows underwent an inflammatory response around calving, but cows with medium BCS seemed to recover faster. The biomarker data suggested that a low BCS induced some degree of liver dysfunction. Different measures of production, inflammatory state, and metabolism indicate that cows calving at BCS 3.5 or 5.5 (1-10 scale) are suboptimal in comparison to a calving BCS of 4.5. (For details see chapter 5). The fifth study used hepatic transcriptome and bioinformatics tools to uncover the most impacted functional categories and top transcriptional regulators in response to changes in calving BCS. The study revealed carbohydrates, lipid terpenoids and polyketides, and vitamin metabolism as the most impacted categories affected by changes in BCS. An increase in BCS induced pathways supports milk production but also predisposes cows to health problems associated with fatty liver, biosynthesis of inflammatory precursors and oxidative stress. In cows with a low BCS, the liver adapts a glucose sparing effect for lactogenesis, but regulates the pathways associated with the biosynthesis of unsaturated fatty acids, antioxidant systems, and immune responses. Overall, the results indicate that subtle changes in cow adiposity at calving can have significant effects on health and production and provide support for an optimum calving BCS of 4.5-5.0 (i.e. 2.75-3.0 in a 5-point scale). Furthermore, the study uncovered TP53 to be a central hub regulating a large spectrum of genes altered by BCS. The interaction effect of BCS and time relative to parturition (BCS  wk) revealed HNF4A had the greatest number of targets (For details see chapter 6). Findings from these experiments are based around biochemical and gene expression profiling techniques that will have a positive impact on future strategic developments for bovine welfare and the dairy industry.
dairy cows, diet, uterine infection, body condition score (BCS), liver transcriptomes
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