Liver transcriptome analysis reveals important factors involved in the metabolic adaptation of the transition cow

Abstract

During early lactation, dairy cows experience a severe metabolic load often resulting in the development of various diseases. The inevitable deficiency in nutrients and energy at the onset of lactation requires an optimal adaptation of the hepatic metabolism to overcome metabolic stress. We conducted a whole-liver transcriptome analysis for the transition cow to identify novel factors crucial for metabolic adaptation. Liver samples were obtained from 6 Red Holstein dairy cows (parity 2 to 7, mean ± standard deviation: 3.7 ± 2.3) at 3 time points: T1 = 22 ± 4 d antepartum, T2 = 10 ± 2 d postpartum, and T3 = 17 ± 2 d postpartum. Using RNA sequencing (RNA-seq), we studied the transcriptomic profile of the transition cow before and after parturition. We performed a differential gene expression analysis (DGEA) and gene-set enrichment analysis (GSEA) for biological processes (gene ontology, GO) and pathways (Kyoto Encyclopedia of Genes and Genomes, KEGG). Among the 10,186 expressed genes, we discovered 1,063 differentially expressed genes (false discovery rate = 5%). The GSEA revealed 16 biological processes and 7 pathways significantly (false discovery rate = 5%) associated with the hepatic changes of the transition cow. Our results confirm that major hepatic changes are related to energy mobilization after parturition; in particular, they are related to fatty acid oxidation/metabolism, cholesterol metabolism, and gluconeogenesis. Using the STRING database (https://string-db.org/), we investigated interactions between significant genes and identified 9 key genes (CYP7A1, APOA1, CREM, LOC522146, CYP2C87, HMGCR, FDFT1, SGLE, and CYP26A1) through which the different processes involved in the metabolic adaptation interact. Comparing our main results with the literature, we could identify further genes that have not yet been associated with the transition period (e.g., CPT1B, ADIPOR2, LEPR, CREB3L3, and CCND1) and that are mainly involved in processes controlled by AMP-activated protein kinase, an important regulator of energy homeostasis.

Invited review: Metabolic challenges and adaptation during different functional stages of the mammary gland in dairy cows: Perspectives for sustainable milk production

“…The concomitant low cholesterol concentrations in early lactation likely limit the hepatic triglyceride export despite an upregulation of hepatic cholesterol biosynthesis . Ha et al (2017a) recently showed with a liver transcriptome analysis that pathways associated with cholesterol are essentially involved in adaptation processes of metabolism during the transition period. Forcing NEB with adipose tissue mobilization at a later lactational stage, however, did not result in a considerable lipid accumulation in the liver as cholesterol concentrations were elevated, supporting hepatic triglyceride export (Gross et al, , 2015a.…”

“…Ha et al (2015Ha et al ( , 2017b showed that phenotypic expressions of the metabolites glucose, nonesterified fatty acids (NEFA), and BHB are associated with a differential expression of genes involved in robustness and resilience traits. The latest technologies such as nextgeneration sequencing and metabolomics allow a more comprehensive view on relevant pathways and potential candidate markers for selection (Loor, 2010;Huber et al, 2016;Ha et al, 2017a). Testing individual cows on farm might be desirable for prediction of metabolic adaptation.…”

Transition Period of the Dairy Cow Revisited: I. Homeorhesis and Its Changes by Selection and Management

“…In agreement with these data is the raised mRNA for FGF21 in dairy cows p.p. (Schlegel et al, 2013;Ha et al, 2017) and of FGF21 concentrations in plasma p.p. and during feed restriction in late-lactating cows (Schoenberg et al, 2011).…”

Metabolomics Integrated with Transcriptomics Reveals a Subtle Liver Metabolic Risk in Dairy Cows Fed Different Crop By‐products

“…Moreover, the significantly different metabolites were highly correlated with genes within this pathway. Linoleic acid is a doubly unsaturated omega‐6 fatty acid and an essential fatty acid for dairy cows, and it is very important in maintaining bone health, regulating metabolism, and maintaining the reproductive system . There are three main pathway directions of linoleic acid: 1) acetyl‐CoA as the intermedium to produce ketone bodies (ketogenesis, only occurred in the liver), to produce fatty acids (lipogenesis, like cholesterol), or to generate ATP (beta‐oxidation); 2) to convert to arachidonic acid; and 3) to generate THF‐dios through downstream reactions .…”