TY - JOUR
T1 - Integrative analyses of hepatic differentially expressed genes and blood biomarkers during the peripartal period between dairy cows overfed or restricted-fed energy prepartum
AU - Shahzad, Khuram
AU - Bionaz, Massimo
AU - Trevisi, Erminio
AU - Bertoni, Giuseppe
AU - Rodriguez-Zas, Sandra L.
AU - Loor, Juan J.
N1 - Funding Information:
With the exception of ‘Notch signaling’ and ‘Hedgehog signaling’ all the pathways involved in signaling communication were more induced in OF vs. RE () ( and ). The inhibition of ‘Notch signaling’ in OF vs. RE is likely a consequence of the greater lipid accumulation. It has been clearly demonstrated that steatosis in mice inhibits Notch signaling . It is noteworthy that the pathway was already more inhibited in OF vs. RE at −14 d, well-before the greater TAG concentration was observed ( and ). This indicate that the larger inhibition of the Notch signaling pathway in OF vs. RE prior to the peak of NEFA might have allowed for a greater lipid accumulation postpartum. This idea is supported by the higher induction of ‘MAPK signaling’ in OF vs. RE particularly during early lactation (). This pathway is mainly involved in the control of cellular growth and proliferation but it also is essential for the induction of liver steatosis in mouse by cross-talk with the peroxisome proliferator-activated receptor gamma (PPARγ; ). Although our data seem to support such a role, the expression of PPARγ in bovine liver is nearly non detectable relative to the alpha and delta isotypes .
PY - 2014/6/10
Y1 - 2014/6/10
N2 - Using published dairy cattle liver transcriptomics dataset along with novel blood biomarkers of liver function, metabolism, and inflammation we have attempted an integrative systems biology approach applying the classical functional enrichment analysis using DAVID, a newly-developed Dynamic Impact Approach (DIA), and an upstream gene network analysis using Ingenuity Pathway Analysis (IPA). Transcriptome data was generated from experiments evaluating the impact of prepartal plane of energy intake [overfed (OF) or restricted (RE)] on liver of dairy cows during the peripartal period. Blood biomarkers uncovered that RE vs. OF led to greater prepartal liver distress accompanied by a low-grade inflammation and larger proteolysis (i.e., higher haptoglobin, bilirubin, and creatinine). Post-partum the greater bilirubinaemia and lipid accumulation in OF vs. RE indicated a large degree of liver distress. The re-analysis of microarray data revealed that expression of >4,000 genes was affected by diet x time. The bioinformatics analysis indicated that RE vs. OF cows had a liver with a greater lipid and amino acid catabolic capacity both pre- and post-partum while OF vs. RE cows had a greater activation of pathways/functions related to triglyceride synthesis. Furthermore, RE vs. OF cows had a larger (or higher capacity to cope with) ER stress likely associated with greater protein synthesis/processing, and a higher activation of inflammatory-related functions. Liver in OF vs. RE cows had a larger cell proliferation and cell-to-cell communication likely as a response to the greater lipid accumulation. Analysis of upstream regulators indicated a pivotal role of several lipid-related transcription factors (e.g., PPARs, SREBPs, and NFE2L2) in priming the liver of RE cows to better face the early postpartal metabolic and inflammatory challenges. An all-encompassing dynamic model was proposed based on the findings.
AB - Using published dairy cattle liver transcriptomics dataset along with novel blood biomarkers of liver function, metabolism, and inflammation we have attempted an integrative systems biology approach applying the classical functional enrichment analysis using DAVID, a newly-developed Dynamic Impact Approach (DIA), and an upstream gene network analysis using Ingenuity Pathway Analysis (IPA). Transcriptome data was generated from experiments evaluating the impact of prepartal plane of energy intake [overfed (OF) or restricted (RE)] on liver of dairy cows during the peripartal period. Blood biomarkers uncovered that RE vs. OF led to greater prepartal liver distress accompanied by a low-grade inflammation and larger proteolysis (i.e., higher haptoglobin, bilirubin, and creatinine). Post-partum the greater bilirubinaemia and lipid accumulation in OF vs. RE indicated a large degree of liver distress. The re-analysis of microarray data revealed that expression of >4,000 genes was affected by diet x time. The bioinformatics analysis indicated that RE vs. OF cows had a liver with a greater lipid and amino acid catabolic capacity both pre- and post-partum while OF vs. RE cows had a greater activation of pathways/functions related to triglyceride synthesis. Furthermore, RE vs. OF cows had a larger (or higher capacity to cope with) ER stress likely associated with greater protein synthesis/processing, and a higher activation of inflammatory-related functions. Liver in OF vs. RE cows had a larger cell proliferation and cell-to-cell communication likely as a response to the greater lipid accumulation. Analysis of upstream regulators indicated a pivotal role of several lipid-related transcription factors (e.g., PPARs, SREBPs, and NFE2L2) in priming the liver of RE cows to better face the early postpartal metabolic and inflammatory challenges. An all-encompassing dynamic model was proposed based on the findings.
UR - http://www.scopus.com/inward/record.url?scp=84902664395&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84902664395&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0099757
DO - 10.1371/journal.pone.0099757
M3 - Article
C2 - 24914544
AN - SCOPUS:84902664395
SN - 1932-6203
VL - 9
JO - PloS one
JF - PloS one
IS - 6
M1 - e99757
ER -