Colchicine acutely reduces liver-secreted inflammatory and metabolic proteins in blood.

OBJECTIVE: Colchicine has recently been approved for use in atherosclerotic cardiovascular disease (ASCVD); however, the mechanism(s) are unclear. The current study adopted a systems-wide approach to identify acute changes induced by colchicine in serum and plasma in mice fed chow or high-cholesterol diet respectively.

APPROACH AND RESULTS: We harnessed quantitative Data Independent Acquisition (DIA) mass spectrometry to identify suppression of a triad of liver-dependent pathways: complement, cholesterol metabolism and coagulation by colchicine in mice fed chow diet. Colchicine reduced specific liver-secreted serum proteins involved in the classical, lectin and alternative complement pathways. Colchicine also reduced the serum content of apolipoproteins A1, B100, C1, C3, C4, E, M and beta-2-glycoprotein 1, which translated into selective reduction of serum LDL/VLDL content. There were also effects of colchicine on immunoglobulins. Reductions in angiotensinogen, angiotensin I and angiopoietin-like protein 3, might contribute to drug effects on vascular tone and lipid homeostasis respectively. Subsequent analysis of plasma from mice fed high-cholesterol diet identified fewer changes in inflammation related components, yet the effect on apolipoproteins was similar. Colchicine also affected coagulation factors in liver and plasma of mice a fed high-cholesterol diet; however, there were no large changes in coagulation assays. Cross-validation by quantitative PCR indicated that serum and plasma changes of the liver-dependent triad are mediated by direct hepatic actions of the drug, partially through ERK1/2 and JNK.

CONCLUSION: In summary, we have identified that acute colchicine in vivo modulates the serum and plasma proteome of liver-derived components, leading to systemic metabolic and immune changes.