Control of fibrinogen biosynthesis: role of the FFA/albumin ratio

Abstract

The rate of biosynthesis and turnover of the plasma protein fibrinogen is a marker of metabolic signaling in aging and disease. The rate in the young normal human subject of 0.260 mg/ml/24 h increases to 0.378 in older normal subjects and to 0.466 in age matched coronary thrombosis patients measured by endogenous labeling of fibrinogen with L: -glutamic acid-C14. The increased rate of fibrinogen turnover has been traced to generation of fibrin by labeling the polymers with glycine C14 ethyl esters in the presence of activated fibrin stabilizing factor. Circulating fibrin increased 520% above normal in ischemic thrombotic cerebrovascular disease. Long chain saturated free fatty acids (FFA) exercise not only primary control over incorporation of Cl4 labeled amino acids into the fibrinogen structure but also activate the cascade sequence of reactions which convert fibrinogen into occlusive fibrin polymers. FFA are normally bound and transported by plasma albumin to mitochondrial sites of energy metabolism. Albumin synthesis declines with aging. This decline is associated with increased plasma levels of FFA resulting in an increase in the plasma FFA/albumin ratio. Correction of this ratio in vitro by restoration of a normal FFA/albumin ratio restores a normal level of fibrinogen synthesis by human hepatocytes.

Fig. 1

FFA/albumin ratio as a function of thrombosis and aging

Fig. 2

Plasma albumin levels as a function of thrombosis and aging

Fig. 3

Plasma FFA as a function of thrombosis and aging

Fig. 4

Regeneration of normal fibrinogen synthesis in human hepatocytes by reduction of the FFA/albumin molar ratio in plasma of patients with thrombosis. SA: specific activity fibrin (counts/min/mg)