Albumin gene expression is down-regulated by albumin or macromolecule infusion in the rat.

Abstract

IntroductionA novel feedback regulatory mechanism operating on transcription of the albumin gene is described in the rat. In 1946, it was proposed that circulating colloids, including serum albumin, may affect the synthesis and/or secretion ofalbumin in the liver. The molecular basis for this proposed regulation has now been investigated by adding oncotically active macromolecules to the circulation of normal or genetically albumin-deficient Nagase analbuminemic rats (NAR) and analyzing the hepatic expression of genes, including albumin after 24 h. The transcription rate of the albumin gene was higher in NAR than in normal rats and was dramatically reduced by raising serum albumin to 1.6 g/dl. Intravenous infusion of albumin into normal rats also decreased transcriptional activity of the albumin gene by 50-60%, and this decrease correlated with changes in serum colloid osmotic pressure after albumin infusion. Inhibition ofalbumin gene transcription was also observed upon intravenous infusion of other protein or nonprotein macromolecules, such as y-globulin and dextran. This down-regulation appears to control the steady-state level of albumin mRNA in the liver.Aside from a concomitant decrease in apo E gene transcription after albumin or macromolecule infusion, there was no change in the transcription rate of other genes, including those exhibiting liver-preferred or -specific expression (e.g., tyrosine aminotransferase, cytochrome P450, a1-antitrypsin, apolipoproteins A-I and B, and transferrin) or general cellular expression (e.g., a-tubulin, pro a2 collagen, and fl-actin). The liver represents the main source of serum albumin (1, 2). Normally, the plasma albumin concentration remains constant at 3.5-4.0 g/dl, suggesting an active regulation ofalbumin metabolism. Several pathophysiological studies have shown that hormones, malnutrition, and stress may influence albumin synthesis (3-7); however, little is known about the "physiological" regulator(s) of albumin or other proteins synthesized by the liver. Many years ago, Biorneboe (8, 9) observed that an increase in the serum concentration ofglobulins is followed by a concomitant decrease ofserum albumin in hepatitis and after immunization, and he proposed that the serum colloid osmotic pressure (COP)' might serve as a regulator for changes in serum protein concentration. In support ofthis hypothesis, hyperglobulinemia, infusion of y-globulin, and administration of dextran were also shown to decrease serum albumin levels (10-12). Moreover, in a variety ofconditions in which serum albumin levels fall either acutely (e.g., plasmapheresis) or chronically (e.g., nephrotic syndrome), hepatic albumin synthesis is increased (13)(14)(15).In the 1960's, Rothschild et al. (16) demonstrated that addition of albumin to the perfusate medium ofthe isolated rabbit liver decreases incorporation of labeled amino acids into albumin. Other studies extended this observation to macromolecules other than albumin, and it was proposed that all these agents may work through a com...

Suppression of albumin enhancer activity by H-ras and AP-1 in hepatocyte cell lines.

“…This could also explain why the albumin enhancer is not active in hepatoma cells, since these cells usually contain high levels of ras and/or AP-1 (5,17). Albumin transcription is known to be modulated by hormones such as glucocorticoids (47,62), insulin (42,47), growth hormones (27,33), estrogen (22), and vasopressin (8) and by other factors such as the acute-phase reaction (45,55), extracellular matrix (39), phenobarbital (3), retinoic acid (25), heat (58), and serum colloid osmolarity (49). The molecular mechanisms of these regulatory effects are still unknown.…”

Management of adult patients with ascites caused by cirrhosis†

“…49 Increasing albumin concentration in cell culture media has recently been shown to decrease albumin synthesis. 51 In view of the cost, i.e., $4 to $25 per gram ϫ Ϸ50 g/tap ϭ $200 to $1,250/tap, it is difficult to justify the expense of routine albumin infusion based on the data at hand.…”

Insulin Is Required to Maintain Albumin Expression by Inhibiting Forkhead Box O1 Protein

“…Clinically, albumin is a crucial biomarker used to assess liver function (2). Multiple factors, including nutritional states, oncotic pressure, and hormonal factors, regulate albumin production (3)(4)(5). In diabetes, the concentration of albumin in blood is decreased, and administration of insulin is required to prevent hypoalbuminemia (6,7).…”