Effects of hemopexin on heme-mediated repression of 5-aminolevulinate synthase and induction of heme oxygenase in cultured hepatocytes

Abstract

The serum protein hemopexin is considered to have a major role in the mechanism of the uptake of heme by hepatocytes by means of a heme-hemopexin receptor. Therefore, we examined in primary cultures of adult rat and embryonic chick hepatocytes whether the presence of hemopexin would affect the heme-mediated repression of 5-aminolevulinate synthase activity (the rate-limiting enzyme of heme biosynthesis) and the heme-induced increase of heme oxygenase activity (the rate-limiting step of heme degradation). Both of these heme-mediated effects were partly or entirely prevented by the presence of hemopexin. We conclude that homologous hemopexin, at molar concentrations exceeding that of heme, inhibited the uptake of heme into hepatocytes. These results suggest that heme, in amounts sufficient to affect the rate-limiting steps of heme synthesis and degradation, can only enter hepatocytes in primary culture when the binding capacity of hemopexin for heme has been exceeded or altered.

Identification of the receptor scavenging hemopexin-heme complexes

“…46,47 Hx has been shown to prevent the heme effects on endothelium including the induction of HO-1. The inhibition by Hx on heme-induced HO-1 mRNA transcription seems to be more pronounced in endothelium than in hepatic cells 44,45 and in monocytes (data presented here). This difference in induction of HO-1 mRNA transcription by the Hx-heme complex might be due the fact that endothelial cells in contrast to monocytes and hepatocytes do not express LRP/CD91.…”

“…44,45 The stimulatory pathway is probably different from the strong HO-1 induction by free heme, which attacks the plasma membranes. 2 The biologic effect of heme has been studied in endothelial cells, which are exposed and highly sensitive to heme-induced generation of reactive oxygen species and oxidized LDL.…”

Initial heme uptake from albumin by short-term cultured rat hepatocytes is mediated by a transport mechanism differing from that of other organic anions

“…28 It has been suggested that hemopexin receptors in the liver are the major mediators of rapid heme uptake from the circulation. 2,6,31 Recent studies in cultured hepatocytes argue against a pivotal role for hemopexin receptors in the heme uptake process, because heme bound to hemopexin in an equimolar ratio does not enter hepatocytes, 3,4 and the number of hepatic hemopexin receptors on cultured adult rat hepatocytes is only about 2,000 per cell. 32 Heme added to plasma in vitro is transferred rapidly to albumin, from which it is transferred slowly to hemopexin.…”

“…[1][2][3][4] Hemopexin and a putative hemopexin receptor on hepatocyte membranes may mediate the uptake process. 2,[5][6][7][8] However, whether there are sufficient hemopexin receptors on rat hepatocytes to account for the bulk of heme entering cells is unknown.…”

“…It is likely that heme may be transferred directly from albumin with the help of a plasma membrane heme transporter. [3][4][5] Several carriers have been identified that mediate hepatocyte uptake of organic anions (e.g., bilirubin, sulfobromophthalein [BSP], and taurocholate), that are bound to albumin. A sodium-dependent bile acid transporter that is especially active toward conjugated bile acids such as taurocholate has been expressioncloned.…”