Hepatocytes heme synthesis

Absorption, transport, and storage of iron. Intestinal epithelial cells actively absorb inorganic iron and heme iron (H). Ferrous iron that is absorbed or released from absorbed heme iron in the intestine (1) is actively transported into the blood or complexed with apoferritin (AF) and stored as ferritin (F). In the blood, iron is transported by transferrin (Tf) to erythroid precursors in the bone marrow for synthesis of hemoglobin (Hgb) (2) or to hepatocytes for storage as ferritin (3). The transferrin-iron complexes bind to transferrin receptors (TfR) in erythroid precursors and hepatocytes and are internalized. After release of the iron, the TfR-Tf complex is recycled to the plasma membrane and Tf is released. Macrophages that phagocytize senescent erythrocytes (RBC) reclaim the iron from the RBC hemoglobin and either export it or store it as ferritin (4). Hepatocytes use several mechanisms to... 

Essential non-steroidal isoprenoids, such as dolichol, prenylated proteins, heme A, and isopentenyl adenosine-containing tRNAs, are also synthesized by this pathway. In extrahepatic tissues, most cellular cholesterol is derived from de novo synthesis [3], whereas hepatocytes obtain most of their cholesterol via the receptor-mediated uptake of plasma lipoproteins, such as low-density lipoprotein (LDL). LDL is bound and internalized by the LDL receptor and delivered to lysosomes via the endocytic pathway, where hydrolysis of the core cholesteryl esters (CE) occurs (Chapter 20). The cholesterol that is released is transported throughout the cell. Normal mammalian cells tightly regulate cholesterol synthesis and LDL uptake to maintain cellular cholesterol levels within narrow limits and supply sufficient isoprenoids to satisfy metabolic requirements of the cell. Regulation of cholesterol biosynthetic enzymes takes place at the level of gene transcription, mRNA stability, translation, enzyme phosphorylation, and enzyme degradation. Cellular cholesterol levels are also modulated by a cycle of cholesterol esterification mediated by acyl-CoA cholesterol acyltransferase (ACAT) and hydrolysis of the CE, by cholesterol metabolism to bile acids and oxysterols, and by cholesterol efflux. 

TABLE II Effects of Endogenous Nitric Oxide Synthesis on Total Cytochrome M50 Heme and Total Microsomal Heme in Microsomes from Freshly Isolated and Cultured Hepatocytes of Corynebacterium parvum-Treated Rats ... 

As shown in Table III, in vitro induction of endogenous -NO synthesis in isolated hepatocytes (similar to the data on catalase in Table I) results in a marked reduction in both total GYP heme (0.053 down to... 

Heme metabolism in hepatocytes is highly regulated (Bonkovsky, 1982). Free heme down-regulates its own synthesis (by decreased mRNA stability and mitochondrial import of ALAS) and up-regulates its degradation (by transcriptional increase in HO). If heme is liberated from hepatocyte CYP [which is the major heme pool in this cell (Bonkovsky, 1982)], this could result in modulation of the activities of these enzymes. As shown in Table V, treatment of hepatocytes in vitro with CME indeed results in a decline (80%) in ALAS and an increase (3.9-fold) in HO activities. This effect is inhibited by NMMA, demonstrating it to be a result of -NO synthesis, and... 

We also demonstrate that inhibition of -NO synthesis in vitro results in substantial recovery of total CYP and microsomal heme. This result shows that, as described previously for hepatocyte mitochondrial electron transfer (Stadler et al., 1991) and intracellular iron-nitrosyl complexes (Nussler et al., 1993), hepatocytes [as well as other cells (Corbett and McDaniel, 1994)] are capable of recovery or repair of the decrease in iron-containing enzyme function caused by -NO. 

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