Liver stellate cells

M. Guido, M. Rugge, L. Chemello, G. Leandro, G. Fattovich, G. Giustina, M. Cassaro, and A. Alberti, Liver stellate cells in chronic viral hepatitis the effect of interferon therapy, J. Hepatol. 24 301-307 (1996). 

The retinyl esters are incorporated into chylomicrons, which in turn enter the lymph. Once in the general circula-tion. chylomicrons arc converted into chylomicron remnants, which arc cleared primarily by the liver. As the c.stcrs enter the hepalocytes. they are hydrolyzed. In the endoplasmic reticulum, the retinol is bound to retinol-binding protein (RBP). This cotnplex is released into the blood or transferred to liver stellate cells fur storage. Within the stellate cells, the retinol is bound to CRBP(I) and e.stcnTicd for storage by ARAT and LRAT. Stellate cells contain up to 95% of the liver vitamin A. stores. The RBP-retinol complex released into the general circulation from hepalocytes or stellate cells, in turn, is bound to transthyretin (TTR), which protects retinol from metabolism and renal excretion. ... 

D-MS CCL, Rat liver stellate cells 150 protein IDs, T in calcyclin, calgizzarin, galectin-1... 

The most striking evidence in support of a pathophysiologic involvement of 4-HNE in gene modulation is the demonstration that the aldehyde externally added could be rapidly recovered within the nuclei of cultured cells. This finding was first obtained in liver stellate cells as reported above," and confirmed in macrophages. This finding paralleled that of increased AP-1 binding. ... 

Hepatocytes sequester RE and cholesteryl esters by receptor-mediated endocytosis of chylomicron remnants. Substantial RE hydrolysis apparently occurs before engulfing of the remnants by lysosomes. CRBP(I) sequesters the atROH released and allows esterification by LRAT but protects from esterification via other acyltransferases, just like CRBP(II) functions in the intestine. Ultimately, liver stellate cells accumulate most of the RE. CRBP(I) seems necessary for retinoid transfer from hepatocytes to stellate cells because the CRBP(I) null mouse does not accumulate RE in stellate cells. The mechanism of transfer, however, has not been estabhshed. 

Yang X, Lu P, Ishida Y, Kuziel WA, Fujii C, Mukaida N. Attenuated liver tumor formation in the absence of CCR2 with a concomitant reduction in the accumulation of hepatic stellate cells, macrophages and neovascularization. Int J Cancer 2006 118 335-345. 

Figure 4.1. Schematic representation of the architecture of the liver. Blood enters the liver through the portal vein (PV) and hepatic arteries (HA), flows through the sinusoids, and leaves the liver again via the central vein (CV). KC, Kupffer cells SEC, sinusoidal endothelial cells HSC, hepatic stellate cells BD, bile duct. Modified from reference 98.

Figure 4.2. Diagram outlining the pathogenesis of liver fibrosis. Injury to parenchymal cells (PC) results in the activation of Kupffer cells (KC) and sinusoidal endothelial cells (SEC) and the recruitment of inflammatory cells (IC). These cells release cytokines, growth factors and reactive oxygen species that induce activation and proliferation of hepatic stellate cells (HSC). HSCs gradually transform into myofibroblasts (MF), the major producers of extracellular matrix (ECM) proteins.

When the receptor binding domain is encoded in a small peptide sequence, the peptide hg-and can also be synthesized and conjugated chemically to the carrier protein. This approach was followed in our laboratory by Beljaars et al. for the development of carriers aimed at the hepatic stellate cell, a cell type involved in liver fibrosis [33] (see also Chapter 4). A peptide sequence derived from the receptor binding domains of collagen VI was incorporated into a cyclic peptide homing device, and subsequently conjugated to lysine residues of HSA. This carrier bound selectively to activated hepatic stellate cells and rapidly accumulated in the livers of fibrotic rats. 

The most abundant cell type in the liver is the hepatocyte, other cells in the liver are the non-parenchymal cells Kupffer cells, the resident macrophages of the liver, endothelial cells and stellate cells. These cells have been discussed in more detail in Chapter 4. 

Isolation from human liver of other cell types, such as Kupffer, endothelial and stellate cells has also been developed and extensively reviewed [29-31]. 

Phenolic and antioxidant substances have usually studied in red wines, however, recently, interest has increased in the study of bioactive phenolics in white wines Frega et al. [374] isolated and measured concentration of ethyl caffeoate in Verdicchio white wine by HPLC-tandem-mass spectrometry (HPLC-ESI-MS/MS) and they also determined its effects on hepatic stellate cells and intracellular peroxidation. The resnlts were interesting in the light of other studies demonstrating the relationship between reactive oxygen species, chronic liver injury, and hepatic fibrosis. 

In the body retinol can also be made from the vitamin precursor carotene. Vegetables like carrots, broccoli, spinach and sweet potatoes are rich sources of carotene. Conversion to retinol can take place in the intestine after which retinyl esters are formed by esterifying retinol to long chain fats. These are then absorbed into chylomicrons. Some of the absorbed vitamin A is transported by chylomicrons to extra-hepatic tissues but most goes to the liver where the vitamin is stored as retinyl palmitate in stellate cells. Vitamin A is released from the liver coupled to the retinol-binding protein in plasma. 

Retinyl esters and the P-carotene are incorporated into chylomicrons and taken up mainly by hepatocytes. In the liver retinol may be stored in stellate cells as retinyl esters, oxidized to retinoic acid or liberated into cells bound to retinol-binding proteins (RBP). All E retinoic acid and its 9Z isomer have an affinity for nuclear receptors. They activate the transcription and bind as dimers to specific nucleotide sequences, present in promoters of target genes. 

Williams EJ, Benyon RC, Trim N, Hadwin R, Grove BH, Arthur MJP, Unemori EN, Iredale JP. Relaxin inhibits effective collagen deposition by cultured hepatic stellate cells and decreases rat liver fibrosis in vivo. Gut 2001, 49, 577-583. 

Figure 1 Schematic representation of the architecture of the liver. Endothelial cells (EC) and Kupffer cells (KC) are located in close contact with the bloodstream, whereas hepatic stellate cells (HSC) and parenchymal cells (PC) reside in or behind the space of Disse.

Hepatic stellate cell activation is also associated with the induction of other liver diseases. In livers of patients with chronic hepatitis, an increased number of activated HSC were detected [87], Recently, an interaction of hepatitis C virus (HCV) with HSC was reported [88], Furthermore, HSC activation is associated with the development of liver tumors, for instance, hepatocellular carcinomas (HCC). Mediators like TGF-a and TGF-P derived from dysplastic hepatocytes... 

Although the cellular and molecular mechanisms underlying fibrosis are not fully explained, it is assumed that an inflammatory reaction is the initiating factor in the early stage of fibrosis and that this inflammatory process continues during the fibrotic process [77, 105, 106], Kupffer and endothelial cells are considered to be the most important resident cells involved in the local production of inflammatory mediators [24, 28, 29, 76], Besides causing the activation of HSC, the inflammatory mediators induce the expression of adhesion molecules, such as ICAM-1 and VCAM on endothelial cells, that direct neutrophils and monocytes into the inflamed liver tissue [41-43], Expression of adhesion molecules is also shown for KC and stellate cells [42, 107], Furthermore, chemotactic compounds are released by endothelial and KC to attract immune competent cells... 

It should be realized, however, that therapeutic interference with only one cell type may not be enough to treat liver cirrhosis, because all hepatic cell types contribute to some extent to the development of the disease. Therefore, a combination of drug-targeting preparations to stellate cells, KC, endothelial cells, and/ or hepatocytes might improve the pharmacological therapies and compete with the liver transplantation technique. In addition to therapeutic applications, modified albumins may also be used for diagnostic purposes (an issue that will be addressed in section VI.C.4). 

M. Pinzani, F. Marra, and V. Carloni, Signal transduction in hepatic stellate cells, Liver 18 2-13 (1998). 

---