9-cis RA




/vvvi aàammam

Extrahepatic target cells Absorptive cells

Intestinal lumen

FIGURE 3. Major pathway for vitamin A transport in the body. Dietary retinyl esters (RE) are hydrolyzed to retinol (ROH) in the intestinal lumen before absorption by enterocytes, and carotenoids are absorbed and then partially converted to retinol in the enterocytes. In the enterocytes, retinol reacts with fatty acid to form esters before incorporation into chylomicrons (CM). Chylomicrons then reach the general circulation by way of the intestinal lymph, and chylomicron remnants (CMR) are formed in blood capillaries. Chylomicron remnants, which contain almost all the absorbed retinol, are mainly cleared by the liver PCs and to some extent also by cells in other organs. In liver PCs, retinyl esters are rapidly hydrolyzed to retinol, which then binds to RBP. A complex of retinol-RBP is secreted and transported to HSCs. SCs store vitamin A mainly as retinyl palmitate and secrete retinol-RBP directly into the blood. Most retinol-RBP in the bloodstream is reversibly complexed with transthyretin (TTR). The uncomplexed retinol-RBP is presumably taken up in a variety of cells by cell surface receptors specific for RBP.

support earlier morphological observations (Wake, 1971,1980) that the SC is the storage site of vitamin A in the liver, and are not inconsistent with reports on the retinol transfer from PCs to SCs (Andersen et al., 1992; Blomhoff et al., 1990; Gy0en et al., 1987; Malaba et al., 1996; Senoo et al., 1990, 1993).

Immunoelectronmicroscopic studies suggest that RBP mediates the para-crine transfer of retinol from hepatic PCs to the SCs and that SCs bind and internalize RBP by receptor-mediated endocytosis (Malaba et al., 1996; Senoo et al., 1993). RBP receptor was cloned and characterized (Bavik et al., 1991, 1992, 1993; Smeland et al., 1995). The SCs may have pivotal roles in type 2 diabetes, because RBP was reported to contribute to insulin resistance in obesity and type 2 diabetes (Yang et al., 2005).


More than 50 years ago, Rodahl reported that animals (polar bears and seals) in the Arctic area were able to store a large amount of vitamin A in the liver (Rodahl, 1949a,b; Rodahl and Moore, 1943). To investigate the cellular and molecular mechanisms in transport and storage of vitamin A in these Arctic animals, we performed a study in the Svalbard archipelago (situated at 80°N, 15°E) (Higashi and Senoo, 2003; Senoo et al., 1999). After getting permission to hunt the animals from the district governor of Svalbard, 11 Arctic foxes (Alopex lagopus), 14 bearded seals (Erignathus barbatus), 22 glaucous gulls (Larus hyperboreus), 5 fulmars (Fulmarus glacia-lis), 4 Brunnich's guillemots (Uria lomvia), 6 ringed seals (Phoca hispida), 5 hooded seals (Cystophora cristata), 6 puffins (Fratercula arctica), 5 Svalbard ptarmigans (Lagopus mutus hyperboreus), and 7 Svalbard reindeers (Rangifer tarandus platyrhynchus) were caught in the period from August 1996 to September 2001. Three polar bears (Ursus maritimus) were shot in self-defense at Svalbard February and August 1998 in Ny Alesund and Hornsund. We also obtained 13 brown bears (Ursus arctos) from Jamtland, Gavleborg, and Dalarna, 4 red foxes (Vulpes vulpes) from Vastergotaland, and 8 gray gulls (Larus argentatus) from Skane, Sweden.

Fresh organs, namely, the liver, kidney, spleen, lung, and jejunum, were examined by morphological methods and high-performance liquid chromatography (HPLC). Serum from each animal was analyzed with HPLC.

The Arctic animals stored vitamin A in HSCs (Figs. 4-6). Only a small amount of vitamin A existed within other organs such as kidney, spleen, lung, and jejunum. Top predators among Arctic animals stored 6- to 23-^mol retinyl ester per gram liver which is 20-100 times the levels normally found in other animals including humans, rats, and mice. These results indicate that the HSCs in these animals have high ability for uptake and enough capacity for storage of vitamin A.

FIGURE 4. Transmission electron micrographs of the liver of polar bears, Arctic foxes, and rats. Electron micrographs of the liver of polar bears (A-C), Arctic foxes (D-F), and rats (G-I) were taken in portal area (A, D, and G), intermediate area (B, E, and H), and central area (C, F, and I) of the hepatic lobule.

FIGURE 4. Transmission electron micrographs of the liver of polar bears, Arctic foxes, and rats. Electron micrographs of the liver of polar bears (A-C), Arctic foxes (D-F), and rats (G-I) were taken in portal area (A, D, and G), intermediate area (B, E, and H), and central area (C, F, and I) of the hepatic lobule.

FIGURE 5. Gold chloride staining specifically demonstrating black-stained HSCs of polar bears (A and B), Arctic foxes (C and D), and rats (E and F). Scale bars indicate 100 mm.

The existence of a gradient of vitamin A-storing capacity in the liver was reported and it was found to be independent on the vitamin A amount in the organ (Figs. 7 and 8; Higashi and Senoo, 2003). This gradient was expressed as a symmetrical biphasic distribution starting at the periportal zone, peaking at the middle zone, and sloping down toward the central zone in the liver lobule.

FIGURE 6. Fluorescence micrographs demonstrating vitamin A autofluorescence in HSCs of polar bears (A), Arctic foxes (B), and rats (C and D). Scale bars indicate 100 mm.

Xenobiotics (such as PCBs and dioxins) may reduce the threshold of vitamin A toxicity (Nilsson et al., 1999) and both vitamin A and fat-soluble xenobiotics have a tendency to accumulate in the food chain (Barrie et al., 1992; Dewailly et al., 1989; Holden, 1998; Jarman et al., 1992; Muir et al., 1998; Skaare et al., 2001; Wiig et al., 1998). Kidney total vitamin A, which may be used as a biomarker for retinoid-related toxicity or excess, in polar

FIGURE 7. Zonal division of the liver lobule. To make a zonal morphometric analysis, the liver lobule was divided histologically into five zonal areas (zones I-V) of equal widths from the portal vein (pv) to the central vein (cv).

bear and bearded seal was below 1% of their liver value, which is in the normal range for most animals (Senoo et al., 2004). Arctic fox and glaucous gull, however, had kidney levels of about 9% and 42% of the liver values, respectively. This increased kidney concentrations and decreased capacity for storage in HSCs of total vitamin A in Arctic fox and glaucous gull are most likely signs of vitamin A toxicity that deserve attention. Nuclear deviation has been reported in PCs on sinusoidal surface in Arctic animals (Sato et al., 2001a). These data are alarming and have not been observed previously in free-living animals.


It is well known that liver cells including PCs and SCs show a remarkable growth capacity after partial hepatectomy (PHx). Following 70% PHx in rodents, liver mass is almost completely restored after 14 days. PC proliferation starts after ~24 h, in the areas surrounding portal tracts and proceeds to the pericentral areas by 36-38 h. As a result of the early PC proliferation, avascular clusters of PCs are observed from 3 days after PHx. Non-parenchymal cells enter DNA synthesis ~24 h after PCs, with peak activity at 48 h or later. Not only proliferation of PCs but also activation of sinusoidal liver cells including HSCs are involved in the regeneration process through cell-cell interaction and cytokine networks (Mabuchi et al., 2004). PCs and

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