Zonal and regional differences identified from precision mapping of vitamin a–storing lipid droplets of the hepatic stellate cells in pig liver: A novel concept of addressing the intralobular area of heterogeneity

✍ Scribed by Zhenzhen Zou; Wichai Ekataksin; Kenjiro Wake

• Publisher: John Wiley and Sons
• Year: 1998
• Tongue: English
• Weight: 368 KB
• Volume: 27
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.510270427

✦ Synopsis

Knowledge of hepatic heterogeneity has been strikingly increased, while an accurate means for addressing intralobular positions is still lacking. We examined pig liver preparations of the gold impregnation method for vitamin A-storing lipid droplets in hepatic stellate cells. Droplet morphometry was performed under oil immersion, and the calculated volumes plotted on computerized maps. The heterogeneous results were assessed with five concentric zones and five radial regions; the latter were determined based on midseptum visualized by portal injection. Zonation and regionation thus subdivided lobules into 5-zone/5region (5Z/5R) compartmentalization. Distribution of values exhibited a distinct zonal gradient, heightened at peripheral zones 1 and 2, decreased over intermediate zone 3 toward centrilobular zones 4 and 5; peak was always found at zone 2. Within a single zone, variations were obvious, forming a regional gradient. Values were significantly higher at periportal than midseptal regions. Digitized mapping showed that low values filled up centrilobular zones, whereas high values concentrated in periportal regions. Along the periphery, inlet venules were quantified, revealing an occurrence rate of 60% at periportal, and 5% at midseptal regions, closely compatible with the regional gradient of vitamin A-storing capacity. The interweaving between zonal and regional gradients results in a vitamin A-low territory, a compound area composed of centrilobular zones plus extensions into midseptal regions. Because the results could account for physiological and pathological events, we regard the 5Z/5R compartmentalization a model worth routine adoption for a precise description of any morphofunctionally demonstrable heterogeneity of the liver lobules. (HEPATOLOGY 1998;27:1098-1108.)

Evidence has accumulated in the literature and established a unique biological nature of the liver called heterogeneity. The hepatic heterogeneity is known primarily of the parenchymal cell compartment, sometimes referred to as the metabolic zonation, which is characterized by zones of similar-looking hepatocytes that are functionally distinct and structurally different. When expressed, interestingly, the patterns of distribution are recognized alike; they manifest in the hepatic lobules basically as concentric zones, appearingly as confined to either a peripheral zone or a centrilobular zone.

Many key enzymes in major metabolic pathways, such as glucose-6-phosphatase, succinate dehydrogenase, phosphoenolpyruvate carboxykinase, and carbamoylphosphate synthetase, are expressed strongly in the peripheral zone (for review, see ref. 3, 5, 6). Reciprocally, several other enzymes are found to dominate the centrilobular zone; these include lactate dehydrogenase, glutamate dehydrogenase, glucokinase, pyruvate kinase, acetyl-Co-A carboxylase, adenosine triphosphatedependent citrate lyase, and fatty acid synthetase. Likewise, the P450 superfamily of isoenzymes are expressed almost exclusively in the centrilobular zone. The fact that some enzymes, e.g., glutamine synthetase 7 and cytochrome P450b,e, 8 and some molecules like glucose transporter protein, 9 are demonstrated to be localized distinctly in an exceedingly limited narrow ring immediately surrounding the central vein, has promptly initiated an idea that the conventional method of expression based on peripheral-centrilobular zones, or even the traditional peripheralintermediate-centrilobular zone addressing, are no longer adequate nor sufficient.

The zone-dependent distribution, zonality, has been found also in the nonparenchymal cell compartment, including Kupffer cells, 10 endothelial cells, 11,12 stellate cells, and pit cells. Furthermore, the zonal heterogeneity has been shown to be present similarly in the extracellular matrix compartment of the hepatic lobules. In addition to the zonal difference, there is a regional difference that expresses different degrees of variations within a single zone. With elaboration of observations, Teutsch 19 could demonstrate in the parenchymal cell compartment that the enzyme and substrate of glucose-6-phosphate hydrolysis exhibited significantly higher values at the ''portal'' region than the ''septal'' region in the same zone. On the other hand, a close reciprocity was demonstrated in the distribution of the ketogenic enzyme, with an increased activity at the ''septal'' region and a decreased activity at the ''portal'' region of the same zone. In the extracellular matrix compartment, we Abbreviations: MCI, map for capacity of individual cells; MCG, map for capacity of groups of cells; 5Z/5R, 5-zone/5-region.