Development of ultrastructural heterogeneity among hepatocytes in the mouse

208

134

With respect to hepatocyte heterogeneity in ammonia and amino acid metabolism, two different patterns of sublobular gene expression are distinguished: ‘gradient-type’ and ‘strict- or compartment-type’ zonation. An example for strict-type zonation is the reciprocal distribution of carbamoylphosphate synthase and glutamine synthase in the liver lobule. The mechanisms underlying the different sublobular gene expressions are not yet settled but may involve the development of hepatic architecture, innervation, blood-borne hormonal and metabolic factors. The periportal zone is characterized by a high capacity for uptake and catabolism of amino acids (except glutamate and aspartate) as well as for urea synthesis and gluconeogenesis. On the other hand, glutamine synthesis, ornithine transamination and the uptake of vascular glutamate, aspartate, malate and a-ketoglutarate are restricted to a small perivenous hepatocyte population. Accordingly, in the intact liver lobule the major pathways for ammonia detoxication, urea and glutamine synthesis, are anatomically switched behind each other and represent in functional terms the sequence of the periportal low affinity system (urea synthesis) and a previous high affinity system (glutamine synthesis) for ammonia detoxication. Perivenous glutamine synthase-containing hepatocytes (‘scavenger cells’) act as a high affinity scavenger for the ammonia, which escapes the more upstream urea-synthesizing compartment. Periportal glutaminase acts as a pH- and hormone- modulated ammonia-amplifying system in the mitochondria of periportal hepatocytes. The activity of this amplifying system is one crucial determinant for flux through the urea cycle in view of the high K(m) (ammonia) of carbamoylphosphate synthase, the ratecontrolling enzyme of the urea cycle. The structural and functional organization of glutamine and ammonia-metabolizing pathways in the liver lobule provides one basis for the understanding of a hepatic role in systemic acid base homeostasis. Urea synthesis is a major pathway for irreversible removal of metabolically generated bicarbonate. The lobular organization enables the adjustment of the urea cycle flux and accordingly the rate of irreversible hepatic bicarbonate elimination to the needs of the systemic acid base situation, without the threat of hyperammonemia.

Section: Lobular Architecturementioning

confidence: 99%

Hepatocyte Heterogeneity in the Metabolism of Amino Acids and Ammonia

Häussinger¹,

Lamers²,

Moorman³

1992

208

134

“…Now the liver acquires the function of a 'glucostat'. The zonation of the ultrastructure [ 100] and of carbohydrate-metabolizing enzymes de velops gradually during the first weeks of life in part before and in part with weaning. Phosphoenolpyruvate carboxykinase [101 -103] showed the first signs of zonation at day 1-3, succinate dehydrogenase [101] and glucose-6-phosphatase [104] …”

Section: Perinatal Developmentmentioning

confidence: 99%

Hepatocyte Heterogeneity in the Metabolism of Carbohydrates

Jungermann

Thurman²

1992

109

Periportal and perivenous hepatocytes possess different amounts and activities of the rate-generating enzymes of carbohydrate and oxidative energy metabolism and thus different metabolic capacities. This is the basis of the model of metabolic zonation, according to which periportal cells catalyze predominantly the oxidative catabolism of fatty and amino acids as well as glucose release and glycogen formation via gluconeogenesis, and perivenous cells carry out preferentially glucose uptake for glycogen synthesis and glycolysis coupled to liponeogenesis. The input of humoral and nervous signals into the periportal and perivenous zones is different; gradients of oxygen, substrates and products, hormones and mediators and nerve densities exist which are important not only for the short-term regulation of carbohydrate metabolism but also for the long-term regulation of zonal gene expression. The specialization of periportal and perivenous hepatocytes in carbohydrate metabolism has been well characterized. In vivo evidence is provided by the complex metabolic situation termed the ‘glucose paradox’ and by zonal flux differences calculated on the basis of the distribution of enzymes and metabolites. In vitro evidence is given by the different flux rates determined with classical invasive techniques, e.g. in periportal-like and perivenouslike hepatocytes in cell culture, in periportal- and perivenous-enriched hepatocyte populations and in perfused livers during orthograde and retrograde flow, as well as with noninvasive techniques using miniature oxygen electrodes, e.g. in livers perfused in either direction. Differences of opinion in the interpretation of studies with invasive and noninvasive techniques by the authors are discussed. The declining gradient in oxygen concentrations, the decreasing glucagon/insulin ratio and the different innervation could be important factors in the zonal expression of the genes of carbohydrate-metabolizing enzymes. While it is clear that the hepatocytes sense the glucagon/insulin gradients via the respective hormone receptors, it is not known how they sense different oxygen tensions; the O(2) sensor may be an oxygen-binding heme protein. The zonal separation of glucose release and uptake appears to be important for the liver to operate as a ‘glucostat’. Thus, zonation of carbohydrate metabolism develops gradually during the first weeks of life, in part before and in part with weaning, when (in rat and mouse) the fat- and protein-rich but carbohydrate-poor nutrition via milk is replaced by carbohydrate-rich food. Similarly, zonation of carbohydrate metabolism adapts to longer lasting alterations in the need of a ‘glucostat’, such as starvation, diabetes, portocaval anastomoses or partial hepatectomy.

“…The cytosol contains soluble proteins, RNA, and enzymes that comprise about 25% of the total cell protein [25], Of the numerous submicroscopic structures present, only those that have been especially studied in hépato cytes or that play a particular role in the function of these cells will be described. It must be stressed that intracellular structures vary both in size and number in hepatocytes lining the sinusoids, not only with respect to their intra-acinar localization but also dur ing postnatal development when sinusoidal gradients develop [26].…”

Section: Ultrastructurementioning

confidence: 99%

Liver Architecture

Sasse

Spornitz

Maly

1992

The development of liver parenchyma starts from entodermal cells which grow out from the gut into the mesenchyma of the septum transversum. In the definitive organ this close association of epithelial cells (hepatocytes) and mesenchyma-derived nonparenchymal cells is maintained. The liver, and with it each hepatocyte, acts in two directions; the vascular poles of the hepatocytes serve in an ingestive sense, while at their biliary poles secretory functions are exerted. Hepatic microvascularization comprises two afferent vessels (arterial and portal terminal branches), the sinusoids and the terminal hepatic venule. Sinusoidal cells surround the capillaries but also have highly specialized functions with regard to filtration, phagocytosis, fat storage and defense. The autonomic innervation plays an important role in the regulation of metabolic functions. Above the cellular level the proper architecture of the liver parenchyma has been the object of controversial discussions for centuries. The concept of the liver lobule, the portal unit, the liver acinus and other structures are presented and discussed. Finally, the liver parenchyma is described as an irregular interdigitating system of regions related to the terminal blood vessels.