Heterogeneity in expression and subcellular localization of claudins 2, 3, 4, and 5 in the rat liver, pancreas, and gut

Feed and energy intake of ruminant animals can change dramatically in response to changes in diet composition or metabolic state, and such changes are poorly predicted by traditional models of feed intake regulation. Recent work suggests that temporal patterns of fuel absorption, mobilization, and metabolism affect feed intake in ruminants by altering meal size and frequency. Research with nonruminants suggests that meals can be terminated by signals carried from the liver to the brain via afferents in the vagus nerve and that these signals are affected by hepatic oxidation of fuels and generation of ATP. We find these results consistent with the effects of diet on feed intake of ruminants. Of fuels metabolized by the ruminant liver, propionate is likely a primary satiety signal because its flux to the liver increases greatly during meals. Propionate is utilized for gluconeogenesis or oxidized in the liver and stimulates oxidation of acetyl CoA. Although propionate is extensively metabolized by the ruminant liver, there is little net metabolism of acetate or glucose, which may explain why these fuels do not consistently induce hypophagia in ruminants. Lactate is metabolized in the liver but has less effect on satiety, probably because of greater latency for reaching the liver within meals and because of less hepatic extraction compared with propionate. Hypophagic effects of fatty acid oxidation in the liver are likely from delaying hunger rather than promoting satiety because beta-oxidation is inhibited during meals by propionate. A shortage of glucose precursors and increased fatty acid oxidation in the liver for early lactation cows lead to a lack of tricarboxylic acid (TCA) cycle intermediates, resulting in a buildup of the intracellular acetyl-CoA pool and export of ketone bodies. In this situation, hypophagic effects of propionate are likely enhanced because propionate entry into the liver provides TCA cycle intermediates that allow oxidation of acetyl-CoA. Oxidizing the pool of acetyl-CoA rather than exporting it increases ATP production and likely causes satiety despite the use of propionate for glucose synthesis. A better understanding of metabolic regulation of feed intake will allow diets to be formulated to increase the health and productivity of ruminants.

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BOARD-INVITED REVIEW: The hepatic oxidation theory of the control of feed intake and its application to ruminants

The enormous number of different liver functions are carried out by parenchymal and four main types of nonparenchymal cells, either alone or in cooperation. Although the liver tissue is uniform on the level of histology, it is heterogenous on the level of morphometry and histochemistry. This heterogeneity is related to the blood supply; cells located in the upstream or periportal zone differ from those in the downstream or perivenous zone in their equipment with key enzymes, translocators, receptors, and subcellular structures and therefore have different functional capacities. This is the basis of the model of metabolic zonation, according to which glucose release from glycogen and via gluconeogenesis, amino acid utilization and ammonia detoxification, protective metabolism, bile formation, and the synthesis of certain plasma proteins such as albumin and fibrinogen occur mainly in the periportal area, whereas glucose utilization, xenobiotic metabolism, and the formation of other plasma proteins such as alpha 1-antitrypsin or alpha-fetoprotein occur predominantly in the perivenous zone. The mor- phologic and functional heterogeneity is the result of zonal differences in the activation of the cellular genome caused by gradients in oxygen, substrate, hormone, and mediator levels, in innervation, as well as in cell-to-cell and cell-to-biomatrix interactions.

Zonation of parenchymal and nonparenchymal metabolism in liver

Apc Tumor Suppressor Gene Is the “Zonation-Keeper” of Mouse Liver

Stem Cells and Liver Regeneration

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 alpha-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 Km (ammonia) of carbamoylphosphate synthase, the rate-controlling 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.

A. F. M. Moorman

Papers

Hepatocyte heterogeneity in the metabolism of amino acids and ammonia.