Benzoate stimulates glutamate release from perfused rat liver

Häussinger, Dieter; Stehlé, Thomas; Colombo, J. P.

doi:10.1042/bj2640837

Cited by 9 publications

(4 citation statements)

References 28 publications

(28 reference statements)

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“…If the assignment of OAT2 as a hepatic glutamate efflux transporter is correct, then there should be a corresponding phenotype. Indeed, release of glutamate from liver into the blood has been reported: in rats fed a protein-free diet, glutamate was released at 64 μmol/l as calculated by the plasma concentration difference between portal vein and hepatic vein [23]; isolated perfused rat liver continuously (observation time of 100 min) released glutamate at a rate of 40-60 nmol • min − 1 • g − 1 [24,25], with this export being sodium independent; and under diets either slightly deficient (11 % casein) or moderately surfeit (22 % casein) in protein, glutamate and glutamine were markedly released by rat liver [26]. Collectively, these observations can now be explained by OAT2 activity and thus reinforce the hypothesis that OAT2 functions as a hepatic glutamate efflux transporter.…”

Section: Discussionmentioning

confidence: 99%

OAT2 catalyses efflux of glutamate and uptake of orotic acid

Fork

Bauer

Gölz

et al. 2011

Biochemical Journal

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OAT (organic anion transporter) 2 [human gene symbol SLC22A7 (SLC is solute carrier)] is a member of the SLC22 family of transport proteins. In the rat, the principal site of expression of OAT2 is the sinusoidal membrane domain of hepatocytes. The particular physiological function of OAT2 in liver has been unresolved so far. In the present paper, we have used the strategy of LC (liquid chromatography)-MS difference shading to search for specific and cross-species substrates of OAT2. Heterologous expression of human and rat OAT2 in HEK (human embryonic kidney)-293 cells stimulated accumulation of the zwitterion trigonelline; subsequently, orotic acid was identified as an excellent and specific substrate of OAT2 from the rat (clearance=106 μl·min⁻¹·mg of protein⁻¹) and human (46 μl·min⁻¹·mg of protein⁻¹). The force driving uptake of orotic acid was identified as glutamate antiport. Efficient transport of glutamate by OAT2 was directly demonstrated by uptake of [³H]glutamate. However, because of high intracellular glutamate, OAT2 operates as glutamate efflux transporter. Thus expression of OAT2 markedly increased the release of glutamate (measured by LC-MS) from cells, even without extracellular exchange substrate. Orotic acid strongly trans-stimulated efflux of glutamate. We thus propose that OAT2 physiologically functions as glutamate efflux transporter. OAT2 mRNA was detected, after laser capture microdissection of rat liver slices, equally in periportal and pericentral regions; previous reports of hepatic release of glutamate into blood can now be explained by OAT2 activity. A specific OAT2 inhibitor could, by lowering plasma glutamate and thus promoting brain-to-blood efflux of glutamate, alleviate glutamate exotoxicity in acute brain conditions.

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Section: Discussionmentioning

confidence: 99%

OAT2 catalyses efflux of glutamate and uptake of orotic acid

Fork

Bauer

Gölz

et al. 2011

Biochemical Journal

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“…Glutamate release by the liver is normally very low, but is markedly stimulated by organic monocarboxylates such as oxoisocaproate, benzoate or oxomethionine [108,109]. Such an organic acid-stimulated glutamate export out of liver cells adds another site of control of hepatic ammonia metabolism [108,109].…”

Section: Intercellular Glutamine Cyclingmentioning

confidence: 98%

“…Such an organic acid-stimulated glutamate export out of liver cells adds another site of control of hepatic ammonia metabolism [108,109]. Whereas vascular glutamate is taken up almost exclusively by perivenous scavenger cells [21,24], it is not yet clear whether glutamate exported under the influence of oxoisocaproate and benzoate also comes from periportal cells.…”

Section: Intercellular Glutamine Cyclingmentioning

confidence: 99%

Nitrogen metabolism in liver: structural and functional organization and physiological relevance

Häussinger

1990

Biochemical Journal

315

166

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INTRODUCTIONThe liver was identified early in the fundamental work of Hans Krebs [1,2] as having a particular role in urea and glutamine metabolism. At the acinar level, these pathways are embedded into a sophisticated structural and functional organization with metabolic interactions between different hepatocyte populations. This provided a new insight into the role of the liver in maintaining ammoniat and bicarbonate homeostasis under physiological and pathological conditions.The functional units of the liver are the so-called acini [3,4], which extend from the terminal portal venule along the sinusoids to the terminal hepatic venule. Periportal hepatocytes (near the sinusoidal inflow) can be distinguished from more downstream located perivenous hepatocytes (near the sinusoidal outflow), whereas the borderline between the periportal and the perivenous compartment is not defined in general anatomical terms. The definition used here is a comparative-functional one, and thus will depend on the metabolic pathways under consideration. This is because periportal and perivenous hepatocytes differ in their complement of enzymes and their metabolic functions ('functional hepatocyte heterogeneity' or 'metabolic zonation'). The size of a periportal or perivenous 'metabolic zone' is pathway-specific. Thus, for example, a periportal compartment exhibiting a certain metabolic function can overlap with a perivenous compartment which is characterized by another pathway. Several reviews have appeared on this subject [5][6][7][8][9][10][11], and the subacinar localization of various metabolic pathways is summarized in Table 1. This article focuses on the functional significance of liver parenchymal cell heterogeneity in nitrogen metabolism.

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“…tion event because intracellular calcium concentration of isolated hepatocytes increased quickly and markedly after exposure to 2,5-AM (Rawson et al, 2003). Hepatocytes secrete numerous compounds that serve as signaling molecule, including glutamate (Häussinger et al, 1989;Remesy et al, 1997), which is known to activate some vagal afferents (Niijima, 2000).…”

Section: Signal To Brain Feeding Centersmentioning

confidence: 99%

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

Allen

Bradford

Oba

2009

Journal of Animal Science

512

407

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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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Benzoate stimulates glutamate release from perfused rat liver

Cited by 9 publications

References 28 publications

OAT2 catalyses efflux of glutamate and uptake of orotic acid

OAT2 catalyses efflux of glutamate and uptake of orotic acid

Nitrogen metabolism in liver: structural and functional organization and physiological relevance

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

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