Autoradiographic evidence for hepatic lobular concentration gradient of bile acid derivative

Jones, A. L.; Hradek, Gary T.; Renston, Richard H.; Wong, K. Y.; Karlaganis, Georg; Paumgartner, Gustav

doi:10.1152/ajpgi.1980.238.3.g233

Cited by 62 publications

(43 citation statements)

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“…A portal-to-central lobular concentration gradient for the uptake of plasma-derived substances by liver has been demonstrated previously, specifically for galactose (33)(34)(35) and the modified bile salt cholylglycylhistamine (36). However, when looked for, no such concentration gradient has been found to exist for the uptake of any plasma-derived protein thus far studied, including insulin (37), IgA (38), and apoprotein B (39).…”

Section: Discussionmentioning

confidence: 78%

“…Zonal differences in lobules have been well documented morphologically (40,41) and also functionally (30,(42)(43)(44). Several theories have been suggested to explain these intralobular differences, including relative differences in blood oxygen level (45), hepatocyte maturity (42,46), blood flow patterns (47), and hepatocyte receptor number or affinity for plasma-derived substances, or both (33,36). A recent study using quantitative morphology has shown that the zone 1 (periportal) sinusoidal surface-to-volume ratio is greater than that of zone 3 (pericentral) sinusoids (48), thereby favoring a greater probability of interaction in zone 1 between circulating compounds and the fenestrae of the sinusoids.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Hepatic sequestration and biliary secretion of epidermal growth factor: evidence for a high-capacity uptake system.

Hilaire¹,

Hradek²,

Jones³

1983

Proc. Natl. Acad. Sci. U.S.A.

108

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Epidermal growth factor (EGF) promotes hepatocyte growth and is bound in the liver by specific receptors. We have determined hepatic uptake of EGF in intact rats after an intravenous or intraportal injection of a bolus of "RI-labeled EGF. Ninety-nine percent of the intraportal dose was taken up by the liver in 3 min, whereas only 58% of the intravenous dose appeared in the liver in 10 min. Uptake was inhibited by simultaneous treatment with an excess of unlabeled EGF. At time zero, uptake appeared to be complete. Disappearance from the liver followed first-order kinetics. Within 90 min of an intraportal injection, an average of 19% of the injected radioisotope appeared in bile, of which approximately one-fifth was shown to be immunoprecipitable with a specific anti-EGF antiserum. Light microscopic autoradiography demonstrated a very steep portal-tocentral lobular concentration gradient consistent with a high-capacity uptake system. After intraportal injection or after incubation with cultured hepatocytes, labeled EGF was shown to be bound to its hepatic receptors. The main receptor-ligand complex had a Mr of 160,000-170,000, determined by NaDodSO4/polyacrylamide gel electrophoresis.Epidermal growth factor (EGF), a single-chain polypeptide exhibiting a Mr of 6,045, is found in high concentrations in salivary and Brunner glands of humans and mice and more recently in the pituitary of goats (1-5). Although EGF has been shown to have a growth-promoting capacity in a variety of in vivo and in vitro cell systems (3,(6)(7)(8)(9)(10)(11)(12)(13)(14), its physiologic role and the mechanisms of homeostasis responsible for maintaining its plasma concentration are poorly understood. In adult rat hepatocytes in vivo or in primary culture, EGF stimulates DNA synthesis (15) and has been reported to induce hepatic hypertrophy and hyperplasia (16). In newborn rats, EGF induces thymidine incorporation into developing liver cells and enhances mitosis (15,17). EGF receptors have been found on hepatocyte membranes (18), and an EGF-receptor complex has been isolated from hepatocytes by using a glutaraldehyde/sodium borohydride crosslinking technique (19). In HT-29, A-431, PANC-1, and other cells, EGF has been found to form a spontaneous covalent crosslinkage with its receptor (20-25). Electron microscopic evaluation of isolated hepatocytes in culture demonstrates that hepatocytes have the capacity to take up EGF in vitro (26).We have investigated the role of the intact liver in EGF uptake and processing and have demonstrated: (i) significant hepatic uptake of 1"I-labeled EGF (125I-EGF); (ii) the presence of EGF in bile; (iii) the existence of an EGF-protein complex consistent with an EGF receptor; and (iv) a portal-to-central lobular concentration gradient for 125I-EGF uptake. METHODS Animals. Male Sprague-Dawley rats obtained from Charles River Breeding Laboratories, weighing 300-350 g, were fed standard Purina chow ad lib and maintained on a standard wakesleep cycle.Materials. Mouse EGF was purified from mouse submaxillary...

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Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Hepatic sequestration and biliary secretion of epidermal growth factor: evidence for a high-capacity uptake system.

Hilaire¹,

Hradek²,

Jones³

1983

Proc. Natl. Acad. Sci. U.S.A.

108

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“…17 Bile acid uptake in the adult is highest in periportal hepatocytes. [49][50][51] However, in early postnatal life, bile acid uptake by the liver is much reduced because of immaturity or absence of transporter proteins and other elements involved, 51 and no lobular gradient for bile acid uptake is observed. 22 Thus, it is unlikely that silencing of C7␣H mRNA expression is regulated solely by bile acids in early life.…”

Section: Discussionmentioning

confidence: 99%

Cholesterol 7α-hydroxylase (CYP7A): Patterns of messenger RNA expression during rat liver development

et al. 1998

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Cholesterol 7␣-hydroxylase is a rate-limiting enzyme in bile acid synthesis, a major pathway for cholesterol catabolism. It plays a crucial role in postnatal development and survival. In an adult liver, its activity and messenger RNA (mRNA) are heterogeneously distributed with concentration in the pericentral area. We defined how the pattern of cholesterol 7␣-hydroxylase mRNA evolves during rat liver development, correlated this with its total liver mRNA levels, and determined when its heterogeneous pattern of expression is established. Cholesterol 7␣-hydroxylase mRNA was undetectable in 18-day-old fetal livers by Northern blot. It was increased markedly in newborns with a homogeneous liver lobular distribution as determined by in situ hybridization. At postnatal day four, mRNA levels were markedly decreased with concomitant appearance of a lobular gradient: mRNA was detected only in a few hepatocytes located around efferent venules. At 22 days, the time of highest mRNA expression, a marked extension of the gradient towards the periportal area was observed, indicating that the increase in total liver cholesterol 7␣-hydroxylase mRNA level was a result of recruitment of hepatocytes upstream from the central vein area. By 28 days, the adult pattern was observed. Thus, expression of cholesterol 7␣-hydroxylase mRNA is tightly regulated during rat liver development, both temporally and spatially supporting its critical role in normal postnatal development.(HEPATOLOGY 1998;28:1064-1072.)Bile acids play a key role in absorption of lipids, including fat-soluble vitamins. Bile acid synthesis represents the major regulated pathway for catabolism and excretion of cholesterol in mammals. The hepatospecific enzyme cholesterol 7␣-hydroxylase (C7␣H; EC 1.14.13.17; CYP7A) catalyzes a rate-limiting step in this important process. [2][3][4] Its activity is tightly regulated in vivo by a number of different effectors acting predominantly at the transcriptional level. C7␣H is modulated by hormones, including thyroxin, glucocorticoids, and insulin 5-7 ; and by dietary factors. [8][9][10] It is regulated in a negative feedback manner by hydrophobic bile acids returning to the liver via the enterohepatic circulation. 11-13 It exhibits a diurnal rhythm, with maximum activity in the dark phase and minimum during the light phase in rats. [13][14][15] The expression of C7␣H in adult rats is tightly regulated spatially along the liver cell plate; the enzymatic activity 16 and mRNA level 17,18 are not distributed uniformly among parenchymal cells; rather, C7␣H is predominantly found in a subgroup of hepatocytes localized around the central vein.Liver cell heterogeneity is considered to be a major determinant for proper execution and regulation of most liver functions. 19,20 It reflects differentiation of hepatocytes within the liver plate, which is established during development. In most cases, it is regulated at the transcriptional level. The role of liver cell heterogeneity in the developmental regulation of bile acid synthesis is unknown....

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“…Although in principle all hepatocytes have equal uptake capacity for bile acids (19,55), the microanatomy of the liver lobule results in a lobular concentration gradient during blood flow through the liver ( 15,16,55). We have suggested that high bile acid concentrations are responsible for major downregulation of bile acid synthesis specifically in the portal area, whereas the route is hardly affected in the pericentral zone (11,12,56).…”

Section: Discussionmentioning

confidence: 99%

“…Bile acids are taken up efficiently by the periportal hepatocytes (15)(16)(17)(18)(19), thereby creating decreasing concentration gradients along the sinusoids (20). Consequently, periportal hepatocytes are exposed to a sixfold higher concentration of bile acids, as compared with pericentral cells ( 15,16). In line with this, a concentration-dependent and direct downregulation of bile acid synthesis, at the level of cholesterol 7a-hydroxylase, was found in vitro when cultured pig (21) and rat (22,23) hepatocytes were incubated with bile acids.…”

Section: Introductionmentioning

confidence: 99%

Heterogeneous expression of cholesterol 7 alpha-hydroxylase and sterol 27-hydroxylase genes in the rat liver lobulus.

Twisk¹,

Hoekman²,

Mager³

et al. 1995

J. Clin. Invest.

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We investigated the lobular localization and molecular level of expression of cholesterol 7a-hydroxylase and sterol 27-hydroxylase, two key enzymes in bile acid synthesis, in isolated periportal and pericentral hepatocytes and by in situ hybridization of rat liver. Enzyme activity, mRNA, and gene transcription of cholesterol 7c-hydroxylase were predominant in pericentral hepatocytes of control rats, being 7.9-, 9.9-, and 4.4-fold higher than in periportal hepatocytes, respectively. Similar localization was found for sterol 27-hydroxylase: 2.9-, 2.5-, and 1.7-fold higher enzyme activity, mRNA, and gene transcription, respectively, was found in pericentral hepatocytes. Interruption of the enterohepatic circulation with colestid resulted in upregulation of these parameters for both enzymes, as a consequence of stimulated gene expression mainly in the periportal zone. In contrast, mRNA levels and gene transcription of 3-hydroxy-3-methylglutaryl CoA reductase showed opposite lobular distribution. Selective periportal expression for the latter was enhanced, but remained local, after colestid treatment. In situ hybridization showed unambiguously that cholesterol 7a-hydroxylase mRNA is localized exclusively in the pericentral zone and that sterol 27-hydroxylase mRNA is expressed preferentially in the pericentral region, though less pronounced. Administration of colestid led to expression of both genes within a larger area of the liver lobulus. In conclusion, we suggest that cholesterol 7a-hydroxylase and sterol 27-hydroxylase are coordinately regulated by the bile acid gradient over the lobulus, resulting in predominant expression in the pericentral zone. Opposite lobular localization of cholesterol and bile acid synthesis provides an alternative view to interregulation of these metabolic pathways. (J. Clin. Invest. 1995Invest. . 95:1235Invest. -1243.) Key words: lobular heterogeneity * bile acid synthetic enzyme * mRNA * transcriptional activity -in situ hybridization

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Autoradiographic evidence for hepatic lobular concentration gradient of bile acid derivative

Cited by 62 publications

References 0 publications

Hepatic sequestration and biliary secretion of epidermal growth factor: evidence for a high-capacity uptake system.

Hepatic sequestration and biliary secretion of epidermal growth factor: evidence for a high-capacity uptake system.

Cholesterol 7α-hydroxylase (CYP7A): Patterns of messenger RNA expression during rat liver development

Heterogeneous expression of cholesterol 7 alpha-hydroxylase and sterol 27-hydroxylase genes in the rat liver lobulus.

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