Metabolic zonation of the liver: Regulation and implications for liver function

Gebhardt, Rolf

doi:10.1016/0163-7258(92)90055-5

Cited by 517 publications

(400 citation statements)

References 621 publications

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“…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.…”

mentioning

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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“…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.…”

mentioning

confidence: 99%

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

et al. 1998

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“…21 It is evident that the oxygen gradient is a main driver of liver zonation. [26][27][28] Liver zonation is an evolutionary optimised segregation of the broad liver functions into spatial, temporarily defined, highly specialized zones. This enables hepatocytes of their respective zone to fully concentrate their cellular and molecular capacities onto the single function to which they are dedicated.…”

Section: Human Liver Architecturementioning

confidence: 99%

Chip-based liver equivalents for toxicity testing – organotypicalness versus cost-efficient high throughput

2013

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Drug-induced liver toxicity dominates the reasons for pharmaceutical product ban, withdrawal or nonapproval since the thalidomide disaster in the late-1950s. Hopes to finally solve the liver toxicity test dilemma have recently risen to a historic level based on the latest progress in human microfluidic tissue culture devices. Chip-based human liver equivalents are envisaged to identify liver toxic agents regularly undiscovered by current test procedures at industrial throughput. In this review, we focus on advanced microfluidic microscale liver equivalents, appraising them against the level of architectural and, consequently, functional identity with their human counterpart in vivo. We emphasise the inherent relationship between human liver architecture and its drug-induced injury. Furthermore, we plot the current socio-economic drug development environment against the possible value such systems may add.Finally, we try to sketch a forecast for translational innovations in the field.

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“…Alternatively, differIt is known that liver-specific gene expression is position dependent along liver plates. [55][56][57][58] It is also known that albumin ences in the cell lines also may be explained by the genetic instability of the SV40 T-antigen-transformed hepatocytes is not expressed equally by all hepatocytes, with expression being generally high in mid-acinar cells and low in all other in vivo and in vitro. The instability could lead to variations in gene expression that alone, or through an unavoidable parenchymal cells.…”

Section: Aidmentioning

confidence: 99%

Cell lines with heterogeneous phenotypes result from a single isolation of albumin-sv40 T-antigen transgenic rat hepatocytes

et al. 1997

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Transgenic animals and the cell lines derived from these Several immortalized cell lines were established from transgenic animals have become important tools in the study the livers of two transgenic rats expressing the simian of many diseases. [1][2][3][4][5][6] The construction of transgenic animals virus protein large T antigen under the control of the involves the introduction of a specific gene into the germ line albumin promoter. Hepatocytes from transgenic rats of an animal, resulting in one or more copies of the transgene were isolated by a two-step perfusion procedure from a in every cell of the adult animal. Expression of the gene may normal-appearing liver and from a liver that contained be regulated through the use of tissue-specific promoters, a single neoplasm. Cells were also isolated from the diswhich allow the gene to be expressed in specific tissues and sociated liver neoplasm. After 5 weeks in culture, cell not to be active in other tissues. colonies were isolated and subcloned as individual cellIn our laboratory, we have developed a line of transgenic lines. Electron microscopy revealed that all cell lines rats to study the process of hepatocellular carcinogenesis in had a high nuclear-to-cytoplasmic ratio compared with this species. 7 These animals were produced by microinjection normal hepatocytes. The cytoplasm contained numerinto fertilized rat eggs of the DNA coding sequence for the ous organelles, including smooth and rough endoplassimian virus large T antigen (SV40) under the control of the mic reticulum, Golgi, mitochondria, peroxisomes, and 5 regulatory region of the mouse albumin gene. 8 These aniannulate lamellae. However, the lines exhibited a varimals develop hepatocellular carcinomas, adenocarcinomas, ety of different cell morphologies. All cell lines, including and hepatoblastomas at about 3 to 5 months of age. Focal those derived from neoplastic cells, exhibited a similar lesions and nodules are observed as early as 2 months, with doubling time of 26 hours and the ability to grow in soft metastases observed in some animals later in life. By 6 to 8 agar. Northern blot analysis revealed that the cell lines months of age, the animals either die of the disease or from differentially expressed hepatocyte markers. Large T other pathological abnormalities that can be attributed to the antigen was expressed in the cultured cell lines at much expression of the transgene. 7 higher levels than was observed in transgenic hepatoThis report presents data characterizing a number of cell cytes in vivo. This suggests that the viral protein is relines derived from isolated alb-SV40 T-antigen transgenic rat quired to maintain cell viability in culture. In addition, hepatocytes. It is important to note that, although the cell the tumor suppressor proteins, p53 and Rbp105, were lines were derived from a single population of isolated hepatodetected in all cultured cell lines. In contrast, these same cytes, the established cell lines exhibit very different cellular proteins were not detected by West...

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Metabolic zonation of the liver: Regulation and implications for liver function

Cited by 517 publications

References 621 publications

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

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

Chip-based liver equivalents for toxicity testing – organotypicalness versus cost-efficient high throughput

Cell lines with heterogeneous phenotypes result from a single isolation of albumin-sv40 T-antigen transgenic rat hepatocytes

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