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Details for anatomical structure: hepatocyte

EndoNet ID: ENC00249

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Synonyms

hepatocyte, parenchymal liver cell, hepatic cell, Epitheliocytus hepatis

General information

Cell of the liver parenchyme; the hepatocytes are responsible for almost all the functions of the liver; builds the blood-bile barrier

Links to other resources

Cytomer cy0011233

Larger structures

    Substructures

      Secreted hormones

      • Hormone: osteopontin

      • Hormone: complement factor B

      • Hormone: CRP

        • Great quantities of serum CRP are produced by the liver during the acute phase response. [1]
      • Hormone: IL-8

        • A proinflammatory cytokine gene program that includes C-X-C and C-C chemokines (IL-8, GRO-alpha, GRO-beta, GRO-gamma, ENA-78 and RANTES) and the cytokines TNF-alpha and M-CSF was upregulated in human hepatocytes after stimulation with IL-1a or TNF-alpha or bacterial invasion. In contrast, expression of hematopoietic/ lymphoid growth factors [2]
      • Hormone: HGF

        • Forced HGF expression by cultured human hepatocytes had a mitogenic effect. [3]
      • Hormone: VEGF-121

        • VEGF-121, VEGF-165 and VEGF-189 were detected in 14 of the 15 HCC samples and in all the corresponding non-cancerous tissue samples. [4]
      • Hormone: VEGF-189

      • Hormone: IGFBP-2

      • Hormone: IGFBP-3

      • Hormone: IGFBP-4

      • Hormone: IGFBP-1 isoform a

        • Hepatocytes have been shown to express IGFBP-1 through IGFBP-4 mRNAs and release the corresponding proteins. [5]
      • Hormone: IL-1 beta

        • Interleukin-1 (IL-1) is a proinflammatory cytokine that participates in the activation of the acute-phase plasma protein genes in hepatic cells during infection and injury. [6]

        Influenced by:

        • EGFR isoform a
          in hepatocyte
          • Induced IL-1alpha release from hepatocyte is contingent on both TNF and autocrine TGF-alpha. [7]
        • TNFR1
          in hepatocyte
          • Induced IL-1alpha release from hepatocyte is contingent on both TNF and autocrine TGF-alpha. [7]
        • TNFR2
          in hepatocyte
          • Induced IL-1alpha release from hepatocyte is contingent on both TNF and autocrine TGF-alpha. [7]
      • Hormone: IL-7

      • Hormone: TGF-beta 1

        • Cytokines from the TGF-beta family play a role in liver development, by induction of Vg1. [8]
        • In the normal adult liver,sinusoidal endothelial cells and Kupffer cells have relatively high, constitutive levels of mRNA for TGF-beta1 and lower but detectable levels for TGF-beta2 and TGF-beta3, whereas stellate cells express very little TGF-beta in the normal state,and hepatocytes essentially none. [9]
      • Hormone: APOA1

      • Hormone: APOE

      • Hormone: apolipoprotein A-II

      • Hormone: APOC1

      • Hormone: IL-15

      • Hormone: APOC2

      • Hormone: APOC3

      • Hormone: APOA4

      • Hormone: hepcidin

        • Studies in knockout mice and cell culture assays indicate that C/EBP-alpha induces and HNF4-alpha reduces hepcidin mRNA expression. [10]
        • The physiological equilibrium of hepcidin is affected by different pathologies. Elevated hepcidin levels are associated with secondary iron overload, type IV hereditary hemochromatosis(HH) and chronic infectious or inflammatory diseases resulting in "anaemia of inflammation". Decreased hepcidin levels are observed during conditions of increased iron absorption such as hypoxia, iron deficiency anaemias and in HH (type l,ll,lll) and thalassemia. [10]

        Influenced by:

        • transferrin receptor 2
          in hepatocyte
        • IL-6R
          in hepatocyte
          • Hepcidin mRNA expression can be induced in response to the inflammatory cytokine IL-6 (Interleukin-6). [10]
      • Hormone: apo B-100

        Influenced by:

        • LDL-R
          in hepatocyte
          • Apolipoprotein B (apoB) is required for the hepatic assembly and secretion of very low density lipoprotein (VLDL). The LDL receptor (LDLR) promotes post-translational degradation of apoB and thereby reduces VLDL particle secretion. [11]
          • LDLR directs apoB to degradation in a post-ER compartment. Furthermore, the reuptake mechanism of degradation occurs via internalization of apoB through a constitutive endocytic pathway and apoE through a ligand-dependent pathway. [11]
        • Sterol O-acyltransferase 1
          in hepatocyte
          • Cholesteryl esters play an important role in regulating the assembly and secretion of apoB-containing lipoproteins. [12]
        • PPAR-alpha
          in hepatocyte
          • The peroxisome proliferator-activated receptor (PPAR) agonist WY 14,643 increased the secretion of apolipoprotein (apo) B-100, but not that of apoB-48, and decreased triglyceride biosynthesis and secretion from primary rat hepatocytes. These effects resulted in decreased secretion of apoB-100-very low density lipoprotein (VLDL) and an increased secretion of apoB-100 on low density lipoproteins/intermediate density lipoproteins. [13]
        • autocrine motility factor receptor
          in hepatocyte
          • Tumor autocrine motility factor receptor, also known as gp78, is an endoplasmic reticulum (ER)-associated E3. This E3 is involved in the ER-associated degradation of nascent apoB. [14]
      • Hormone: apolipoprotein A-related gene C

      • Hormone: adipsin

      • Hormone: chondromodulin 2

      • Hormone: sNRP1

      • Hormone: APOA1(1-242)

      • Hormone: erythropoietin

      • Hormone: cardiotrophin 1

        • CT-1 is up-regulated during liver regeneration and exerts potent antiapoptotic effects on hepatocytic cells. [15]
      • Hormone: RANTES

      • Hormone: GROalpha

      • Hormone: TNF-alpha

      • Hormone: M-CSF

      • Hormone: GRObeta

      • Hormone: GROgamma

      • Hormone: SCF

      • Hormone: FGF-19

        Influenced by:

        • bile acid receptor
          in hepatocyte
          • FXR induces expression of FGF-19 in primary cultures of human hepatocytes. [17]
      • Hormone: VEGF-165

        • VEGF protein was strongly expressed in both well-differentiated HCC cells and non-cancerous hepatocytes. [4]
      • Hormone: APOA5

        • APOA5 is expressed in human hepatoma HepG2 cells with levels comparable with human primary hepatocytes. [18]

        Influenced by:

        • THRA1
          in hepatocyte
          • Treatment with T3 significantly increased APOA5 mRNA levels at 6 h, and a 2-fold induction was achieved after 24 h of T3 addition. [18]
        • THRB1
          in hepatocyte
          • T3-activated TRbeta1 enhanced the activity of APOA5 DR4-driven promoter constructs. [18]
          • Treatment with T3 significantly increased APOA5 mRNA levels at 6 h, and a 2-fold induction was achieved after 24 h of T3 addition. [18]
        • bile acid receptor
          in hepatocyte
          • Bile acids induce human apoAV promoter activity via FXR. [19]
        • LXR-alpha
          in hepatocyte
          • Co-transfection of SREBP-1c downregulates APOA5 promoter activity. [20]
        • PPAR-alpha
          in hepatocyte
          • Overexpression of PPAR-alpha enhances the activity of the human ApoA5 gene promoter. [19]
      • Hormone: angiotensinogen

        • Freshly isolated human hepatocytes expressed higher levels of angiotensinogen and lower levels of renin and ACE compared with activated HSCs. [21]
        • Hepatocytes are the main source of angiotensinogen in the human liver. [21]

        Influenced by:

        • angiotensin II type 1 receptor
          in hepatocyte
          • Angiotensin II stimulates the hepatic synthesis and secretion of angiotensinogen, the substrate of renin. This effect is mainly related to a transient inhibition of adenylylcyclase. [22]
      • Hormone: renin

      • Hormone: cholesterol

        Influenced by:

        • LXR-alpha
          in hepatocyte
          • Liver X receptor (LXR) alpha and beta are the nuclear receptors responsible for regulation of cholesterol metabolism. In physiological conditions, high intracellular cholesterol levels cause increased synthesis of oxysterols, which activate LXR, thus triggering a transcriptional response for cholesterol secretion and catabolism. [23]
        • LXR-beta
          in hepatocyte
          • Liver X receptor (LXR) alpha and beta are the nuclear receptors responsible for regulation of cholesterol metabolism. In physiological conditions, high intracellular cholesterol levels cause increased synthesis of oxysterols, which activate LXR, thus triggering a transcriptional response for cholesterol secretion and catabolism. [23]
      • Hormone: CBG

        • CBG is secreted from hepatocytes as a 383-amino-acid peptide after cleavage of a 22-amino-acid signal peptide and circulates at concentrations ranging from 30 to 52 pg/ml. [24]

        Influenced by:

        • glucocorticoid receptor
          in hepatocyte
          • Levels of CBG are decreased by glucocorticoids. The effects of glucocorticoids on CBG synthesis are glucocorticoid receptor dependent. [24]
        • ER-alpha
          in liver
          • Our results show that o,p′-DDD (mitotane) increases CBG expression and secretion by an ERα-dependent mechanism. [25]
      • Hormone: IGF-1

        Influenced by:

        • glucocorticoid receptor
          in hepatocyte
          • IGF-1 is synthesized in hepatocytes upon GH stimulation. [26]
      • Hormone: apo B-48

        Influenced by:

        • LDL-R
          in hepatocyte
          • Apolipoprotein B (apoB) is required for the hepatic assembly and secretion of very low density lipoprotein (VLDL). The LDL receptor (LDLR) promotes post-translational degradation of apoB and thereby reduces VLDL particle secretion. [11]
          • LDLR directs apoB to degradation in a post-ER compartment. Furthermore, the reuptake mechanism of degradation occurs via internalization of apoB through a constitutive endocytic pathway and apoE through a ligand-dependent pathway. [11]
        • Sterol O-acyltransferase 1
          in hepatocyte
          • Cholesteryl esters play an important role in regulating the assembly and secretion of apoB-containing lipoproteins. [12]
      • Hormone: Dynamin-2

      • Hormone: TGF-alpha

        Influenced by:

        • TNFR1
          in hepatocyte
          • In primary hepatocyte cultures, TNF not only potentiates growth factor-stimulated proliferation, but acts as a mitogen itself through the induced release of autocrine transforming growth factor- (TGF-) and its activation of serine-threonine protein kinase B (PKB)/Akt and extracellular signal-regulated kinase (ERK). [7]
        • TNFR2
          in hepatocyte
          • In primary hepatocyte cultures, TNF not only potentiates growth factor-stimulated proliferation, but acts as a mitogen itself through the induced release of autocrine transforming growth factor- (TGF-) and its activation of serine-threonine protein kinase B (PKB)/Akt and extracellular signal-regulated kinase (ERK). [7]
      • Hormone: IL-1 alpha

        Influenced by:

        • EGFR isoform a
          in hepatocyte
          • Induced IL-1alpha release from hepatocyte is contingent on both TNF and autocrine TGF-alpha. [7]
        • TNFR1
          in hepatocyte
          • Induced IL-1alpha release from hepatocyte is contingent on both TNF and autocrine TGF-alpha. [7]
        • TNFR2
          in hepatocyte
          • Induced IL-1alpha release from hepatocyte is contingent on both TNF and autocrine TGF-alpha. [7]
      • Hormone: IL-1RA

        Influenced by:

        • TNFR1
          in hepatocyte
          • TNF induces the release of IL-1ra. [7]
        • TNFR2
          in hepatocyte
          • TNF induces the release of IL-1ra. [7]
      • Hormone: fetuin-A

        • Ahsg (fetuin-A) is a 55-59kDa phosphorylated glycoprotein synthesized in the adult predominantly by hepatocytes, from which it enters the circulation. [27]
      • Hormone: fibrinogen

        Influenced by:

        • IL-6R
          in hepatocyte
          • We determined the role of IL-6-receptor-gp130-Stat3 signaling in IL-6 activation of the γFBG promoter in liver and lung epithelial cells. [28]

      Receptors

      • Receptor: LXR-beta

        Influences:

        • cholesterol
          • Liver X receptor (LXR) alpha and beta are the nuclear receptors responsible for regulation of cholesterol metabolism. In physiological conditions, high intracellular cholesterol levels cause increased synthesis of oxysterols, which activate LXR, thus triggering a transcriptional response for cholesterol secretion and catabolism. [23]
      • Receptor: H1

      • Receptor: H2

      • Receptor: histamine H4 receptor

      • Receptor: ferroportin-1

      • Receptor: transferrin receptor 2

        Influences:

        • hepcidin
      • Receptor: IL-6R

        Influences:

        • hepcidin
          • Hepcidin mRNA expression can be induced in response to the inflammatory cytokine IL-6 (Interleukin-6). [10]
        • SAA1
        • fibrinogen
          • We determined the role of IL-6-receptor-gp130-Stat3 signaling in IL-6 activation of the γFBG promoter in liver and lung epithelial cells. [28]
      • Receptor: transferrin receptor 1

        Induced phenotype:

        • regulation of iron ion transmembrane transport
          • Absorbed iron is bound to circulating transferrin and passes initially through the portal system of the liver, which is the major site of iron storage. Hepatocytes take up transferrin-bound iron via the classical transferrin receptor (TfR1) but likely in greater amounts by the homologous protein, TfR2. [29]
      • Receptor: RXR-alpha

      • Receptor: SR-BI

      • Receptor: BMP receptor type II

      • Receptor: hepatocyte growth factor receptor

      • Receptor: CAR

      • Receptor: glucocorticoid receptor

        Influences:

        • IGF-1
          • IGF-1 is synthesized in hepatocytes upon GH stimulation. [26]
        • CBG
          • Levels of CBG are decreased by glucocorticoids. The effects of glucocorticoids on CBG synthesis are glucocorticoid receptor dependent. [24]
      • Receptor: VDR

        • VDR protein and mRNA were identified in primary human hepatocytes. [30]

        Induced phenotype:

        • negative regulation of bile acid biosynthetic process
          • Lithocholic acid acetate or 1α, 25-dihydroxy-vitamin D3-activated VDR strongly inhibites cholesterol 7α-hydroxylase mRNA expression and reduces bile acid synthesis in human hepatocytes. [30]
      • Receptor: PPAR-alpha

        • PPARα is expressed at high levels in organs that carry out significant catabolism of fatty acids such as the brown adipose tissue, liver, heart, kidney, and intestine [31]

        Influences:

        • APOA5
          • Overexpression of PPAR-alpha enhances the activity of the human ApoA5 gene promoter. [19]
        • apo B-100
          • The peroxisome proliferator-activated receptor (PPAR) agonist WY 14,643 increased the secretion of apolipoprotein (apo) B-100, but not that of apoB-48, and decreased triglyceride biosynthesis and secretion from primary rat hepatocytes. These effects resulted in decreased secretion of apoB-100-very low density lipoprotein (VLDL) and an increased secretion of apoB-100 on low density lipoproteins/intermediate density lipoproteins. [13]
      • Receptor: TNFR1

        Induced phenotype:

        • antagonizing IL-1alpha/beta ligand activity
          • TNF induces the release of IL-1ra, which antagonizes IL-1alpha/beta ligand activity. [7]
        • positive regulation of apoptosis
          • TNF-induced autocrine TGF- and IL-1alpha/beta contribute to multiple intracellular signaling pathways that govern hepatocyte apoptosis. [7]
          • Autocrine IL-1alpha/beta regulates proapoptotic signaling through JNK and p38 pathways. [7]
        • positive regulation of cell proliferation
          • TNF-induced autocrine TGF- and IL-1alpha/beta contribute to multiple intracellular signaling pathways that govern hepatocyte proliferation. [7]
          • 101 Autocrine TGF-alpha regulates pro-proliferative/antiapoptotic signaling through the ERK and, in the absence of Adenoviral infection, Akt pathways. 2452 [32]

        Influences:

        • TGF-alpha
          • In primary hepatocyte cultures, TNF not only potentiates growth factor-stimulated proliferation, but acts as a mitogen itself through the induced release of autocrine transforming growth factor- (TGF-) and its activation of serine-threonine protein kinase B (PKB)/Akt and extracellular signal-regulated kinase (ERK). [7]
        • IL-1 alpha
          • Induced IL-1alpha release from hepatocyte is contingent on both TNF and autocrine TGF-alpha. [7]
        • IL-1 beta
          • Induced IL-1alpha release from hepatocyte is contingent on both TNF and autocrine TGF-alpha. [7]
        • IL-1RA
          • TNF induces the release of IL-1ra. [7]
      • Receptor: fas receptor

      • Receptor: EGFR isoform a

        Influences:

        • IL-1 alpha
          • Induced IL-1alpha release from hepatocyte is contingent on both TNF and autocrine TGF-alpha. [7]
        • IL-1 beta
          • Induced IL-1alpha release from hepatocyte is contingent on both TNF and autocrine TGF-alpha. [7]
      • Receptor: RXR-beta

      • Receptor: LXR-alpha

        Influences:

        • APOA5
          • Co-transfection of SREBP-1c downregulates APOA5 promoter activity. [20]
        • cholesterol
          • Liver X receptor (LXR) alpha and beta are the nuclear receptors responsible for regulation of cholesterol metabolism. In physiological conditions, high intracellular cholesterol levels cause increased synthesis of oxysterols, which activate LXR, thus triggering a transcriptional response for cholesterol secretion and catabolism. [23]
      • Receptor: growth hormone receptor

      • Receptor: bile acid receptor

        Influences:

        • FGF-19
          • FXR induces expression of FGF-19 in primary cultures of human hepatocytes. [17]
        • APOA5
          • Bile acids induce human apoAV promoter activity via FXR. [19]
        • fetuin-B
          • FXR agonists induce fetuin-B expression in human primary hepatocytes. [33]
      • Receptor: PXR

      • Receptor: FGFR-4

      • Receptor: LRP5

      • Receptor: THRB1

        Influences:

        • APOA5
          • T3-activated TRbeta1 enhanced the activity of APOA5 DR4-driven promoter constructs. [18]
          • Treatment with T3 significantly increased APOA5 mRNA levels at 6 h, and a 2-fold induction was achieved after 24 h of T3 addition. [18]
      • Receptor: THRA1

        Influences:

        • APOA5
          • Treatment with T3 significantly increased APOA5 mRNA levels at 6 h, and a 2-fold induction was achieved after 24 h of T3 addition. [18]
      • Receptor: LDL-R

        Influences:

        • apo B-48
          • Apolipoprotein B (apoB) is required for the hepatic assembly and secretion of very low density lipoprotein (VLDL). The LDL receptor (LDLR) promotes post-translational degradation of apoB and thereby reduces VLDL particle secretion. [11]
          • LDLR directs apoB to degradation in a post-ER compartment. Furthermore, the reuptake mechanism of degradation occurs via internalization of apoB through a constitutive endocytic pathway and apoE through a ligand-dependent pathway. [11]
        • apo B-100
          • Apolipoprotein B (apoB) is required for the hepatic assembly and secretion of very low density lipoprotein (VLDL). The LDL receptor (LDLR) promotes post-translational degradation of apoB and thereby reduces VLDL particle secretion. [11]
          • LDLR directs apoB to degradation in a post-ER compartment. Furthermore, the reuptake mechanism of degradation occurs via internalization of apoB through a constitutive endocytic pathway and apoE through a ligand-dependent pathway. [11]
      • Receptor: angiotensin receptor 2

      • Receptor: angiotensin II type 1 receptor

        Influences:

        • angiotensinogen
          • Angiotensin II stimulates the hepatic synthesis and secretion of angiotensinogen, the substrate of renin. This effect is mainly related to a transient inhibition of adenylylcyclase. [22]
      • Receptor: VPAC1

        Induced phenotype:

        • regulation of cell proliferation
          • The fact that VIP exerts a mitogenic action on rat hepatocytes strongly suggests that PACAP could be also involved in the control of liver cell proliferation via stimulation of adenylate cyclase. [34]
      • Receptor: GL-R

        Induced phenotype:

        • glycogenolysis
          • Glucagon stimulates glycogenolysis in liver, resulting in elevation of plasma glucose. [35]
        • gluconeogenesis
          • Glucagon stimulates gluconeogenesis in liver, resulting in elevation of plasma glucose. [35]
        • maintainence of serum glucose concentration
          • Glucagon has a critical role in maintaining serum glucose concentration. [35]
      • Receptor: V1a

      • Receptor: Sterol O-acyltransferase 1

        Influences:

        • apo B-100
          • Cholesteryl esters play an important role in regulating the assembly and secretion of apoB-containing lipoproteins. [12]
        • apo B-48
          • Cholesteryl esters play an important role in regulating the assembly and secretion of apoB-containing lipoproteins. [12]
      • Receptor: autocrine motility factor receptor

        Influences:

        • apo B-100
          • Tumor autocrine motility factor receptor, also known as gp78, is an endoplasmic reticulum (ER)-associated E3. This E3 is involved in the ER-associated degradation of nascent apoB. [14]
      • Receptor: TNFR2

        Induced phenotype:

        • antagonizing IL-1alpha/beta ligand activity
          • TNF induces the release of IL-1ra, which antagonizes IL-1alpha/beta ligand activity. [7]
        • positive regulation of cell proliferation
          • TNF-induced autocrine TGF- and IL-1alpha/beta contribute to multiple intracellular signaling pathways that govern hepatocyte proliferation. [7]
          • Autocrine TGF-alpha regulates pro-proliferative/antiapoptotic signaling through the ERK and, in the absence of Adenoviral infection, Akt pathways. [32]
        • positive regulation of apoptosis
          • TNF-induced autocrine TGF- and IL-1alpha/beta contribute to multiple intracellular signaling pathways that govern hepatocyte apoptosis. [7]
          • Autocrine IL-1alpha/beta regulates proapoptotic signaling through JNK and p38 pathways. [7]

        Influences:

        • TGF-alpha
          • In primary hepatocyte cultures, TNF not only potentiates growth factor-stimulated proliferation, but acts as a mitogen itself through the induced release of autocrine transforming growth factor- (TGF-) and its activation of serine-threonine protein kinase B (PKB)/Akt and extracellular signal-regulated kinase (ERK). [7]
        • IL-1 beta
          • Induced IL-1alpha release from hepatocyte is contingent on both TNF and autocrine TGF-alpha. [7]
        • IL-1 alpha
          • Induced IL-1alpha release from hepatocyte is contingent on both TNF and autocrine TGF-alpha. [7]
        • IL-1RA
          • TNF induces the release of IL-1ra. [7]
      • Receptor: PLXNB1

      • Receptor: leptin receptor

        Induced phenotype:

        • negative regulation of insulin receptor signaling pathway
          • Exposure of hepatic cells to leptin, at concentrations comparable with those present in obese individuals, caused attenuation of several insulin-induced activities, including tyrosine phosphorylation of the insulin receptor substrate-1 (IRS-1), association of the adapter molecule growth factor receptor-bound protein 2 with IRS-1, and down-regulation of gluconeogenesis. In contrast, leptin increased the activity of IRS-1-associated phosphatidylinositol 3-kinase. These in vitro studies raise the possibility that leptin modulates insulin activities in obese individuals. [36]
      • Receptor: PRLR

        Induced phenotype:

        • increase in glycogen phosphorylase-a activation
          • PRL at physiological concentrations produced a 4-fold increase in glycogen phosphorylase-a activation in isolated hepatocytes. [37]
        • positive regulation of cell proliferation
          • PRL plays an important role in the turnover of hepatocytes. There was a striking increase in the number of mitotic figures in livers of transgenic mice expressing hGH, which binds equally well to PRL and GH receptors. [38]
      Reference