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Le Funzioni dei Colangiociti e delle Cellule Endoteliali.
D. Alvaro, Dip. Med. Clinica, UOC Gastroenterologia,
Univ. “La Sapienza”, Polo PontinoPalermo, 31 Maggio 2008.
Circeo
Immunology
Secretion/absorption
Target of damage in cholangiophaties
CholangiocytesCholangiocytes
Proliferation
The Biliary Tree: Structural and Functional Heterogeneity of different segments…
The Biliary Tree: Structural and Functional Heterogeneity of different segments…
The Biliary Tree: Structural and FunctionalHeterogeneity of different segments…
THE BILIARY TREE IN THE ADULT
Cholangiocytes Ductal Bile
RAT Functional Heterogeneity
Calcium Dependent FunctionSmall Cholangiocytes
ReceptorsExpressedon SmallSignal via
Ca2+
cAMP Dependent Secretion Large Cholangiocytes
RAT Functional Heterogeneity
Only expressed by Large
Ca++
Immunology
Secretion/absorption
Target of damage in cholangiophaties
CholangiocytesCholangiocytes
Proliferation
ANIT
TLCA-feeding, CCl4, partial hepatectomy, L-proline,…
Bile Duct LigationCHOLANGIOCYTE PROLIFERATIONIN EXPERIMENTAL CONDITIONS
Partial Hepatectomy)
Proliferating
Cholangiocytes
Proliferating
Cholangiocytes
REGULATION OF CHOLANGIOCYTE PROLIFERATION.
Proliferating
Reactive Cholangiocytes
Hormones/NeuropeptidesSomatostatin, PTHrP, Acetylcholine, Norepinephrine,
Dopamine, Estrogens, Gastrin, Secretin, Insulin,CCK,Serotonin, opioids, prolactin, T3, Hystamine
Growth Factors HGF, NGF, IGF1, PDGF,VEGF, EGF, bFGF, TGFα,TGFβ1-2, KGF
CytokinesIL6, CINC, IL1α, TNFα,IFN-γ
Vasoactive agentsNO, ET1, PGE2, PGF2
Heterogeneity of Cholangiocyte Proliferation
Obstructive Cholestasis
CCL4
Heterogeneity of Cholangiocyte Proliferation
Partial Hepatectomy
Proliferating
Cholangiocytes
Proliferating
Cholangiocytes
ViralChronic Liver
DiseaseAlcoholic Liver
Disease
Cholangiophaties
Non Alcoholic Fatty Liver Disease,Hemocromatosis, Regeneration after submassive necrosis
CHOLANGIOCYTE PROLIFERATIONIN HUMAN PATHOLOGY
Heterogeneity of Cholangiocyte Damage in Cholangiopathies.
PBC
PSC
Heterogeneity of Cholangiocyte Damage in Cholangiopathies.
ADPKD
The Significance of CHOLANGIOCYTE PROLIFERATION in Cholestatic Liver Diseases
Chronic Cholestatic Liver Diseases(PBC, PSC,……..)
↓Cholangiocyte/duct DAMAGE
↓Cholangiocyte Proliferation
↓Repair/compensation for the anatomical
and functional loss of injured ducts
Proliferation/Apoptosis balance in the progressive stages of PBC.
0
5
10
15
20
25
30
PBC I PBC II PBC III PBC IV
(Alvaro D….Gaudio E. et al.J. of Hepatology 2004)
(*= p<0.01; n= 8)
Proliferation/Apoptosis*
**
Ductopenia
Proliferation Apoptosis
stages
Proliferation/Apoptosis balance in the progressive stages of PBC.
*
**
Ductopenia
Proliferation Apoptosis
stages
WORKING HYPOTHESIS !
SUSTAINING CHOLANGIOCYTE PROLIFERATION COULD DELAY THE EVOLUTION OF PBC TOWARD DUCTOPENIA.
SERMs ?
Effects of SERMs on HuH-28 Proliferation
-60
-40
-20
0
20
40
60
80
without serum
serumERα selective agonist
PTT17β-estradiol
ERβ selective agonistDPN
ERα selective antagonist
MPP
ERα partial agonistERβ full antagonist
R,R-THC
H3-
Thim
idin
e in
corp
orat
ion
(% c
hang
e vs
con
trols
)
n= 10, *=p< 0.01 vs controls
%
**
**
*
*
*
Effects of SERMs on HuH-28 Proliferation
without serum
ERα selective antagonist
MPP
*
*
*
*
ERα positivelyERβ negatively
affect cholangiocyte (HuH-29 cells)
proliferation!
Ongoing pilot clinical trials…SERMs
Normal Liver PBC stage II PBC stage IV
IGF1
IGF1-R
Treatment of Established Cirrhosis with SV40 VectorsEncoding Insulin-Like Growth Factor I.
Sobrevals L. et al. AASLD 2007
Casp
ase
3 ac
tivity
(fold
incr
ease
)
Basa
l
GLC
DA
Exe
ndin
-4 +
G
LCD
A
Exe
ndin
-4
*
Exendin-4 prevents GLCDA-inducedincrease in caspase 3 activity
0
0,5
1
1,5
2
2,5
3
3,5
4
4,5
*: p < 0.05
CYTOPROTECTIVE EFFECTS OF EXENDIN-4, A GLP-1
RECEPTOR AGONIST, ON THE BILIARY EPITHELIUM
M. Marzioni et al. EASL 2008.
Casp
ase
3 ac
tivity
(fold
incr
ease
)
Basa
l
GLC
DA
Exe
ndin
-4 +
G
LCD
A
Exe
ndin
-4
*
Exendin-4 prevents GLCDA-inducedincrease in caspase 3 activity
0
0,5
1
1,5
2
2,5
3
3,5
4
4,5
*: p < 0.05
Atresia dotti biliari S. e M. di AlagilleS. e M. di CaroliFibrosi Congenita M. Policistica
Duttopenia Idiopatica dell’adultoSarcoidosi
Fibrosi CisticaDeficit α-1 antitripsinaDeficit Acil-coA ossidasi
Iniezione intraepatica di:Agenti chemioembolizzanti
EtanoloFormalina
Lesioni Iatrogene
Cirrosi BiliareColangite SclerosanteColangite Autoimmune
GVHDAR
BatteriVirus
ProtozoiParassitiFunghi
IDIOPATICHE
GENESI VASCOLARE
IMMUNO-MEDIATE
INFETTIVE
ColangiocarcinomaDuttopenia associata a:
M. HodgkinIstiocitosi X
NEOPLASTICHE
Amoxicillina-ClavulanicoClorpromazina
EritromicinaCarbamazepina
Trimetropim-sulfametossazolo
ecc.
DA FARMACI
ACQUISITECONGENITE/ANOMALO SVILUPPO/EREDITARIE
LE COLANGIOPATIE
Atresia dotti biliari S. e M. di AlagilleS. e M. di CaroliFibrosi Congenita M. Policistica
Duttopenia Idiopatica dell’adultoSarcoidosi
Fibrosi CisticaDeficit α-1 antitripsinaDeficit Acil-coA ossidasi
Iniezione intraepatica di:Agenti chemioembolizzanti
EtanoloFormalina
Lesioni Iatrogene
Cirrosi BiliareColangite SclerosanteColangite Autoimmune
GVHDAR
BatteriVirus
ProtozoiParassitiFunghi
IDIOPATICHE
GENESI VASCOLARE
IMMUNO-MEDIATE
INFETTIVE
ColangiocarcinomaDuttopenia associata a:
M. HodgkinIstiocitosi X
NEOPLASTICHE
Amoxicillina-ClavulanicoClorpromazina
EritromicinaCarbamazepina
Trimetropim-sulfametossazolo
ecc.
DA FARMACI
ACQUISITECONGENITE/ANOMALO SVILUPPO/EREDITARIE
LE COLANGIOPATIE
Modulazione della Proliferazione Colangiociticome potenziale strategia terapetica:
Inibire Proliferazione → ADPKD, Colangio-KSostenere Proliferazione→ Sindromi duttopeniche
Proliferating
Cholangiocytes
Proliferating
Cholangiocytes
ViralChronic Liver
DiseaseAlcoholic Liver
Disease
Cholangiophaties
Non Alcoholic Fatty Liver Disease,Hemocromatosis, Regeneration after submassive necrosis
CHOLANGIOCYTE PROLIFERATIONIN HUMAN PATHOLOGY
Proliferating
Cholangiocytes
Proliferating
Cholangiocytes
ViralChronic Liver
DiseaseAlcoholic Liver
Disease
Cholangiophaties
Non Alcoholic Fatty Liver Disease,Hemocromatosis, Regeneration after submassive necrosis
ViralChronic Liver
DiseaseAlcoholic Liver
Disease
Non Alcoholic Fatty Liver Disease
Cholangiophaties, Hemocromatosis, Regeneration after submassive necrosis
Ductular Reaction
Chronic HCV
Proliferation of Canals of Hering and DuctulesTHE DUCTULAR REACTION
Ductular Reaction
Popper H. Ductular reaction in the liver in hepatic injury.
J Mt Sinai Hosp 1957;24:551–556.
ViralChronic Liver
DiseaseAlcoholic Liver
Disease
Non Alcoholic Fatty Liver Disease
Cholangiophaties, Hemocromatosis, Regeneration after submassive necrosis
Ductular Reaction
Chronic HCV
Proliferation of Canals of Hering and DuctulesTHE DUCTULAR REACTION
Ductular Reaction
Popper H. Ductular reaction in the liver in hepatic injury.
J Mt Sinai Hosp 1957;24:551–556.
“ductular reaction”identify the expanded population of epithelial cells
at the interface of the biliary tree and the hepatocytes, and which refers to proliferation of
pre-existing ductules, progenitor cell activation and appearance of intermediate hepatocytes.
THE DUCTULAR REACTIONThe different types of “ductular reaction,”
Type 1: “typical” cholang. proliferation confined to portal spaces(obstructive cholestasis, extrahepatic biliary atresia, early phases of chronic cholestatic liverdiseases in association with “atypical proliferation.”).
Type II: “atypical” .. irregular proliferation of intrahepatic bileducts sprouting into periportal and parenchymal regions(“biliary piecemeal necrosis”, chronic cholestatic liver diseases)
Type III: massive proliferation of hepatic progenitor cells, in liverwith submassive hepatic necrosis !
Type IV: ductular hyperplasia or “oval cell” proliferation early stages of carcinogenesis (caused by ethionine, acetylaminofluorene,furan)
Ductular Reaction
Popper H. Ductular reaction in the liver in hepatic injury.
J Mt Sinai Hosp 1957;24:551–556.
Proliferation of Canals of Hering and DuctulesTHE DUCTULAR REACTION
Ductular Reaction
Popper H. Ductular reaction in the liver in hepatic injury.
J Mt Sinai Hosp 1957;24:551–556.
Proliferation of Canals of Hering and DuctulesTHE DUCTULAR REACTION
The activated stem cell compartment in the
injured liver !
Cholangiocytes Hepatocytes
Reactive ductules Intermediatehepatocytes
HepaticProgenitor cells
CK7,8,18,19, OV6
CK8,18, hepar1
CK7,8,18,19,chromA, NCAM, OV6
CK7, 8, 18, chromA, OV6, hepar
CK7,19, chromA, OV6, (ckit, CD34)
Biliary diseases Hepatocyte loss
Roskams et al J Hepatol 98Libbrecht et al J Hepatol 00
Ductular Reaction
Ductular reaction and its diagnostic significanceRoskams T, Desmet V.( Semin Diagn Pathol 1998; Hepatology 2004).
Ductular Reaction Ductular Reaction
The Significance of Ductal Reactionin Liver Diseases
Chronic Liver Diseases↓
Hepatocyte senescence/replicative arrest↓
HPC/Cholangiocyte Proliferation↓
Hepatocyte regeneration, periportalfibrogenesis
HPC-derived hepatocytes increase in the late stage HCV disease: evidence from EpCAM expression and
serum stem cell factor. Glazer E. et al. AASLD 2006
Stage EpCAM+Hepatocyte
Clusters
Semiquan-titation
EpCAM+Hepatocyte
per cm tissue
Serum stem cell
factor1 3 <5% 1
2 12 6-10% 5
3 19 11-50% 8
4 31 >50% 2436
31
EVIDENCES FOR EMT IN THE LIVER!
EXPERIMENTAL:-In vitro isolated mouse cholangiocytes: DeMetris A. et al. J. Hepaytol 2008
-Polycystic (PCK) rat liver: Sato Y et al. Am.J. Pathol. 2007
HUMAN LIVER DISEASES-Chronic Liver Disease: Rygiel K. et al. Lab. Invest. 2008
-Human Cholangiocarcinoma: Fabris L. et al. AISF 2008
Gastroenterology 2007
Gastroenterology 2007
Gastroenterology 2007
ViralChronic Liver
DiseaseAlcoholic Liver
Disease
Non Alcoholic Fatty Liver Disease
Cholangiophaties, Hemocromatosis, Regeneration after submassive necrosis
Ductular Reaction
ViralChronic Liver
DiseaseAlcoholic Liver
Disease
Non Alcoholic Fatty Liver Disease
Cholangiophaties, Hemocromatosis, Regeneration after submassive necrosis
Ductular ReactionA neuroendocrine
compartmentin the diseased
LIVER
ViralChronic Liver
DiseaseAlcoholic Liver
Disease
Non Alcoholic Fatty Liver Disease
Cholangiophaties, Hemocromatosis, Regeneration after submassive necrosis
Ductular Reaction
The activated stem cellcompartment in the
injued liver !
REGULATION OF CHOLANGIOCYTE PROLIFERATION.
Proliferating
Reactive Cholangiocytes
Hormones/NeuropeptidesSomatostatin, PTHrP, Acetylcholine, Norepinephrine,
Dopamine, Estrogens, Gastrin, Secretin, Insulin,CCK,Serotonin, opioids, prolactin, T3, Hystamine
Growth Factors HGF, NGF, IGF1, PDGF,VEGF, EGF, bFGF, TGFα,TGFβ1-2, KGF
CytokinesIL6, CINC, IL1α, TNFα,IFN-γ
Vasoactive agentsNO, ET1, PGE2, PGF2
PROLIFERATING “REACTIVE” CHOLANGIOCYTES EXPRESS:
Neuroendocrine molecules: (Chromogranin A, SP100, M3-AChR, Glicolipide A2-B4, GLP-1, serotonin….)
Adhesion Molecules:(NCAM, ICAM, CD40, MHC-II…..)
REGULATION OF CHOLANGIOCYTE PROLIFERATION.
Proliferating
Reactive Cholangiocytes
Hormones/NeuropeptidesSomatostatin, PTHrP, Acetylcholine, Norepinephrine,
Dopamine, Estrogens, Gastrin, Secretin, Insulin,CCK,Serotonin, opioids, prolactin, T3, Hystamine
Growth Factors HGF, NGF, IGF1, PDGF,VEGF, EGF, bFGF, TGFα,TGFβ1-2, KGF
CytokinesIL6, CINC, IL1α, TNFα,IFN-γ
Vasoactive agentsNO, ET1, PGE2, PGF2
Nerve Regulation of Cholangiocyte Growth
BDL
BDL + parasympathetic denervation
Enhanced apoptosis
Loss of proliferation
Loss of the functional response to secretin
BDL + sympathetic denervation
Enhanced apoptosis
Loss of proliferation
Loss of the functional response to secretin
LeSage et al., Gastroenterology 1999; Hepatology 2004; Alvaro et al., JCI 1997; Glaser et al., Am J Phsyiol 2006
Nerve Regulation of Cholangiocyte Growth
BDL
BDL + parasympathetic denervation
Enhanced apoptosis
Loss of proliferation
Loss of the functional response to secretin
BDL + sympathetic denervation
Enhanced apoptosis
Loss of proliferation
Loss of the functional response to secretin
LeSage et al., Gastroenterology 1999; Hepatology 2004; Alvaro et al., JCI 1997; Glaser et al., Am J Phsyiol 2006
Taurocholic Acid Prevent …..
Cytoprotective effects of taurocholic acid feeding on the biliary tree after adrenergic denervation of the liver.
Taurocholic acid feeding prevents TNF-alpha-induced damage ofcholangiocytes by a PI3K-mediated pathway.
Marzioni M,….Alpini G. 2006, 2007
Nerves and the Reparative Capacity of Transplanted Liver.
The number of HPC and “atypical” reactive
ductular cells in the transplanted liver injured
by HCV lower than in innervated livers
(Cassiman D . Am J Pathol 2002)
Rapid progression of injury in the transplanted liver toward terminal and/or ductopenic conditions facilitated by impaired regenerative and repair capacity !?
C. Hering
DuctuleInterlobular
duct
M3-ACh ↑ HPC proliferationacetyl cholinesterase,
Hormones/Neuropeptides PTHrP, GIP, GLP-1, Serotonin, prolactin
PROLIFERATING CHOLANGIOCYTES SECRETE…..
Proliferating
Cholangiocytes
Growth FactorsHGF, NGF, IGF1, PDGF,VEGF, SCF, TGFβ1-2, bFGF, PDGFβ, CTGF, SDF-1
CytokinesIL6, IL8, IL18,IL16,
IL12,TNα,IFNγ,MCP-1,CINC, OSM,TIMP, KALL.-5, RANTES,MCP-1, IP-10,MIP-1A/1B, TCA3
Vasoactive Agents
NO, Endothelin 1, Angiopoietin 1, 2
Coagulation Factor XIII,
Proliferating
Reactive Cholangiocytes
Hepatic Stellate Cells
Endothelial Cells
Immune System Cells
Hepatocytes
CROSS-TALK BETWEEN PROLIFERATING CHOLANGIOCYTES AND LIVER CELLS
VEGF, IGF1,NO, ET, HGF
VEGF, IGF1,NO, ET,Ag1,2
IGF1, NGF, VEGFNO, ET, Serotonin, opioids, PDGF, IL-1,IL-6, IL-8, IFN-γ,TGF-β, MCP-1,
CytokinesIL1,6,8,IFγ
Portal Fibroblast
Proliferating
Reactive Cholangiocytes
Hepatic Stellate Cells
Endothelial Cells
Immune System Cells
HepatocytesVEGF, IGF1,NO, ET, HGF
VEGF, IGF1,NO, ET,Ag1,2
IGF1, NGF, VEGFNO, ET, Serotonin, opioids, PDGF, IL-1,IL-6, IL-8, IFN-γ,TGF-β, MCP-1,
CytokinesIL1,6,8,IFγ
Portal Fibroblast
Reparative events of liver damageLiver Fibrosis
Reparative events of liver damageLiver Fibrosis
CHOLANGIOCYTES – H. STELLATE CELLSCROSS-TALK
Reparative events of liver damageLiver Fibrosis
- Ductular Reaction -“the pace-maker of portal fibrosis”
(Desmet. V. Semin Diagn Pathol 1998)
CHOLANGIOCYTES – H. STELLATE CELLSCROSS-TALK
Cholangiocytes/Stellate Cells cross-talk.
proliferatingcholangiocytes
Stellate cells
serotonin
Block secretion of serotonin from cholangiocytes and favor their proliferation
Cholangiocytes/Stellate Cells cross-talk.
proliferatingcholangiocytes
Stellate cells
serotonin
Block secretion of serotonin from cholangiocytes and favor their proliferation
Cross-talk between hepatic stellate cells and cholangiocytes regulates biliary growth through serotonin
A Omenetti, Y X Li, W Chen, R R Gainetdnidov, L Yang, A M Diehl
Hepatology 44, A392 2006
2006 AASLD Liver Meeting
Cholangiocytes/Stellate Cells cross-talk.
proliferatingcholangiocytes
Stellate cells
serotonin
Block secretion of serotonin from cholangiocytes and favor their proliferation
Am J Pathol. 2006 Sep;169(3):861-76. Links
A role for serotonin (5-HT) in hepatic stellate cell function and liver fibrosis.
Ruddell RG, Oakley F, Hussain Z, Yeung I, Bryan-Lluka LJ, Ramm GA, Mann DA.
Gastroenterology 2006INHIBITION !
ACTIVATION !
Role of endogenous opioids in modulating HSC activity in vitro and liver fibrosis in vivo.
De Minicis S. et al. GUT 2008.
Cholangiocytes/SECs/Hepatocytes cross-talk.
VEGFEndothelin
NO
Liver Transpl 2005;11:410-419.)
Cholangiocytes/SECs/Hepatocytes cross-talk.
VEGFEndothelin
NO
Liver Transpl 2005;11:410-419.)
Cholangiocytes/SECs/Hepatocytes cross-talk.
VEGFEndothelin
NO
Science 2005Liver Transpl 2005;11:410-419.)
The Biliary Tree and the Peribiliary Plexus
Hepatic Artery
Hepatic Artery
BDL 1wk = bile duct poliferationBDL 2wk = bile duct proliferation+
PBP adaptive proliferation
Gastroenterology 2006
Proliferating Cholangiocytes produce and secrete VEGF
Gaudio et al.,
Gastroenterology 2006
cholangiocytes hepatocytes
VEGF administration mantains the arterial peribiliary plexus (PBP) after hepatic artery ligation (HAL)
Gaudio et al., Am J Pathol 2006
S
P
PBP
P
Liver Transpl 2005;11:410-419.)
Bile Salts, Antigens, Endotoxins, Xenobiotics
THE BILE DUCT SYSTEM: BARRIER FUNCTION
Alkaline Phosphatase: Major Function in Endotoxin Detoxification
IMMUNOLOGIC BARRIER FUNCTION: Secretory IgA
THE BILE DUCT SYSTEM: BARRIER FUNCTION
TNF-α IFNγ
Normal Liver
PBC
ZO-1 and 7H6
THE BILE DUCT SYSTEM: BARRIER FUNCTION
IFNγ
ZO-1 and 7H6
H20
NtcpBS
BS(-40%)
Ntcp(-40%)
MECHANISMS OF INFLAMMATION-INDUCED CHOLESTASIS
BSEP(-80%)
BSEPBSEP(-80%)
ATP ATPATP
HCO3
CFTRATP
Cl-(Ca++)
HEPATOCYTES⇓ BS tranport
CHOLANGIOCYTES⇓ HCO3 secretion
BS
LPS
TNFαIL-1βIL-6IFγNO
Hepatocytes= BS accumulationCholangiocytes: Inhibition of bicarbonate secretion (Spirli’ C, Gastro 2003)
Hepatology 1999
Hepatology 1999
Hepatology 1999
Progenitor/stem cells give rise to liver cancer due toAberrant TGF-beta and IL-6 signaling. Tang Y et al. PNAS 2008
IL-6 secreted by cholangiocytes
Hepatology 1999
Progenitor/stem cells give rise to liver cancer due toAberrant TGF-beta and IL-6 signaling. Tang Y et al. PNAS 2008
IL-6 secreted by cholangiocytes
The recombinant humanized anti-IL-6 receptor antibody TOCILIZUMAB
an innovative drug for the treatment of rheumatoid arthritis.
Ohsugi Y et al. Expert Opinion on Biological Therapy 2008.
Targeting IL-6 in cholangiocarcinoma therapy.Mott JL, Gores GJ.
Am J Gastroenterol. 2007 Oct;102(10):2171-2.
Cholangiocytes have developed mechanisms to respond to infection by recruiting and interacting with effector leukocytes to clear bacterial or
viral pathogens.
THE ROLE OF CHOLANGIOCYTES IN THE DEVELOPMENT OF CHRONIC INFLAMMATORY LIVER DISEASE
CBP: MALATTIA AUTOIMMUNE
= PDC-E2
J
J FS
J
IgA-dimero
MHC-I MHC-II
CD4+
CD8+
PDC-E2
pIgA-R
Molecurar mimicry: xenobiotici, agenti infettivi ?
AMA
MITOCONDRI
Colangiocita
Characterization of Recombinant Monoclonal IgA Anti–PDC-E2 Autoantibodies Derived From Patients With PBC
Fukushima M.. Hepatology 2002
Liver Sinusoidal EndothelialCells (LSEC)-First study only 35 years ago (E. Wisse) *Open fenestration without a diaphragmor basement membrane;
*High amounts of endocytic vesicles; *Engaged in uptake of protein from blood
(hyaluronan).
LSECs are a specialized type of scavenger endothelium that uses clathrin-mediated endocytosis to clear an array of physiological and foreign macromolecules and colloids from the blood !
LSEC: Fenestration
LSEC: Fenestration
Fenestrae, caveolin-1 and NO.Caveolin-1 and eNOS co-exist in the fenestrae
plasma membrane, implying that the fenestrae correspond to a permanent
(stationary) type of fused and interconnected caveolae, thus contributing to
the local control of hepatic sinusoidal blood flow by the regulation of NO synthesis.
C. Endoteliali (LSEC)-Loss of Fenestration
•In old humans, rats, mice, and primates:Pseudocapillarization and impaired endocytosis and increased leukocyte adhesion which contributes to reduced hepatic perfusion.
↓Impaired lipoprotein clearance
↓Dyslipidemia, and vascular disease (aging).
A mechanism of drug-induced liver injury (arsenic..,) ?
Age-related changes in the liver sinusoidal endothelium: a mechanism for dyslipidemia.LE Couteur DG et al. Ann N Y Acad Sci. 2007 Oct
LSEC and InsulinSoda R. et al. Distribution of insulin receptors in liver cell suspensions
using a minibead probe. Highest density is on endothelial cell.Exp Cell Res. 1983
The highest density of Insulin-R found on Liver Endothelial Cells !
The magnitude of insulin uptake was at least double that of the uptake by the hepatocyte-rich fraction !
SECs and AGEs (advanced glycation end-products)
AGEs → cytokine release and oxidative stress
•Up to 60% of total liver AGEs, generated byhyperglycaemia, taken up by SEC and20% by KC (Smedsrod B, Biochem J. 1997).•Dependent on scavenger receptors CD36, SR1 and SR2.
•The influence of AGEs on liver SECs not yet explored.
Adipocytokines and SECs
Leptin → upregulation of TGF-β in SECs
Expression of long-form leptin receptor (Ob-Rb) in sinusoidal endothelial cells (RT-PCR)
KENICHI IKEJIMA Gastroenterology. 2002
Sinusoidal cells as actors of insulin resistance?
Sinusoidal cells as actors of insulin resistance?
