Le Funzioni dei Colangiociti e delle Cellule...

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?