Intrahepatic cholestasis after liver transplantation

Ben‐Ari, Ziv; Pappo, Orit; Mor, Eytan

doi:10.1053/jlts.2003.50212

Cited by 79 publications

(60 citation statements)

References 138 publications

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“…This hypothesis may also relate to the association of IQGAP1 with the endocytic machinery (clathrin and AP-2) we observed in human liver. 2 Indeed this association was only detected before ischemia and 1 h postreperfusion. Interestingly this correlates with our fractionation results (Fig.…”

Section: Discussionmentioning

confidence: 95%

Proteomic Analysis of Ischemia-Reperfusion Injury upon Human Liver Transplantation Reveals the Protective Role of IQGAP1

Emadali

Muscatelli-Groux

Delom

et al. 2006

Molecular & Cellular Proteomics

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Ischemia-reperfusion injury (IRI) represents a major determinant of liver transplantation. IRI-induced graft dysfunction is related to biliary damage, partly due to a loss of bile canaliculi (BC) integrity associated with a dramatic remodeling of actin cytoskeleton. However, the molecular mechanisms associated with these events remain poorly characterized. Using liver biopsies collected during the early phases of organ procurement (ischemia) and transplantation (reperfusion), we characterized the global patterns of expression and phosphorylation of cytoskeletonrelated proteins during hepatic IRI. This targeted functional proteomic approach, which combined protein expression pattern profiling and phosphoprotein enrichment followed by mass spectrometry analysis, allowed us to identify IQGAP1, a Cdc42/Rac1 effector, as a potential regulator of actin cytoskeleton remodeling and maintenance of BC integrity. Cell fractionation and immunohistochemistry revealed that IQGAP1 expression and localization were affected upon IRI and related to actin reorganization. Furthermore using an IRI model in human hepatoma cells, we demonstrated that IQGAP1 silencing decreased the basal level of actin polymerization at BC periphery, reflecting a defect in BC structure coincident with reduced cellular resistance to IRI. In summary, this study uncovered new mechanistic insights into the global regulation of IRI-induced cytoskeleton remodeling and led to the identification of IQGAP1 as a regulator of BC structure.

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Section: Discussionmentioning

confidence: 95%

Proteomic Analysis of Ischemia-Reperfusion Injury upon Human Liver Transplantation Reveals the Protective Role of IQGAP1

Emadali

Muscatelli-Groux

Delom

et al. 2006

Molecular & Cellular Proteomics

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“…After liver transplantation, ischemic lesions of bile ducts may occur presumably by surgical lesions of the hepatic artery (13,15,47). In cholangiopathies, mainly primary sclerosing Fig.…”

Section: Discussionmentioning

confidence: 99%

“…However, limited information exists on the role of blood supply through the hepatic artery in pathological conditions characterized by cholangiocyte proliferation/loss (14,48). This concept has clinical implications since ischemic bile duct lesions are considered possible causes of cholestatic disorders, in particular after liver transplantation, hepatic surgery, and intra-arterial chemotherapy (13,15).…”

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confidence: 99%

Administration of r-VEGF-A prevents hepatic artery ligation-induced bile duct damage in bile duct ligated rats

Gaudio¹,

Barbaro²,

Alvaro³

et al. 2006

American Journal of Physiology-Gastrointestinal and Liver Physi

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pini. Administration of r-VEGF-A prevents hepatic artery ligationinduced bile duct damage in bile duct ligated rats. Am J Physiol Gastrointest Liver Physiol 291: G307-G317, 2006. First published March 30, 2006 doi:10.1152/ajpgi.00507.2005.-The hepatic artery, through the peribiliary plexus, nourishes the intrahepatic biliary tree. During obstructive cholestasis, the nutritional demands of intrahepatic bile ducts are increased as a consequence of enhanced proliferation; in fact, the peribiliary plexus (PBP) displays adaptive expansion. The effects of hepatic artery ligation (HAL) on cholangiocyte functions during cholestasis are unknown, although ischemic lesions of the biliary tree complicate the course of transplanted livers and are encountered in cholangiopathies. We evaluated the effects of HAL on cholangiocyte functions in experimental cholestasis induced by bile duct ligation (BDL). By using BDL and BDL ϩ HAL rats or BDL ϩ HAL rats treated with recombinant-vascular endothelial growth factor-A (r-VEGF-A) for 1 wk, we evaluated liver morphology, the degree of portal inflammation and periductular fibrosis, microcirculation, cholangiocyte apoptosis, proliferation, and secretion. Microcirculation was evaluated using a scanning electron microscopy vascular corrosion cast technique. HAL induced in BDL rats 1) the disappearance of the PBP, 2) increased apoptosis and impaired cholangiocyte proliferation and secretin-stimulated ductal secretion, and 3) decreased cholangiocyte VEGF secretion. The effects of HAL on the PBP and cholangiocyte functions were prevented by r-VEGF-A, which, by maintaining the integrity of the PBP and cholangiocyte proliferation, prevents damage of bile ducts following ischemic injury. cAMP; ductal secretion; intrahepatic biliary epithelium; mitosis; microcirculation; secretin CHOLANGIOCYTES, THE EPITHELIAL CELLS lining the intrahepatic biliary epithelium (6), modify bile, originally secreted at the bile canaliculus (43), by a series of absorptive and secretory events regulated by a number of factors including gastrointestinal hormones/peptides, bile salts, and nerve receptor agonists (4 -7, 11, 31, 38). The gastrointestinal hormone secretin increases ductal secretion by interaction with specific receptors (expressed only by cholangiocytes) (10), an interaction that induces an increase in intracellular adenosine 3Ј,5Ј-monophosphate (cAMP) levels (4,7,25,26,31,38). Increased intracellular cAMP levels induce activation of the CFTR Cl Ϫ channels (9, 31) and Cl Ϫ

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“…Corticosteroids are usually tapered in the early post-LT period, and thus have minimal long-term influence on serum lipids [61] . Post-transplant cholestasis is also relatively common, and often secondary to anastomotic or non-anastomotic biliary stricturing [62] . Prolonged cholestasis may lead to Lp-X formation, but very few post-LT cases are reported [52,63,64] .…”

Section: Post-transplant Follow-upmentioning

confidence: 99%

Cholesterol metabolism in cholestatic liver disease and liver transplantation: From molecular mechanisms to clinical implications

Nemes¹,

Åberg²,

Gylling³

et al. 2016

WJH

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The aim of this review is to enlighten the critical roles that the liver plays in cholesterol metabolism. Liver transplantation can serve as gene therapy or a source of gene transmission in certain conditions that affect cholesterol metabolism, such as low-density-lipoprotein (LDL) receptor gene mutations that are associated with familial hypercholesterolemia. On the other hand, cholestatic liver disease often alters cholesterol metabolism. Cholestasis can lead to formation of lipoprotein X (Lp-X), which is frequently mistaken for LDL on routine clinical tests. In contrast to LDL, Lp-X is non-atherogenic, and failure to differentiate between the two can interfere with cardiovascular risk assessment, potentially leading to prescription of futile lipid-lowering therapy. Statins do not effectively lower Lp-X levels, and cholestasis may lead to accumulation of toxic levels of statins. Moreover, severe cholestasis results in poor micellar formation, which reduces cholesterol absorption, potentially impairing the cholesterol-lowering effect of ezetimibe. Apolipoprotein B-100 measurement can help distinguish between atherogenic and non-atherogenic hypercholesterolemia. Furthermore, routine serum cholesterol measurements alone cannot reflect cholesterol absorption and synthesis. Measurements of serum non-cholesterol sterol biomarkers -such as cholesterol precursor sterols, plant sterols, and cholestanol -may help with the comprehensive assessment of cholesterol metabolism. An adequate cholesterol supply is essential for liver-regenerative capacity. Low preoperative and perioperative serum cholesterol levels seem to predict mortality in liver cirrhosis and after liver transplantation. Thus, accurate lipid profile evaluation is highly important in liver disease and after liver transplantation.

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Intrahepatic cholestasis after liver transplantation

Cited by 79 publications

References 138 publications

Proteomic Analysis of Ischemia-Reperfusion Injury upon Human Liver Transplantation Reveals the Protective Role of IQGAP1

Proteomic Analysis of Ischemia-Reperfusion Injury upon Human Liver Transplantation Reveals the Protective Role of IQGAP1

Administration of r-VEGF-A prevents hepatic artery ligation-induced bile duct damage in bile duct ligated rats

Cholesterol metabolism in cholestatic liver disease and liver transplantation: From molecular mechanisms to clinical implications

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