High preoperative recipient plasma 7β-hydroxycholesterol is associated with initial poor graft function after liver transplantation

Abstract

Oxidative stress is implicated in the pathogenesis of hepatic ischemia-reperfusion injury, a major determinant of initial poor graft function (IPGF) after orthotopic liver transplantation (OLT). We prospectively investigated the association between the recipient plasma preoperative oxidative stress and the occurrence of IPGF after deceased-donor OLT and indirectly studied the sourcehepatic or extra-hepatic-of systemic oxidative stress in vivo in cirrhosis. We used a recently developed specific and sensitive mass spectrometry assay to measure 7␤-hydroxycholesterol and 7-ketocholesterol (oxysterols), markers of oxidative stress, in biological matrices. At univariate analysis, preoperative recipient 7␤-hydroxycholesterol plasma concentration was significantly higher in transplants with subsequent IPGF (n ‫؍‬ 9) compared with those with initial good graft function (IGGF; n ‫؍‬ 23) [mean ؎ SD: 30.63 ؎ 26.42 and 11.57 ؎ 15.76 ng/mL, respectively] (P ‫؍‬ 0.017). In a logistic regression model, which included also the Model for End-Stage Liver Disease (MELD) score, 7␤-hydroxycholesterol plasma concentration was an independent predictor of IPGF with an odds ratio of 1.17 (95% CI, 1.02-1.33, P ‫؍‬ 0.028). Patients with cirrhosis (n ‫؍‬ 32) had increased oxysterol plasma levels compared with healthy controls (n ‫؍‬ 49); livers with cirrhosis (n ‫؍‬ 21), however, had oxysterol content comparable with normal livers obtained from organ donors (n ‫؍‬ 19). Oxysterols persisted elevated in plasma 1 month after OLT (n ‫؍‬ 23). In conclusion, cirrhosis presents upregulated systemic oxidative stress likely of extrahepatic source that is associated with graft failure after OLT. (Liver Transpl 2005;11:1494-1504.)

7‐ketocholesterol and 5,6‐secosterol modulate differently the stress‐activated mitogen‐activated protein kinases (MAPKs) in liver cells

“…Previous studies on oxysterol-mediated cell cytotoxicity were carried out using concentrations between 10 À4 and 10 À5 M, largely exceeding the highest concentrations found in human plasma (ranging from 0.2 to 2 Â 10 À7 M) (Savouret et al, 2001;Arca et al, 2007). The concentrations used in the present study (from 10 À9 to 10 À5 M) are closer to physiological concentrations and have been previously reported in human diseases, such as atherosclerosis, myocardial infarction, and chronic hepatitis (Biasi et al, 2004;Corradini et al, 2005).…”

“…In fact, previously data have been obtained using concentrations (>10 mM) that highly exceed either physiological than pathological concentrations described in humans (Javitt, 2008). We were interested to study the effects and the molecular basis of two different oxysterols (7-K and 5,6-S) on liver cells homeostasis; to this aim we used concentrations, ranging from 10 À9 to 10 À5 M, described to be effectively present in plasma of patients (Biasi et al, 2004;Corradini et al, 2005).…”

“…Oxysterols (such as 7-K and 5,6-S), compounds derived from peroxidation of cholesterol, are considered reliable markers of oxidative stress in vivo and believed involved in progression of CLDs (Corradini et al, 2005). High concentrations of 7-K cause oxidative burst that occurs very early after cell intoxication and may lead to programmed cell death (Lemaire et al, 1998;Leonarduzzi et al, 2006).…”

“…Oxysterols are specific markers of oxidative stress in chronic liver disease (CLD) patients, which present high plasma levels of these compounds, in particular 7-beta-hydroxycholesterol (7-bOH) and 7-ketocholesterol (7-K), in a manner strictly related to disease stage and accompanied by reduced levels of alpha-tocopherol. Plasma concentration of 7-bOH and 7-K one order of magnitude higher than sex-and age-matched controls was observed, highlighting the importance to comprehend the origin and biological relevance of these compounds in the pathophysiology of chronic liver damage (Corradini et al, 2005). The mechanism of cell death induction by oxidative stress depends on its origin and on the cell type affected.…”

Plasma fatty acid lipidome is associated with cirrhosis prognosis and graft damage in liver transplantation

“…Serum bilirubin, prothrombin activity (INR), and creatinine for the calculation of the model for end-stage liver disease (MELD) score according to the following formula (15): 9:57 3 log e ½creatinineðmg=dLÞ þ 3:78 3 log e ½bilirubinðmg=dLÞ +11.20 3 log e (INR) + 6.43 (1) and serum total cholesterol and triglycerides concentrations (n = 47) were determined in cirrhotic patients by using standard automated techniques as previously described (16). Laboratory analyses were done in a blinded fashion.…”