Enterically derived high-density lipoprotein restrains liver injury through the portal vein.
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ABSTRACT:
SUBMITTER: Han YH
PROVIDER: S-EPMC8478306 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The proteomes of HDL subspecies, HDL2 and HDL3, from pooled human serum purified by density gradient centrifugation were generated and compared to the proteomes of HDL2 and HDL3 derived from tportal venouhe s and antecubital venous blood matched across these two locations from the same individual. The latter were purified by size exclusion chromatography coupled with immunoprecipitation with anti-apoA1 mAb.
2021-04-27 | MSV000087310 | MassIVE
Project description:ObjectiveThe liver is one of the critical organs for lipoprotein metabolism and a major source for phospholipid transfer protein (PLTP) expression. The effect of liver-specific PLTP deficiency on plasma lipoprotein production and metabolism in mice was investigated.Approach and resultsWe created a liver-specific PLTP-deficient mouse model. We measured plasma high-density lipoprotein (HDL) and apolipoprotein B (apoB)-containing lipoprotein (or non-HDL) levels and their production rates. We found that hepatic ablation of PLTP leads to a significant decrease in plasma PLTP activity, HDL lipids, non-HDL lipids, apoAI, and apoB levels. In addition, nuclear magnetic resonance examination of lipoproteins showed that the deficiency decreases HDL and apoB-containing lipoprotein particle numbers, as well as very low-density lipoprotein particle size, which was confirmed by electron microscopy. Moreover, HDL particles from the deficient mice are lipid-poor ones. To unravel the mechanism, we evaluated the apoB and triglyceride production rates. We found that hepatic PLTP deficiency significantly decreases apoB and triglyceride secretion rates. To investigate the role of liver PLTP on HDL production, we set up primary hepatocyte culture studies and found that the PLTP-deficient hepatocytes produce less nascent HDL. Furthermore, we found that exogenous PLTP promotes nascent HDL production through an ATP-binding cassette A 1-mediated pathway.ConclusionsLiver-specific PLTP deficiency significantly reduces plasma HDL and apoB-containing lipoprotein levels. Reduction of production rates of both particles is one of the mechanisms.
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Project description:High-density lipoproteins (HDL) are important endogenous inhibitors of inflammatory responses. Functional impairment of HDL might contribute to the excess mortality experienced by patients with liver disease, but the effect of cirrhosis on HDL metabolism and function remain elusive. To get an integrated measure of HDL quantity and quality, we assessed several metrics of HDL function using apolipoprotein (apo) B-depleted sera from patients with compensated cirrhosis, patients with acutely decompensated cirrhosis and healthy controls. We observed that sera of cirrhotic patients showed reduced levels of HDL-cholesterol and profoundly suppressed activities of several enzymes involved in HDL maturation and metabolism. Native gel electrophoresis analyses revealed that cirrhotic serum HDL shifts towards the larger HDL2 subclass. Proteomic assessment of isolated HDL identified several proteins, including apoA-I, apoC-III, apoE, paraoxonase 1 and acute phase serum amyloid A to be significantly altered in cirrhotic patients. With regard to function, these alterations in levels, composition and structure of HDL were strongly associated with metrics of function of apoB-depleted sera, including cholesterol efflux capability, paraoxonase activity, the ability to inhibit monocyte production of cytokines and endothelial regenerative activities. Of particular interest, cholesterol efflux capacity appeared to be strongly associated with liver disease mortality. Our findings may be clinically relevant and improve our ability to monitor cirrhotic patients at high risk.
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Project description:BackgroundInsufficient remnant liver volume (RLV) after the resection of hepatic malignancy could lead to liver failure and mortality. Portal vein ligation (PVL) prior to hepatectomy is subsequently introduced to increase the remnant liver volume and improve the outcome of hepatic malignancy. IL-22 has previously been reported to promote liver regeneration, while facilitating tumor development in the liver via Steap4 upregulation. Here we performed PVL in mouse models to study the role of IL-22 in liver regeneration post-PVL.MethodsLiver weight and volume was measured via magnetic resonance imaging (MRI). Immunohistochemistry for Ki67 and hepatocyte growth factor (HGF) was performed. IL-22 was analyzed by flow cytometry and quantitative polymerase chain reaction (qPCR) was used for acquisition of Il-33, Steap4, Fga, Fgb and Cebpd. To analyze signaling pathways, mice with deletion of STAT3 and a neutralizing antibody for IL-22 were used.ResultsThe remnant liver weight and volume increased over time after PVL. Additionally, we found that liver regenerative molecules, including Ki67 and HGF, were significantly increased in remnant liver at day 3 post-PVL, as well as IL-22. Administration of IL-22 neutralizing antibody could reduce Ki67 expression after PVL. The upregulation of IL-22 after PVL was mainly derived from innate cells. IL-22 blockade resulted in lower levels of IL-33 and Steap4 in the remnant liver, which was also the case in mice with deletion of STAT3, the main downstream signaling molecule of IL-22, in hepatocytes.ConclusionIL-22 promotes liver regeneration after PVL. Thus, a combination of IL-22 supplementation and Steap4 blockade could potentially be applied as a novel therapeutic approach to boost liver regeneration without facilitating tumor progression after PVL.
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Project description:Portal vein thrombosis (PVT) is associated with inferior pretransplantation and posttransplantation outcomes. We aimed to create a predictive model to risk stratify transplant candidates for PVT. Data on adult transplants in the United States during the Model for End-Stage Liver Disease (MELD) era through September 2016 were reviewed. We constructed and validated a scoring system composed of routine, readily available clinical information to predict the development of incident PVT at 12 months from transplantation listing. A total of 66,568 liver transplant candidates were dichotomized into 2 groups to construct (n = 34,751) and validate (n = 31,817) a scoring system. In general, the derivation and validation cohorts were clinically similar. Although nonalcoholic steatohepatitis was a significant predictor of incident PVT (hazard ratio, 1.29; 95% confidence interval, 1.08-1.54; P < 0.001), age, MELD score, and moderate-to-severe ascites were also associated with increased risk. African American race was associated with decreased risk. A scoring system (PVT risk index [RI]) of these 5 variables had an area under the curve of 0.71 and 0.70 in both derivation and validation cohorts, respectively. By applying the low cutoff score of 2.6, incident PVT could be accurately excluded (negative predictive value 94%). Using the high cutoff score of 4.6 (positive predictive value 85%), PVT could be diagnosed with high accuracy. The PVT-RI predicts which candidates awaiting lifesaving liver transplantation will and will not develop future PVT. Although this scoring system will require prospective validation, it provides a powerful new tool for the clinician when risk stratifying cirrhosis patients prior to liver transplantation for future PVT development.
| S-EPMC6864229 | biostudies-literature
Project description:BackgroundMany patients with bi-lobar liver tumours are not eligible for liver resection due to an insufficient future liver remnant (FLR). To reduce the risk of posthepatectomy liver failure and the primary cause of death, regenerative procedures intent to increase the FLR before surgery. The aim of this systematic review is to provide an overview of the available literature and outcomes on the effectiveness of simultaneous portal and hepatic vein embolization (PVE/HVE) versus portal vein embolization (PVE) alone.MethodsA systematic literature search was conducted in PubMed, Web of Science, and Embase up to September 2022. The primary outcome was resectability and the secondary outcome was the FLR volume increase.ResultsEight studies comparing PVE/HVE with PVE and six retrospective PVE/HVE case series were included. Pooled resectability within the comparative studies was 75 per cent in the PVE group (n = 252) versus 87 per cent in the PVE/HVE group (n = 166, OR 1.92 (95% c.i., 1.13-3.25)) favouring PVE/HVE (P = 0.015). After PVE, FLR hypertrophy between 12 per cent and 48 per cent (after a median of 21-30 days) was observed, whereas growth between 36 per cent and 67 per cent was reported after PVE/HVE (after a median of 17-31 days). In the comparative studies, 90-day primary cause of death was similar between groups (2.5 per cent after PVE versus 2.2 per cent after PVE/HVE), but a higher 90-day primary cause of death was reported in single-arm PVE/HVE cohort studies (6.9 per cent, 12 of 175 patients).ConclusionBased on moderate/weak evidence, PVE/HVE seems to increase resectability of bi-lobar liver tumours with a comparable safety profile. Additionally, PVE/HVE resulted in faster and more pronounced hypertrophy compared with PVE alone.
| S-EPMC9702575 | biostudies-literature
Project description:Characterization of HDL proteome in patients diagnosed with non-alcoholic fatty liver disease and to evaluate the impact on HDL function.
2018-09-13 | PXD005847 | Pride
Project description:Nontumoral portal vein thrombosis (PVT) is an increasingly recognized complication in patients with cirrhosis. Substantial evidence shows that portal flow stasis, complex thrombophilic disorders, and exogenous factors leading to endothelial dysfunction have emerged as key factors in the pathogenesis of PVT. The contribution of PVT to hepatic decompensation and mortality in cirrhosis is debatable; however, the presence of an advanced PVT increases operative complexity and decreases survival after transplantation. The therapeutic decision for PVT is often determined by the duration and extent of thrombosis, the presence of symptoms, and liver transplant eligibility. Evidence from several cohorts has demonstrated that anticoagulation treatment with vitamin K antagonist or low molecular weight heparin can achieve recanalization of the portal vein, which is associated with a reduction in portal hypertension-related events and improved survival in cirrhotic patients with PVT. Consequently, interest in direct oral anticoagulants for PVT is increasing, but clinical data in cirrhosis are limited. Although the most feared consequence of anticoagulation is bleeding, most studies indicate that anticoagulation therapy for PVT in cirrhosis appears relatively safe. Interestingly, the data showed that transjugular intrahepatic portosystemic shunt represents an effective adjunctive therapy for PVT in cirrhotic patients with symptomatic portal hypertension if anticoagulation is ineffective. Insufficient evidence regarding the optimal timing, modality, and duration of therapy makes nontumoral PVT a challenging consequence of cirrhosis. In this review, we summarize the current literature and provide a potential algorithm for the management of PVT in patients with cirrhosis.
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Project description:BackgroundRegenerative liver surgery expands the limitations of technical resectability by increasing the future liver remnant (FLR) volume before extended resections in order to avoid posthepatectomy liver failure (PHLF). Portal vein rerouting with ligation of one branch of the portal vein bifurcation (PVL) or embolization (PVE) leads to a moderate liver volume increase over several weeks with a clinical dropout rate of 20-40%, mostly due to tumor progression during the waiting period. Accelerated liver regeneration by the Associating Liver Partition and Portal vein Ligation for Staged hepatectomy (ALPPS) was poised to overcome this limitation by reduction of the waiting time, but failed due increased perioperative complications. Simultaneous portal and hepatic vein embolization (PVE/HVE) is a novel minimal invasive way to induce rapid liver growth without the need of two surgeries.PurposeThis article summarizes published results of PVE/HVE and analyzes what is known about its efficacy to achieve resection, safety, and the volume changes induced.ConclusionsPVE/HVE holds promise to induce accelerated liver regeneration in a similar safety profile to PVE. The demonstrated accelerated hypertrophy may increase resectability. Randomized trials will have to compare PVE/HVE and PVE to determine if PVE/HVE is superior to PVE.
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Project description:The potential mechanism were successfully illustrated through detecting different expression of microRNAs in between proinflammatory high density lipprotein (pHDL), nomal high density lipprotein (nHDL) and control group, to study whether microRNAs play important roles in the endothelial dysfunction caused by pHDL.
2020-08-31 | GSE156800 | GEO