Partial Liver Transplantation Research Articles

SYK promotes the formation of neutrophil extracellular traps by inducing PKM2 nuclear translocation and promoting STAT3 phosphorylation to exacerbate hepatic ischemia-reperfusion injury and tumor recurrence

BackgroundAt present, hepatic ischemia-reperfusion injury (IRI) is an important complication of partial hepatectomy and liver transplantation, and it is an important cause of poor prognosis. Spleen tyrosine kinase(SYK) plays an important role in a variety of signaling pathways in the liver, but its role in hepatic IRI is still unclear. This study aims to investigate the role and mechanism of SYK in hepatic IRI and tumor recurrence.MethodsWe first observed the activation of SYK in the liver of mice in response to hepatic IRI. Subsequently, Pharmacological inhibitions of SYK were used to evaluated the effect of SYK on neutrophil recruitment and NETosis, and further explored the effect of SYK on IRI and tumor recurrence.ResultsOur study shows that SYK is activated in response to hepatic IRI and aggravates liver injury. On the one hand, neutrophils SYK during the early stage of liver reperfusion increases neutrophil extracellular traps (NETs) production by promoting Pyruvate kinase M2(PKM2) nuclear translocation leading to upregulation of phosphorylated STAT3, thereby exacerbating liver inflammation and tumor recurrence. On the other hand, macrophages SYK can promote the recruitment of neutrophils and increase the activation of NLRP3 inflammasome and IL1β, which further promotes the formation of NETs.ConclusionsOur study demonstrates that neutrophil and macrophage SYK synergistically promote hepatic IRI and tumor recurrence, and SYK may be a potential target to improve postoperative hepatic IRI and tumor recurrence.

In-depth Clinical, Haemodynamic and Volumetric Assessment of the RAPID-type Auxiliary Liver Transplantation in Non-cirrhotic Setting; are we Simply Dealing with a Transplant Model of ALPPS?

The RAPID (Resection And Partial Liver Transplantation with Delayed total hepatectomy) procedure involves left hepatectomy with orthotopic implantation of a left lobe and right portal vein ligation. This technique induces volumetric graft increase, allowing for a right completion hepatectomy within 15 days. Notably, there is a lack of data on the hemodynamics of Small-for-Size (SFS) grafts exposed to portal overflow without triggering SFS syndrome. A prospective single-center protocol included eight living donors and eight RAPID non-cirrhotic recipients. Comprehensive clinical and biological data were collected, accompanied by intraoperative arterial and portal flow and pressure measurements. Early kinetic growth rate (eKGR%) and graft function were assessed using CT and 99Tc-mebrofenin scintigraphy on postoperative days 7 and 14. Findings were compared with retrospective data from13 left Living Donor Liver Transplantation (LDLT) recipients. The median Graft-body weight ratio was 0.41% (IQR, 0.34 to 0.49), markedly lower than in LDLT. However, there was no significant difference in eKGR between RAPID and LDLT grafts. Sequential analysis revealed variable eKGR per day: 10.6% (7.8-13.2) in the first week and 7.6% (6-9.1) in the second week post-transplantation. Indexed portal flow (iQpv) was significantly higher in RAPID compared to left LDLT (P=0.01). No hemodynamic parameters were found to correlate with regeneration speed. We modulated portal flow in 2 out of 8 cases. This study presents the first report of hemodynamic and volumetric data for the RAPID technique. Despite initial graft volumes falling below conventional LDLT recommendations, the study highlights acceptable clinical outcomes.

Auxiliary Partial Orthotopic Liver Transplantation Is a Safe and Effective Option for Yellow Phosphorus Toxin-induced Acute Liver Failure.

Ingestion of yellow phosphorus-containing rodenticides (YPR) or firecrackers is an important cause of acute liver failure (ALF) in young adults and children, particularly in South and South-East Asia and South America. Emergency liver transplantation is indicated in cases refractory to intensive supportive therapy, including low-volume plasma exchange. There are no published reports on the feasibility of auxiliary partial orthotopic liver transplantation (APOLT) for YPR-induced ALF. Clinical details of patients undergoing APOLT for YPR-induced ALF in 1 unit are reported. Details of postoperative follow-up, native remnant regeneration, and immunosuppression withdrawal are also reported. Between January 2021 and December 2023, 3 patients (4 y, 1.5 y, and 26 y) underwent emergency living donor liver transplantation for YPR-induced ALF. All patients were refractory to supportive therapies, including therapeutic plasma exchange, and demonstrated progression of liver injury in the form of severe encephalopathy needing intubation, ventilation, and organ support. APOLT was considered because of their young age and minimal intraoperative inotropic requirement. All explants showed confluent parenchymal necrosis with microvesicular and macrovesicular steatosis. Patients were initially maintained on standard immunosuppression. Good remnant regeneration was noted on follow-up imaging in all cases, enabling gradual withdrawal of immunosuppression. Currently, 1 child has been off immunosuppression for 15 mo and 2 others are on reduced doses of immunosuppression. All patients demonstrated good liver function. APOLT procedure can be an appropriate transplant option in YPR-related ALF for children and young adults without severe hemodynamic instability.

Perioperative management in pediatric domino liver transplantation for metabolic disorders: A narrative review.

Domino liver transplantation and domino-auxiliary partial orthotopic liver transplantation are emerging techniques that can expand the liver donor pool and provide hope for children with liver disease. The innovative technique of domino liver transplantation has emerged as a pioneering strategy, capitalizing on structurally preserved livers from donors exhibiting single enzymatic defects within a morphologically normal context, effectively broadening the donor pool. Concurrently, the increasingly prevalent domino-auxiliary partial orthotopic liver transplantation method assumes a critical role in bolstering available donor resources. These advanced transplantation methods present a unique opportunity for pediatric patients who, despite having structurally and functionally intact livers and lacking early signs of portal hypertension or extrahepatic involvement, do not attain priority on conventional transplant lists. Utilizing optimal clinical conditions enhances posttransplant outcomes, benefiting patients who would otherwise endure extended waiting periods for traditional transplantation. The perioperative management of children undergoing these procedures is complex and requires careful consideration of some factors, including clinical and metabolic conditions of the specific metabolic disorder, and the need for tailored perioperative management planning. Furthermore, the prudent consideration of de novo disease development in the recipient assumes paramount significance when selecting suitable donors for domino liver transplantation, as it profoundly influences prognosis, mortality, and morbidity. This narrative review of domino liver transplantation will discuss the pathophysiology, clinical evaluation, perioperative management, and prognostic expectations, focusing on perioperative anesthetic considerations for children undergoing domino liver transplantation.

Road To Deceased Donor Transplantation in Egypt.

In Egypt, there is presently a growing need to have a deceased donor transplant program. Egypt conducted its first kidney transplant from a living donor in 1976 and a first partial liver transplant in 2001. Since 2009, the Egyptian Health Authorities Combat Transplant Tourism in concordance with ethics codes and the Declaration of Istanbul Custodian Group has been in place. The Egyptian Transplantation Law of 2011 mentions that organs could be procured from deceased donors based on a will and on family consent. This law has had many critics, including religious authorities who have stressed that organs cannot be taken from a person with brain death because, in their view, life ends with death of all organs. Many intensivists disagree over the definition of death. In addition, the media has communicated contradicting and sometimes misleading health care information. Mummification is rooted in pharos practice and linked to religious beliefs. The ancient Egyptians believed that, by burying the deceased with their organs, they may rejoin with them in the afterlife. Since 2019, the transplant community in Egypt has started collaborations with international transplant organizations and campaigns with doctors and celebrities to donate their organs after death, which have stressed that a deceased donor program could help against end-stage organ mortality. In November 2022, after communications with politicians, President Abdelfattah El Sisi directed the government to establish a regional center for organ transplantation, which aimed to be the biggest in the Middle East and North Africa region. The new center will be part of a new medical city that would replace Nasser Medical Institution in Cairo, Egypt. The Ministry of Health issued an official form to be signed by a person before his death, accepting use of organs, to give hope and support to other patients in need.

SNX10 promoted liver IR injury by facilitating macrophage M1 polarization via NLRP3 inflammasome activation

BackgroundLiver ischemia reperfusion (IR) injury is a common cause of liver dysfunction in patients post liver partial resection and liver transplantation. However, the cellular defense mechanisms underlying IR are not well understood. Macrophage mediated sterile inflammation plays critical roles in liver IR injury. Sorting nexin (SNX) 10, a member of the SNX family which functions in regulation of endosomal sorting. This study aimed to explore the role of sorting nexin 10 (SNX10) during liver IR injury with a focus on regulating macrophage function. MethodsBoth the gene and protein expression levels of SNX10 were analyzed in human specimens from 10 patients undergoing liver partial resection with ischemic insult and in a mouse model of liver IR. The in vivo effects of SNX10 in liver IR injury and sterile inflammation in mice were investigated. Bone marrow derived macrophages (BMDMs) were used to determine the role of SNX10 in modulating macrophage function in vitro. ResultsIncreased expression of SNX10 was observed both in human specimens and mice livers post IR. SNX10 knockdown alleviated IR induced sterile inflammation and liver damage in mice. SNX10 promoted M1 polarization of macrophage treated with LPS and facilitated inflammatory response by activating NLRP3 inflammasome. ConclusionsWe report for the first time that SNX10 is upregulated in IR-stressed livers. SNX10 activation aggravates liver IR injury and sterile inflammation by facilitating macrophage M1 polarization and inflammatory response suggesting SNX10 as a potential therapeutic target for liver IR injury.

Dimethyloxalylglycine pretreatment of living donor alleviates both donor and graft liver ischemia-reperfusion injury in rats.

Background: Under the circumstance of the increasing waiting list for liver transplantation, living donor liver transplantation (LDLT) can alleviate the shortage of liver donors to some extent. However, how to reduce both donor and graft ischemia-reperfusion injury (IRI) is still an unsolved problem in LDLT. Hypoxia-induced transcription factor 1 (HIF1) activation is considered an important mechanism of cellular adaptation to hypoxia, and early activation of HIF1 may be a new way to alleviate liver IRI. Therefore, we aimed to investigate the impact of the HIF1 stabilizer dimethyloxalylglycine (DMOG) on IRI and the survival rate of donors and recipients of rat LDLT. Methods: Seventy percent partial liver resection and 30% partial liver transplantation were used to simulate donor and recipient of clinical LDLT. Rats were treated with DMOG (40mg/kg) or with an equivalent amount of saline. The expression of HIF1 and downstream targets was analyzed after 2h of reperfusion. Liver function and histopathology, apoptosis and oxidative stress levels were detected 6h after reperfusion. At the same time, the 7-day survival rate of rats was calculated. Results: DMOG pretreatment significantly reduced IR-induced injury in the donor and recipient, which was manifested by reducing liver function damage and promoting tissue recovery. Meanwhile, compared with the untreated group, the oxidative stress level and the cell apoptosis rate were decreased in the group pretreated with DMOG. In addition, the transcription and expression of HIF1 target genes in the DMOG group were significantly enhanced. Remarkably, DMOG also increased the survival rate of the recipient. Conclusion: This study provides the first evidence that DMOG pretreatment of donors significantly alleviates liver IRI in both donors and recipients and increases the survival rate of recipients in LDLT. Therefore, DMOG may be a promising strategy for improving LDLT in the future.

Myeloid Deletion of Cdc42 Protects Liver From Hepatic Ischemia-Reperfusion Injury via Inhibiting Macrophage-Mediated Inflammation in Mice

Background & AimsHepatic ischemia-reperfusion injury (HIRI) often occurs in liver surgery such as partial hepatectomy and liver transplantation, in which myeloid macrophage-mediated inflammation plays a critical role. Cell division cycle 42 (Cdc42) regulates cell migration, cytoskeleton rearrangement and cell polarity. In this study, we aim to explore the role of myeloid Cdc42 in HIRI. MethodsMouse HIRI models were established with 1 hr ischemia followed by 12 hr reperfusion in myeloid Cdc42 knockout (Cdc42mye) and Cdc42flox mice. Myeloid-derived macrophages were traced with RosamTmG fluorescent reporter under LyzCre mediated excision. The experiments for serum or hepatic enzymic activities, histological and immunological analysis, gene expressions, flow cytometry analysis and cytokine antibody array were performed. ResultsMyeloid deletion of Cdc42 significantly alleviated hepatic damages with the reduction of hepatic necrosis and inflammation, and reserved hepatic functions following HIRI in mice. Myeloid Cdc42 deficiency suppressed the infiltration of myeloid macrophages, reduced the secretion of proinflammatory cytokines, restrained M1 polarization and promoted M2 polarization of myeloid macrophages in livers. In addition, inactivation of Cdc42 promoted M2 polarization via suppressing the phosphorylation of STAT1 and promoting phosphorylation of STAT3 and STAT6 in myeloid macrophages. Furthermore, pretreatment with Cdc42 inhibitor, ML141, also protected mice from hepatic ischemia-reperfusion injury. ConclusionInhibition or deletion of myeloid Cdc42 protects liver from HIRI via restraining the infiltration of myeloid macrophages, suppressing proinflammatory response and promoting M2 polarization in macrophages.

Auxiliary partial orthotopic liver transplantation (APOLT) for Crigler-Najjar syndrome: a retrospective analysis

Auxiliary partial orthotopic liver transplantation (APOLT) for Crigler-Najjar syndrome: a retrospective analysis

The roles of liver sinusoidal endothelial cells in liver ischemia/reperfusion injury.

Liver ischemia/reperfusion injury (IRI) is a major complication after partial hepatectomy and liver transplantation and during hypovolemic shock and hypoxia-related diseases. Liver IRI is a current research hotspot. The early stage of liver IRI is characterized by injury and dysfunction of liver sinusoidal endothelial cells (LSECs), which, along with hepatocytes, are the major cells involved in liver injury. In this review, we elaborate on the roles played by LSECs in liver IRI, including the pathological features of LSECs, LSECs exacerbation of the sterile inflammatory response, LSECs interactions with platelets and the promotion of liver regeneration, and the activation of LSECs autophagy. In addition, we discuss the study of LSECs as therapeutic targets for the treatment of liver IRI and the existing problems when applying LSECs in liver IRI research.

Short-Term Monitoring of Graft Regeneration in Partial Liver Transplantation Recipients

Short-Term Monitoring of Graft Regeneration in Partial Liver Transplantation Recipients

Comparison of Postoperative Hemorrhage Risk After Partial Liver Transplantation Versus Whole Liver Transplantation: A Single-Center Experience

We aimed to identify risk factors associated with reoperation for postoperative intraperitoneal hemorrhage (PIH) after orthotopic liver transplantation and investigate if partial liver transplantation (PLT) increases the risk of PIH. We retrospectively analyzed the medical records of 304 consecutive recipients who underwent orthotopic liver transplantation at the Affiliated Lihuili Hospital, Ningbo University, from January 2016 to July 2022. Data were compared between recipients who experienced PIH requiring reoperation and those who did not. Subgroup propensity score matching analysis was performed to assess the impact of PLT on PIH risk. Neither prisoners nor participants who were coerced or paid were used in the study. Among the 304 recipients, 22 (7.2%) underwent reoperation for PIH. Multivariate analysis revealed that the recipient Model for End-Stage Liver Disease (MELD) score (odds ratio=1.066, 95% CI [1.025-1.109], P = .001) and volume of intraoperative packed red blood cell transfusion (odds ratio=1.089, 95% CI [1.032-1.481], P = .002) were independent risk factors for PIH. No significant differences were observed in the risk of PIH between PLT and whole liver transplantation. Preoperative MELD score and intraoperative packed red blood cell transfusion should be carefully considered to manage the risk of PIH in liver transplantation recipients. Partial liver transplantation, a crucial approach for addressing donor shortages, does not increase the risk of reoperation for PIH in recipients.

Xiao-Ping Chen: the “Master of the Scalpel” who saves lives by entering the forbidden territory of hepatopancreatobiliary surgery

In his 50 years of practice, he has performed more than 20,000 hepatopancreatobiliary surgeries, being the first one to propose the concept of the “auxiliary partial orthotopic liver transplantation” internationally. Furthermore, he developed the “Chen's inserting biliary-enteric anastomosis and pancreato-enteric anastomosis,” “Chen's hepatic vascular occlusion,” “Chen's liver double-hanging maneuver,” and “Chen's hepatic vascular occlusion without liver portal dissection.” He also popularized these theories and techniques both in China and worldwide. His name is Xiao-Ping Chen, an academician of the Chinese Academy of Sciences and honorary president of the Tongji Medical College of Huazhong University of Science and Technology.

Blockade of Hepatocyte PCSK9 Ameliorates Hepatic Ischemia-Reperfusion Injury by Promoting Pink1-Parkin–Mediated Mitophagy

Hepatic ischemia-reperfusion injury is a significant complication of partial hepatic resection and liver transplantation, impacting the prognosis of patients undergoing liver surgery. The protein proprotein convertase subtilisin/kexin type 9 (PCSK9) is primarily synthesized by hepatocytes and has been implicated in myocardial ischemic diseases. However, the role of PCSK9 in hepatic ischemia-reperfusion injury remains unclear. This study aims to investigate the role and mechanism of PCSK9 in hepatic ischemia-reperfusion injury. We first examined the expression of PCSK9 in mouse warm ischemia-reperfusion models and AML12 cells subjected to hypoxia/reoxygenation. Subsequently, we explored the impact of PCSK9 on liver ischemia-reperfusion injury by assessing mitochondrial damage and the resulting inflammatory response. Our findings reveal that PCSK9 is up-regulated in response to ischemia-reperfusion injury and exacerbates hepatic ischemia-reperfusion injury. Blocking PCSK9 can alleviate hepatocyte mitochondrial damage and the consequent inflammatory response mediated by ischemia-reperfusion. Mechanistically, this protective effect is dependent on mitophagy. Inhibiting PCSK9 in hepatocytes attenuates the inflammatory responses triggered by reactive oxygen species and mitochondrial DNA by promoting PINK1-Parkin-mediated mitophagy. This, in turn, ameliorates hepatic ischemia-reperfusion injury.

Auxiliary partial orthotopic liver transplantation (APOLT) for Crigler-Najjar syndrome: A retrospective analysis

BackgroundCrigler-Najjar syndrome is an ultra-rare hereditary disorder characterized by severe jaundice and risk of neurological complications. Current treatments, such as phototherapy, have limitations, and liver transplantation is often necessary. Auxiliary partial orthotopic liver transplantation (APOLT) is a potential treatment option. Still, its safety and efficacy in Pakistani patients with Crigler-Najjar syndrome Type I (CNS-I) have not been well established. MethodsThis retrospective study reviewed the outcomes of five pediatric patients with CNS-I who underwent APOLT at a tertiary care center in Pakistan. Patient demographics, surgical details, postoperative course, complications, and follow-up data were analyzed. The primary endpoint was the feasibility and safety of APOLT, while secondary endpoints included improvement in serum bilirubin levels, neurological symptoms, and survival rates. ResultsAmong five patients diagnosed with CNS-I, APOLT was performed without intraoperative complications. During the median follow-up period of 6 months, there were no cases of relaparotomy, graft rejection, biliary complications, or portal venous thrombosis. One patient developed a portal venous stricture, but his symptoms were controlled with conservative measures. Postoperative liver function tests showed a significant improvement, with an average reduction of 90% in serum bilirubin levels. There was some improvement in neurological symptoms, and the overall patient and graft survival rate was 100%. ConclusionThis study suggests that APOLT is a feasible and safe treatment option in patients with CNS-I. It improves liver function, bilirubin levels, and neurological symptoms. Further research with larger sample sizes is warranted to confirm these findings and evaluate the long-term outcomes of APOLT in this patient population.

The Role of Immune Cells in Liver Regeneration

The liver is the only organ that can regenerate and regain its original tissue-to-body weight ratio within a short period of time after tissue loss. Insufficient liver regeneration in patients after partial hepatectomy or liver transplantation with partial liver grafts often leads to post-hepatectomy liver failure or small-for-size syndrome, respectively. Enhancing liver regeneration after liver injury might improve outcomes and increase patient survival. Liver regeneration comprises hepatocyte proliferation, and hepatic progenitor cell expansion and differentiation into hepatocytes. The immune system is intensively involved in liver regeneration. The current review provides a comprehensive overview of the diverse roles played by immune cells in liver regeneration. Macrophages, neutrophils, eosinophils, basophils, mast cells, platelets, dendritic cells, type 1 innate lymphoid cells, B cells, and T cells are implicated in promoting liver regeneration, while natural killer cells and overactivated natural killer T cells are supposed to inhibit hepatocyte proliferation. We also highlight the predominant underlying mechanisms mediated by immune cells, which may contribute to the development of novel strategies for promoting liver regeneration in patients with liver diseases.

Synergy of 5-aminolevulinate supplement and CX3CR1 suppression promotes liver regeneration via elevated IGF-1 signaling

Inadequate remnant volume and regenerative ability of the liver pose life-threatening risks to patients after partial liver transplantation (PLT) or partial hepatectomy (PHx), while few clinical treatments focus on safely accelerating regeneration. Recently, we discovered that supplementing 5-aminolevulinate (5-ALA) improves liver cold adaptation and functional recovery, leading us to uncover a correlation between 5-ALA metabolic activities and post-PLT recovery. In a mouse 2/3 PHx model, 5-ALA supplements enhanced liver regeneration, promoting infiltration and polarization of anti-inflammatory macrophages via P53 signaling. Intriguingly, chemokine receptor CX3CR1 functions to counterbalance these effects. Genetic ablation or pharmacological inhibition of CX3CR1 (AZD8797; phase II trial candidate) augmented the macrophagic production of insulin-like growth factor 1 (IGF-1) and subsequent hepatocyte growth factor (HGF) production by hepatic stellate cells. Thus, short-term treatments with both 5-ALA and AZD8797 demonstrated pro-regeneration outcomes superior to 5-ALA-only treatments in mice after PHx. Overall, our findings may inspire safe and effective strategies to better treat PLT and PHx patients.

Outcome of split liver transplantation vs living donor liver transplantation: A systematic review and meta-analysis.

The outcomes of liver transplantation (LT) from different grafts have been studied individually and in combination, but the reports were conflicting with some researchers finding no difference in both short-term and long-term outcomes between the deceased donor split LT (DD-SLT) and living donor LT (LDLT). To compare the outcomes of DD-SLT and LDLT we performed this systematic review and meta-analysis. This systematic review was performed in compliance with the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. The following databases were searched for articles comparing outcomes of DD-SLT and LDLT: PubMed; Google Scholar; Embase; Cochrane Central Register of Controlled Trials; the Cochrane Database of Systematic Reviews; and Reference Citation Analysis (https://www.referencecitationanalysis.com/). The search terms used were: "liver transplantation;" "liver transplant;" "split liver transplant;" "living donor liver transplant;" "partial liver transplant;" "partial liver graft;" "ex vivo splitting;" and "in vivo splitting." Ten studies were included for the data synthesis and meta-analysis. There were a total of 4836 patients. The overall survival rate at 1 year, 3 years and 5 years was superior in patients that received LDLT compared to DD-SLT. At 1 year, the hazard ratios was 1.44 (95% confidence interval: 1.16-1.78; P = 0.001). The graft survival rate at 3 years and 5 years was superior in the LDLT group (3 year hazard ratio: 1.28; 95% confidence interval: 1.01-1.63; P = 0.04). This meta-analysis showed that LDLT has better graft survival and overall survival when compared to DD-SLT.

Swine Partial Liver Transplantation Model for Practicing Living Donor Liver Transplantation Based on a New Liver Segmentation Method.

Living donor liver transplantation (LDLT) is one of the most technically demanding and complicated procedures. However, unlike deceased donor liver transplantation, there is no suitable animal model for practicing LDLT. Herein, we propose a new liver segmentation method and a feasible pig LDLT model for practicing for LDLT in humans. Four Landrace pigs weighing 25, 25, 27, and 28 kg were used as donors and recipients to establish a partial liver transplantation model. Partial liver transplantation was performed using a right liver and a left liver, respectively, based on a new segmentation system compatible with that of humans. We established a new segmentation system for porcine liver transplantation and a partial liver transplantation model. For right liver transplantation, 91 and 142 min were required to operate on the donor and recipient, respectively; for left liver transplantation, 57 and 104 min were required to operate on the donor and recipient, respectively. All pigs that underwent partial liver transplantation remained alive until the operation was completed. It is expected that this new pig model based on the new segmentation system will be suitable as an educational tool for LDLT training and will replace the existing animal models for partial liver transplantation.

A novel HIF2A mutation causes dyslipidemia and promotes hepatic lipid accumulation

Hypoxia-inducible factor-2α (HIF-2α) is a transcription factor responsible for regulating genes related to angiogenesis and metabolism. This study aims to explore the effect of a previously unreported mutation c.C2473T (p.R825S) in the C-terminal transactivation domain (CTAD) of HIF-2α that we detected in tissue of patients with liver disease. We sequenced available liver and matched blood samples obtained during partial liver resection or liver transplantation performed for clinical indications including hepatocellular carcinoma and liver failure. In tandem, we constructed cell lines and a transgenic mouse model bearing the corresponding identified mutation in HIF-2α from which we extracted primary hepatocytes. Lipid accumulation was evaluated in these cells and liver tissue from the mouse model using Oil Red O staining and biochemical measurements. We identified a mutation in the CTAD of HIF-2α (c.C2473T; p.R825S) in 5 of 356 liver samples obtained from patients with hepatopathy and dyslipidemia. We found that introduction of this mutation into the mouse model led to an elevated triglyceride level, lipid droplet accumulation in liver of the mutant mice and in their extracted primary hepatocytes, and increased transcription of genes related to hepatic fatty acid transport and synthesis in the mutant compared to the control groups. In mutant mice and cells, the protein levels of nuclear HIF-2α and its target perilipin-2 (PLIN2), a lipid droplet-related gene, were also elevated. Decreased lipophagy was observed in mutant groups. Our study defines a subpopulation of dyslipidemia that is caused by this HIF-2α mutation. This may have implications for personalized treatment.