Pub Date : 2024-11-11DOI: 10.1097/hep.0000000000001154
Anna Di Sessa, Emanuele Miraglia del Giudice
{"title":"Letter to Editor: Prevalence of subclinical hypothyroidism and longitudinal thyroid stimulating hormone changes in youth with metabolic dysfunction-associated steatotic liver disease: an observational study","authors":"Anna Di Sessa, Emanuele Miraglia del Giudice","doi":"10.1097/hep.0000000000001154","DOIUrl":"https://doi.org/10.1097/hep.0000000000001154","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"1 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-11DOI: 10.1097/hep.0000000000001159
Ziyi He, Chenxi Wang, Huichuan Tian
{"title":"Letter to the editor : Association of hepatitis delta virus infection and hepatocellular carcinoma, hepatic decompensation, all-cause and liver-related death in a national cohort","authors":"Ziyi He, Chenxi Wang, Huichuan Tian","doi":"10.1097/hep.0000000000001159","DOIUrl":"https://doi.org/10.1097/hep.0000000000001159","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"5 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-08DOI: 10.1097/hep.0000000000001146
Benjamin J. Bruno, Joshua C. Weavil, Jonathan Ogle, Nachiappan Chidambaram, Elizabeth J. Carey, Christopher J. Danford, Zarchary P. Fricker, Joseph S. Galati, William M. Lee, Parvez S. Mantry, Kirti Shetty, Anthony DelConte, Mahesh V. Patel, Jennifer C. Lai, Arun J. Sanyal
Background & Aims: Sarcopenia is highly prevalent in patients with liver cirrhosis and is associated with adverse clinical outcomes including hepatic encephalopathy (HE). Androgen receptor agonists, ARAs, can address these conditions through multimodal mechanisms of action, however their safety and efficacy in patients with cirrhosis have not been well established. Approach & Results: In this multicenter, double-blind, phase 2 trial, men with sarcopenia and cirrhosis awaiting liver transplant were randomized 1:1 to receive either oral ARA LPCN 1148 or placebo for 24 weeks (NCT04874350). The primary endpoint was the change from baseline to 24 weeks in skeletal muscle index measured by computed tomography scan of the L3 region (L3-SMI), analyzed with a prespecified modified intent-to-treat population. The secondary endpoint was the number of overt HE events. 29 participants (mean age=59 y, MELD=17) received at least one dose of LPCN 1148 (n=15) or placebo (n=14). Baseline characteristics were similar between groups. Primary endpoint analysis demonstrated an increase in L3-SMI in the LPCN 1148 group (n=15) compared to placebo (n=10), with a mean group difference of 4.4 cm2/m2 (95% CI, 1.3-7.4 cm2/m2, p=0.007). Participants in LPCN 1148 experienced fewer episodes of overt HE (CTCAE grade ≥2; p=0.02) than placebo. The number and severity of treatment-emergent adverse events were similar between arms. Conclusions: LPCN 1148 treatment improved sarcopenia and reduced the number of overt HE episodes in men with cirrhosis and sarcopenia awaiting liver transplant. These findings support additional research on the efficacy of LPCN 1148 in treating sarcopenia and preventing HE recurrence.
背景& 目的：肌肉疏松症在肝硬化患者中非常普遍，并与包括肝性脑病（HE）在内的不良临床结果有关。雄激素受体激动剂（ARA）可通过多模式作用机制解决这些问题，但其在肝硬化患者中的安全性和有效性尚未得到充分证实。方法与amp; 结果：在这项多中心、双盲、2 期试验中，患有肌肉疏松症和肝硬化并等待肝移植的男性患者按 1:1 的比例随机接受口服 ARA LPCN 1148 或安慰剂治疗 24 周（NCT04874350）。主要终点是通过L3区域计算机断层扫描测量的骨骼肌指数（L3-SMI）从基线到24周的变化，并对预设的修正意向治疗人群进行分析。次要终点是明显 HE 事件的数量。29名参与者（平均年龄=59岁，MELD=17）接受了至少一剂LPCN 1148（15人）或安慰剂（14人）。各组的基线特征相似。主要终点分析表明，与安慰剂组（10 人）相比，LPCN 1148 组（15 人）的 L3-SMI 有所增加，平均组间差异为 4.4 cm2/m2（95% CI，1.3-7.4 cm2/m2，p=0.007）。与安慰剂相比，LPCN 1148 参与者发生明显 HE（CTCAE 分级≥2；p=0.02）的次数更少。两组患者在治疗过程中出现的不良反应次数和严重程度相似。结论LPCN 1148 治疗可改善患有肝硬化和肌肉疏松症并等待肝移植的男性患者的肌肉疏松症，并减少明显 HE 的发作次数。这些发现支持对 LPCN 1148 治疗肌肉疏松症和预防 HE 复发的疗效进行更多研究。
{"title":"Oral LPCN 1148 improves sarcopenia and hepatic encephalopathy in male patients with cirrhosis: A randomized, placebo-controlled phase 2 trial","authors":"Benjamin J. Bruno, Joshua C. Weavil, Jonathan Ogle, Nachiappan Chidambaram, Elizabeth J. Carey, Christopher J. Danford, Zarchary P. Fricker, Joseph S. Galati, William M. Lee, Parvez S. Mantry, Kirti Shetty, Anthony DelConte, Mahesh V. Patel, Jennifer C. Lai, Arun J. Sanyal","doi":"10.1097/hep.0000000000001146","DOIUrl":"https://doi.org/10.1097/hep.0000000000001146","url":null,"abstract":"Background & Aims: Sarcopenia is highly prevalent in patients with liver cirrhosis and is associated with adverse clinical outcomes including hepatic encephalopathy (HE). Androgen receptor agonists, ARAs, can address these conditions through multimodal mechanisms of action, however their safety and efficacy in patients with cirrhosis have not been well established. Approach & Results: In this multicenter, double-blind, phase 2 trial, men with sarcopenia and cirrhosis awaiting liver transplant were randomized 1:1 to receive either oral ARA LPCN 1148 or placebo for 24 weeks (NCT04874350). The primary endpoint was the change from baseline to 24 weeks in skeletal muscle index measured by computed tomography scan of the L3 region (L3-SMI), analyzed with a prespecified modified intent-to-treat population. The secondary endpoint was the number of overt HE events. 29 participants (mean age=59 y, MELD=17) received at least one dose of LPCN 1148 (n=15) or placebo (n=14). Baseline characteristics were similar between groups. Primary endpoint analysis demonstrated an increase in L3-SMI in the LPCN 1148 group (n=15) compared to placebo (n=10), with a mean group difference of 4.4 cm<jats:sup>2</jats:sup>/m<jats:sup>2</jats:sup> (95% CI, 1.3-7.4 cm<jats:sup>2</jats:sup>/m<jats:sup>2</jats:sup>, <jats:italic toggle=\"yes\">p</jats:italic>=0.007). Participants in LPCN 1148 experienced fewer episodes of overt HE (CTCAE grade ≥2; <jats:italic toggle=\"yes\">p</jats:italic>=0.02) than placebo. The number and severity of treatment-emergent adverse events were similar between arms. Conclusions: LPCN 1148 treatment improved sarcopenia and reduced the number of overt HE episodes in men with cirrhosis and sarcopenia awaiting liver transplant. These findings support additional research on the efficacy of LPCN 1148 in treating sarcopenia and preventing HE recurrence.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"33 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142597834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background & Aims: Immune system activation along with lipotoxicity due to excessive lipid droplet (LD) accumulation in the liver are key drivers of non-alcoholic steatohepatitis (NASH). Extracellular vesicles (EVs) released by cells that carry biological signals to contribute intercellular communication. But the roles of immune cells-derived EVs in pathogenesis of NASH are unclear. Approach & Results: Platelets are abundant in blood. We explored the role of platelet-derived EVs (pEVs) in LD accumulation from 30 patients with non-alcoholic fatty liver disease of different severity as well as 20 healthy subjects, a rat model, and an in vitro cell-based assay. There was increased platelet activation, accompanied by pEVs release, in NASH patients/rat model, and palmitate-treated cells. The mitochondria in the platelets and pEVs from NASH patients/rats were increased but dysfunctional, including a reduction in fatty acid β-oxidation, inactivated ACC2, and suppressed oxidative phosphorylation system complex II/III/IV activity. These damaged mitochondria could be transferred to hepatocytes via pEVs to increase the number of lipid droplet–bound mitochondria (LDM). An increase in dysfunctional LDM in hepatocytes affects lipid metabolism, resulting in excessive LD accumulation, elevated mitochondrial ROS production, and apoptosis. Conclusions: We offer a novel molecular mechanism that connects platelets, pEVs, and excessive LD accumulation to the development of NASH. Our results suggest that NASH progression may be alleviated by specifically inhibiting the production and release of pEVs, or by targeting pEVs components and inhibiting their uptake. Additional experiments are required to confirm this potentiality.
{"title":"Platelet-derived mitochondria regulate lipid metabolism in nonalcoholic steatohepatitis via extracellular vesicles","authors":"Tsai-Ling Liao, Der-Yuan Chen, Shie-Liang Hsieh, Ying-Ying Yang, Yi-Ming Chen, Kuo-Tung Tang, Chung-Hsin Chang, Sheng-Shun Yang","doi":"10.1097/hep.0000000000001149","DOIUrl":"https://doi.org/10.1097/hep.0000000000001149","url":null,"abstract":"Background & Aims: Immune system activation along with lipotoxicity due to excessive lipid droplet (LD) accumulation in the liver are key drivers of non-alcoholic steatohepatitis (NASH). Extracellular vesicles (EVs) released by cells that carry biological signals to contribute intercellular communication. But the roles of immune cells-derived EVs in pathogenesis of NASH are unclear. Approach & Results: Platelets are abundant in blood. We explored the role of platelet-derived EVs (pEVs) in LD accumulation from 30 patients with non-alcoholic fatty liver disease of different severity as well as 20 healthy subjects, a rat model, and an <jats:italic toggle=\"yes\">in vitro</jats:italic> cell-based assay. There was increased platelet activation, accompanied by pEVs release, in NASH patients/rat model, and palmitate-treated cells. The mitochondria in the platelets and pEVs from NASH patients/rats were increased but dysfunctional, including a reduction in fatty acid β-oxidation, inactivated ACC2, and suppressed oxidative phosphorylation system complex II/III/IV activity. These damaged mitochondria could be transferred to hepatocytes via pEVs to increase the number of lipid droplet–bound mitochondria (LDM). An increase in dysfunctional LDM in hepatocytes affects lipid metabolism, resulting in excessive LD accumulation, elevated mitochondrial ROS production, and apoptosis. Conclusions: We offer a novel molecular mechanism that connects platelets, pEVs, and excessive LD accumulation to the development of NASH. Our results suggest that NASH progression may be alleviated by specifically inhibiting the production and release of pEVs, or by targeting pEVs components and inhibiting their uptake. Additional experiments are required to confirm this potentiality.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"6 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-07DOI: 10.1097/hep.0000000000001122
Nicole Hilbert, Georg Lurje, Frank Tacke, Linda Hammerich, Isabella Lurje
{"title":"Letter to the Editor: Clonally expanded CD8+ T cells in MASH – invited guests overstaying their welcome","authors":"Nicole Hilbert, Georg Lurje, Frank Tacke, Linda Hammerich, Isabella Lurje","doi":"10.1097/hep.0000000000001122","DOIUrl":"https://doi.org/10.1097/hep.0000000000001122","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"148 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-07DOI: 10.1097/hep.0000000000001148
Edilmar Alvarado-Tapias, Anna Brujats, Angela Puente, Alba Ardevol, Ainhoa Rodriguez-Arias, Javier Fajardo, Oanna Pavel, Marta Garcia-Guix, Carles Aracil, Maria Poca, Berta Cuyàs, Elisabet Cantó, Rosa Montañés, Alvaro Garcia-Osuna, Àngels Escorsell, Xavier Torras, Càndid Villanueva
Background & Aims: Carvedilol is a non-selective β-blocker (NSBBs) with anti-α1-adrenergic activity, more effective than traditional NSBBs in reducing portal-pressure (HVPG). However, 35%-45% of patients still have insufficient HVPG-decrease. Statins ameliorate endothelial dysfunction, reduce hepatic vascular resistance, and have pleiotropic effects. We investigated whether the addition of simvastatin improves the efficacy of carvedilol on HVPG in cirrhosis with severe portal-hypertension and suboptimal response to traditional-NSBBs. Methods: Patients with cirrhosis and high-risk varices referred for primary prophylaxis were consecutively included. HVPG was measured at baseline and again after i.v.propranolol. Suboptimal responders (HVPG-decrease <20%) were treated with carvedilol and were randomized to double-blind administration of placebo or simvastatin. Chronic HVPG response was assessed after 4-6-weeks, repeating HVPG-measurements after a standard liquid meal to estimate endothelial dysfunction. Plasma samples were obtained before each study to investigate inflammatory parameters. Results: Of 184 eligible patients, 82 were randomized to carvedilol+simvastatin (N=41) or carvedilol+placebo (N=41). Baseline characteristics were similar. HVPG significantly decreased with both, carvedilol+simvastatin (18.6±4-to-15.7±4 mm Hg, p<0.001) and carvedilol+placebo (18.9±3-to-16.9±3 mm Hg, p<0.001). The decrease was greater with carvedilol+simvastatin (2.97±2.5 vs. 2.05±1.6 mm Hg, p=0.031). An HVPG-decrease ≥20% occurred in 37% versus 15% patients respectively (OR:3.37, 95% CI=1.15-9.85; p=0.021). With test-meal, HVPG increased in both groups (p<0.01), although carvedilol+simvastatin attenuated such increment (12±8% vs. 23±16%, p<0.001). Cytokine levels (IL-6,MCP-1,MDA) decreased significantly more with carvedilol+simvastatin (p<0.01). Incidence of adverse events was similar. Conclusion: In patients with severe portal hypertension (all with high-risk varices) and suboptimal hemodynamic response to traditional NSBBs, combined therapy with carvedilol plus simvastatin significantly enhances the portal-pressure reduction achieved with carvedilol-monotherapy, improves endothelial dysfunction and reduces pro-inflammatory cytokines.
背景& 目的：卡维地洛是一种非选择性β受体阻滞剂（NSBB），具有抗α1肾上腺素能活性，在降低门脉压力（HVPG）方面比传统的非选择性β受体阻滞剂更有效。然而，仍有 35%-45% 的患者 HVPG 降幅不足。他汀类药物可改善内皮功能障碍，降低肝血管阻力，并具有多重效应。我们研究了在严重门脉高压且对传统 NSBBs 反应不佳的肝硬化患者中添加辛伐他汀是否能改善卡维地洛对 HVPG 的疗效。研究方法连续纳入转诊接受一级预防治疗的肝硬化和高危静脉曲张患者。在基线和静脉注射普萘洛尔后再次测量 HVPG。疗效不佳者（HVPG 下降 <20%）接受卡维地洛治疗，并随机接受安慰剂或辛伐他汀的双盲治疗。4-6周后评估慢性 HVPG 反应，在标准流食后重复测量 HVPG，以估计内皮功能障碍。每次研究前都会采集血浆样本，以调查炎症参数。研究结果在184名符合条件的患者中，82人被随机分配到卡维地洛+辛伐他汀（41人）或卡维地洛+安慰剂（41人）。基线特征相似。卡维地洛+西伐他汀（18.6±4 至 15.7±4 mm Hg，p<0.001）和卡维地洛+安慰剂（18.9±3 至 16.9±3 mm Hg，p<0.001）均能明显降低 HVPG。卡维地洛+西伐他汀的降幅更大（2.97±2.5 vs. 2.05±1.6 mm Hg，p=0.031）。HVPG下降≥20%的患者分别占37%和15%（OR:3.37, 95% CI=1.15-9.85; p=0.021）。在试餐时，两组患者的 HVPG 均有所增加（p<0.01），但卡维地洛+辛伐他汀可减轻这种增加（12±8% vs. 23±16%，p<0.001）。卡维地洛+辛伐他汀可显著降低细胞因子水平（IL-6、MCP-1、MDA）（p<0.01）。不良反应发生率相似。结论对于重度门静脉高压患者（均伴有高危静脉曲张）和对传统非苯并噻唑类药物血流动力学反应不理想的患者，卡维地洛+辛伐他汀联合治疗可显著提高卡维地洛单药治疗所达到的门静脉压力降低效果，改善内皮功能障碍并减少促炎细胞因子。
{"title":"Hemodynamic effects of carvedilol plus simvastatin in cirrhosis with severe portal hypertension and suboptimal response to β-blockers: A double-blind, placebo-controlled, randomized-trial","authors":"Edilmar Alvarado-Tapias, Anna Brujats, Angela Puente, Alba Ardevol, Ainhoa Rodriguez-Arias, Javier Fajardo, Oanna Pavel, Marta Garcia-Guix, Carles Aracil, Maria Poca, Berta Cuyàs, Elisabet Cantó, Rosa Montañés, Alvaro Garcia-Osuna, Àngels Escorsell, Xavier Torras, Càndid Villanueva","doi":"10.1097/hep.0000000000001148","DOIUrl":"https://doi.org/10.1097/hep.0000000000001148","url":null,"abstract":"Background & Aims: Carvedilol is a non-selective β-blocker (NSBBs) with anti-α1-adrenergic activity, more effective than traditional NSBBs in reducing portal-pressure (HVPG). However, 35%-45% of patients still have insufficient HVPG-decrease. Statins ameliorate endothelial dysfunction, reduce hepatic vascular resistance, and have pleiotropic effects. We investigated whether the addition of simvastatin improves the efficacy of carvedilol on HVPG in cirrhosis with severe portal-hypertension and suboptimal response to traditional-NSBBs. Methods: Patients with cirrhosis and high-risk varices referred for primary prophylaxis were consecutively included. HVPG was measured at baseline and again after i.v.propranolol. Suboptimal responders (HVPG-decrease <20%) were treated with carvedilol and were randomized to double-blind administration of placebo or simvastatin. Chronic HVPG response was assessed after 4-6-weeks, repeating HVPG-measurements after a standard liquid meal to estimate endothelial dysfunction. Plasma samples were obtained before each study to investigate inflammatory parameters. Results: Of 184 eligible patients, 82 were randomized to carvedilol+simvastatin (N=41) or carvedilol+placebo (N=41). Baseline characteristics were similar. HVPG significantly decreased with both, carvedilol+simvastatin (18.6±4-to-15.7±4 mm Hg, <jats:italic toggle=\"yes\">p</jats:italic><0.001) and carvedilol+placebo (18.9±3-to-16.9±3 mm Hg, <jats:italic toggle=\"yes\">p</jats:italic><0.001). The decrease was greater with carvedilol+simvastatin (2.97±2.5 vs. 2.05±1.6 mm Hg, <jats:italic toggle=\"yes\">p</jats:italic>=0.031). An HVPG-decrease ≥20% occurred in 37% versus 15% patients respectively (OR:3.37, 95% CI=1.15-9.85; <jats:italic toggle=\"yes\">p</jats:italic>=0.021). With test-meal, HVPG increased in both groups (<jats:italic toggle=\"yes\">p</jats:italic><0.01), although carvedilol+simvastatin attenuated such increment (12±8% vs. 23±16%, <jats:italic toggle=\"yes\">p</jats:italic><0.001). Cytokine levels (IL-6,MCP-1,MDA) decreased significantly more with carvedilol+simvastatin (<jats:italic toggle=\"yes\">p</jats:italic><0.01). Incidence of adverse events was similar. Conclusion: In patients with severe portal hypertension (all with high-risk varices) and suboptimal hemodynamic response to traditional NSBBs, combined therapy with carvedilol plus simvastatin significantly enhances the portal-pressure reduction achieved with carvedilol-monotherapy, improves endothelial dysfunction and reduces pro-inflammatory cytokines.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"45 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-07DOI: 10.1097/hep.0000000000001151
Patricia P. Bloom, Anna S. Lok
{"title":"Reply: Enhancing automated speech analysis for hepatic encephalopathy detection","authors":"Patricia P. Bloom, Anna S. Lok","doi":"10.1097/hep.0000000000001151","DOIUrl":"https://doi.org/10.1097/hep.0000000000001151","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"11 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-04DOI: 10.1097/HEP.0000000000001131
Beat Moeckli, Joana Rodrigues Ribeiro, Christian Toso
{"title":"Liver transplantation for nonstandard oncological indications: Are we there yet?","authors":"Beat Moeckli, Joana Rodrigues Ribeiro, Christian Toso","doi":"10.1097/HEP.0000000000001131","DOIUrl":"https://doi.org/10.1097/HEP.0000000000001131","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":""},"PeriodicalIF":12.9,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01Epub Date: 2023-10-23DOI: 10.1097/HEP.0000000000000638
Tao Yang, Xiaoye Qu, Xiao Wang, Dongwei Xu, Mingwei Sheng, Yuanbang Lin, Michael Ke, Ci Song, Qiang Xia, Longfeng Jiang, Jun Li, Douglas G Farmer, Bibo Ke
Background and aims: The hallmark of NAFLD or hepatic steatosis is characterized by lipid droplet (LD) accumulation in hepatocytes. Autophagy may have profound effects on lipid metabolism and innate immune response. However, how innate immune activation may regulate the autophagic degradation of intracellular LDs remains elusive.
Approach and results: A mouse model of a high-fat diet-induced NASH was used in the myeloid-specific stimulator of interferon genes (STING) knockout or STING/yes-associated protein (YAP) double knockout mice. Liver injury, lipid accumulation, lipid droplet proteins, autophagic genes, chromatin immunoprecipitation coupled with massively parallel sequencing, and RNA-Seq were assessed in vivo and in vitro . We found that high-fat diet-induced oxidative stress activates STING and YAP pathways in hepatic macrophages. The acrophage STING deficiency (myeloid-specific STING knockout) enhances nuclear YAP activity, reduces lipid accumulation, and increases autophagy-related proteins ATG5, ATG7, and light chain 3B but diminishes LD protein perilipin 2 expression. However, disruption of STING and YAP (myeloid STING and YAP double knockout) increases serum alanine aminotransferase and triglyceride levels and reduces β-fatty acid oxidation gene expression but augments perilipin 2 levels, exacerbating high-fat diet-induced lipid deposition. Chromatin immunoprecipitation coupled with massively parallel sequencing reveals that macrophage YAP targets transmembrane protein 205 and activates AMP-activated protein kinase α, which interacts with hepatocyte mitofusin 2 and induces protein disulfide isomerase activation. Protein disulfide isomerase activates hypoxia-inducible factor-1α signaling, increases autophagosome colocalization with LDs, and promotes the degradation of perilipin 2 by interacting with chaperone-mediated autophagy chaperone HSC70.
Conclusions: The macrophage STING-YAP axis controls hepatic steatosis by reprogramming lipid metabolism in a transmembrane protein 205/mitofusin 2/protein disulfide isomerase-dependent pathway. These findings highlight the regulatory mechanism of the macrophage STING-driven YAP activity on lipid control.
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