VLDL lipidomics reveals hepatocellular lipidome changes in metabolic dysfunction-associated steatotic liver disease.

IF 5.6 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Hepatology Communications Pub Date : 2025-05-23 eCollection Date: 2025-06-01 DOI:10.1097/HC9.0000000000000716
David Guardamino Ojeda, Yusuf Yalcin, Yered Pita-Juarez, Aaron Hakim, Susmita Bhattarai, Zsu-Zsu Chen, John M Asara, Margery A Connelly, Melissa R Miller, Michelle Lai, Z Gordon Jiang
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Abstract

Background: The production of VLDL is one of the primary mechanisms through which liver cells regulate intracellular lipid homeostasis. We hypothesize that the disease characteristics of metabolic dysfunction-associated steatotic liver disease (MASLD) differentially impact VLDL lipid composition. This study comprehensively examines the relationship between VLDL-lipidome and MASLD histology and disease-associated genetics, aiming to define MASLD-related VLDL changes.

Methods: We performed untargeted lipidomics on serum VLDL particles in a cohort of biopsy-proven MASLD patients to examine the relationship between VLDL-lipidome and MASLD disease features as well as MASLD-related genetic variants.

Results: Among 1514 detected lipid species in VLDL, triglyceride (TG), phosphatidylcholine (PC), and ceramide (Cer) were the top classes. Moderate to severe hepatic steatosis was associated an increase in VLDL-TG, especially those with palmitic acid (C16:0). A unified acyl chain distribution analysis revealed that steatosis was associated with increases in TGs with saturated and monounsaturated fatty acyl chains, but decreases in polyunsaturated fatty acyl chains, a pattern that was not mirrored in acyl chains from VLDL-PC or VLDL-Cer. Lobular inflammation was associated with reductions in lipids with polyunsaturated acyl chains, particularly docosahexaenoic acid (C22:6). Meanwhile, patients with advanced liver fibrosis (stages 3-4) had reductions in VLDL-TGs with both saturated and polyunsaturated acyl chains and overall enrichment in Cer species. Furthermore, MASLD-associated genetic variants in PNPLA3, TM6SF2, GPAM, HSD17B13, and MTARC1 demonstrated distinct VLDL-lipidomic signatures in keeping with their biology in lipoprotein metabolism.

Conclusions: Hepatic steatosis and liver fibrosis in MASLD are associated with distinct VLDL-lipidomic signatures, respectively. This relationship is further modified by MASLD-genetics, suggesting a differential impact of pathogenic features on hepatocellular lipid homeostasis.

VLDL脂质组学揭示代谢功能障碍相关脂肪变性肝病的肝细胞脂质组改变。
背景:VLDL的产生是肝细胞调节细胞内脂质稳态的主要机制之一。我们假设代谢功能障碍相关脂肪变性肝病(MASLD)的疾病特征对VLDL脂质组成的影响存在差异。本研究全面探讨了VLDL-脂质组与MASLD组织学和疾病相关遗传学的关系,旨在明确MASLD相关的VLDL变化。方法:我们对一组活检证实的MASLD患者的血清VLDL颗粒进行了非靶向脂质组学研究,以研究VLDL-脂质组学与MASLD疾病特征以及MASLD相关遗传变异之间的关系。结果:在VLDL检测到的1514种脂质中,甘油三酯(TG)、磷脂酰胆碱(PC)和神经酰胺(Cer)为最高类别。中度至重度肝脂肪变性与VLDL-TG升高相关,尤其是棕榈酸组(C16:0)。一项统一的酰基链分布分析显示,脂肪变性与饱和和单不饱和脂肪酰基链的TGs增加有关,而与多不饱和脂肪酰基链的TGs减少有关,这种模式在VLDL-PC或VLDL-Cer的酰基链中没有反映出来。小叶炎症与多不饱和酰基链脂质减少有关,特别是二十二碳六烯酸(C22:6)。同时,晚期肝纤维化患者(3-4期)饱和和多不饱和酰基链的vldl - tg均减少,Cer物种总体富集。此外,在PNPLA3、TM6SF2、GPAM、HSD17B13和MTARC1中与masld相关的遗传变异显示出不同的vldl -脂质组学特征,这与它们在脂蛋白代谢中的生物学特性保持一致。结论:MASLD的肝脂肪变性和肝纤维化分别与不同的vldl -脂质组学特征相关。这种关系被masld遗传学进一步修正,表明致病特征对肝细胞脂质稳态有不同的影响。
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来源期刊
Hepatology Communications
Hepatology Communications GASTROENTEROLOGY & HEPATOLOGY-
CiteScore
8.00
自引率
2.00%
发文量
248
审稿时长
8 weeks
期刊介绍: Hepatology Communications is a peer-reviewed, online-only, open access journal for fast dissemination of high quality basic, translational, and clinical research in hepatology. Hepatology Communications maintains high standard and rigorous peer review. Because of its open access nature, authors retain the copyright to their works, all articles are immediately available and free to read and share, and it is fully compliant with funder and institutional mandates. The journal is committed to fast publication and author satisfaction. ​
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