Lee Jaejun, Cha Jung Hoon, Cho Hee Sun, Yang Keungmo, Yang Hyun, Nam Heechul, Byun Mi Young, Cho Seok Keun, Park Jinsung, Ko Hyuk Wan, Yang Seong Wook, Sung Pil Soo, Bae Si Hyun
Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
The Catholic University Liver Research Center, Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
J Gastroenterol. 2025 Jul 21. doi: 10.1007/s00535-025-02285-1.
Increasing evidence reveals that immune cells significantly contribute to metabolic dysfunction-associated steatotic liver disease (MASLD) progression. The patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148M variant has been linked to hepatic inflammation and fibrosis; however, its role in immune cell infiltration and activation within the liver remains unclear.
Seventy patients with MASLD were prospectively enrolled. Genomic DNA was extracted from buccal swabs or liver biopsy samples, followed by single nucleotide polymorphism genotyping to determine the rs738409 SNP genotype at codon 148 of PNPLA3. Immunohistochemistry was conducted using CD3 and CD68 antibodies to quantify T cell and macrophage infiltration, respectively. Total RNA extracted from biopsy specimens was used for quantitative reverse transcription polymerase chain reaction to assess the expression of specific markers associated with immune cell activation.
Among the 70 patients with MASLD, 34 had the GG genotype, whereas 21 and 15 had the GC and CC genotypes, respectively. The GG genotype group showed a higher proportion of advanced fibrosis (F3 or F4) than the GC + CC group (P = 0.051). GG genotype carriers exhibited significantly higher CD3 and CD68 cell counts in the periportal region than the GC/CC carriers (P < 0.05). The transcriptomic analysis revealed elevated expression of markers associated with chronic antigen stimulation and immune cell activation (CD8A, GZMB, CCL2, and TIMP1) in GG carriers compared with those of GC and CC (P < 0.05). Furthermore, correlations among various markers, including inflammatory, steatosis-associated, and fibrosis-associated markers, exhibited consistent positive correlations.
Our findings revealed that the PNPLA3 I148M variant and increased immune cell infiltration and activation were significantly correlated within the MASLD liver. Further studies are needed to elucidate the mechanistic links between this genetic variant and liver inflammation.
越来越多的证据表明，免疫细胞在代谢功能障碍相关脂肪性肝病（MASLD）进展中起重要作用。含patatin样磷脂酶结构域蛋白3（PNPLA3）的I148M变体与肝脏炎症和纤维化有关；然而，其在肝脏免疫细胞浸润和激活中的作用仍不清楚。
前瞻性纳入70例MASLD患者。从口腔拭子或肝活检样本中提取基因组DNA，然后进行单核苷酸多态性基因分型，以确定PNPLA3第148位密码子的rs738409单核苷酸多态性基因型。分别使用CD3和CD68抗体进行免疫组织化学，以定量T细胞和巨噬细胞浸润。从活检标本中提取的总RNA用于定量逆转录聚合酶链反应，以评估与免疫细胞激活相关的特定标志物的表达。
在70例MASLD患者中，34例具有GG基因型，而21例和15例分别具有GC和CC基因型。GG基因型组的晚期纤维化（F3或F4）比例高于GC + CC组（P = 0.051）。GG基因型携带者在门静脉周围区域的CD3和CD68细胞计数显著高于GC/CC携带者（P < 0.05）。转录组分析显示，与GC和CC携带者相比，GG携带者中与慢性抗原刺激和免疫细胞激活相关的标志物（CD8A、GZMB、CCL2和TIMP1）表达升高（P < 0.05）。此外，包括炎症、脂肪变性相关和纤维化相关标志物在内的各种标志物之间的相关性呈现一致的正相关。
我们的研究结果表明，在MASLD肝脏中，PNPLA3的I148M变体与免疫细胞浸润和激活增加显著相关。需要进一步研究以阐明这种基因变体与肝脏炎症之间的机制联系。
