目标：通过研究与脂肪胰腺相关的因素，阐明胰腺癌的危险因素和病理生理学。方法：对非酒精性脂肪肝病（NAFLD）患者（n = 281）和具有胰腺癌家族史的导管内乳头状黏液性肿瘤（IPMN）患者（n = 38），检测其脂肪胰腺程度、背景因素和胰腺癌发生率。通过胰腺CT值/脾脏CT值比值（P/S比）确认脂肪胰腺的存在。经手术病理证实脂肪胰腺的10例进行免疫组织化学染色。结果：在NAFLD组中，126例（44.8%）患者出现脂肪胰腺，这些患者年龄较大（p = 0.0002），更容易患有高血压（p < 0.0001）。IPMN组中有18例（47.4%）患者出现脂肪胰腺，男性患者数量多于女性患者（p = 0.0056），并且更容易患有高血压（p = 0.0010）。在组织学检查中，脂肪细胞明显浸润到从胰腺间质到腺泡的区域，导致胰腺实质的萎缩，并在脂肪细胞侵入胰腺实质的区域检测到M1和M2巨噬细胞。在脂肪区域的胰腺腺泡细胞、腺泡-导管转化和胰腺癌细胞中检测到p62积累和自噬功能紊乱相关的NQO1分子的阳性染色。脂肪胰腺区域中p62阳性细胞区域的比例和NQO1阳性细胞区域的比例明显高于对照病变（胰腺区域少有脂肪细胞浸润）的比例。此外，p62阳性细胞区域的比例或NQO1阳性细胞区域的比例与脂肪胰腺病变的比例显示出强烈的正相关。这些结果表明，脂肪细胞侵入胰腺实质诱导了巨噬细胞浸润和自噬底物p62积累。脂肪区域中的NQO1表达水平可能依赖于p62的积累。结论：高血压是NAFLD和IPMN患者脂肪胰腺的重要危险因素。在脂肪胰腺中，脂肪浸润到胰腺实质可能导致自噬功能紊乱，进而激活抗氧化蛋白NQO1。因此，脂肪胰腺患者需要进行仔细的随访。版权所有© 2023 Otsuka, Shimizu, Taniai and Tokushige。

Objective: This study clarified the risk factors and pathophysiology of pancreatic cancer by examining the factors associated with fatty pancreas. Methods: The degree of fatty pancreas, background factors, and incidence of pancreatic cancer were examined among nonalcoholic fatty liver disease (NAFLD) patients (n = 281) and intraductal papillary mucinous neoplasm (IPMN) patients with a family history of pancreatic cancer (n = 38). The presence of fatty pancreas was confirmed by the pancreatic CT value/splenic CT value ratio (P/S ratio). Immunohistochemical staining was performed on 10 cases with fatty pancreas, confirmed via postoperative pathology. Results: Fatty pancreas occurred in 126 patients (44.8%) in the NAFLD group who were older (p = 0.0002) and more likely to have hypertension (p < 0.0001). The IPMN group had 18 patients (47.4%) with fatty pancreas, included more men than women (p = 0.0056), and was more likely to have patients with hypertension (p = 0.0010). On histological examination, a significant infiltration of adipocytes into the acini from the pancreatic interstitium induced atrophy of the pancreatic parenchyma, and both M1 and M2 macrophages were detected in the area where adipocytes invaded the pancreatic parenchyma. Accumulation of p62 and increased positive staining of NQO1 molecules related to autophagy dysfunction were detected in pancreatic acinar cells in the fatty area, acinar-ductal metaplasia, and pancreatic cancer cells. The rate of p62-positive cell area and that of NQO1-positive cell area were significantly higher in the fatty pancreatic region than those in the control lesion (pancreatic region with few adipocyte infiltration). Furthermore, the rate of p62-positive cell area or that of NQO1-positive cell area showed strong positive correlations with the rate of fatty pancreatic lesion. These results suggest that adipocyte invasion into the pancreatic parenthyme induced macrophage infiltration and autophagy substrate p62 accumulation. High levels of NQO1 expression in the fatty area may be dependent on p62 accumulation. Conclusion: Hypertension was a significant risk factor for fatty pancreas in patients with NAFLD and IPMN. In fatty pancreas, fatty infiltration into the pancreatic parenchyme might induce autophagy dysfunction, resulting in activation of antioxidant proteins NQO1. Thus, patients with fatty pancreas require careful follow-up.Copyright © 2023 Otsuka, Shimizu, Taniai and Tokushige.