Department of Physiology and Pharmacology, The University of Toledo College of Medicine and Life Sciences, Toledo, Ohio.
Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia.
Gastroenterology. 2022 Dec;163(6):1658-1671.e16. doi: 10.1053/j.gastro.2022.08.033. Epub 2022 Aug 18.
BACKGROUND & AIMS: Pathogenesis of hepatocellular carcinoma (HCC), which kills millions annually, is poorly understood. Identification of risk factors and modifiable determinants and mechanistic understanding of how they impact HCC are urgently needed.
We sought early prognostic indicators of HCC in C57BL/6 mice, which we found were prone to developing this disease when fed a fermentable fiber-enriched diet. Such markers were used to phenotype and interrogate stages of HCC development. Their human relevance was tested using serum collected prospectively from an HCC/case-control cohort.
HCC proneness in mice was dictated by the presence of congenitally present portosystemic shunt (PSS), which resulted in markedly elevated serum bile acids (BAs). Approximately 10% of mice from various sources exhibited PSS/cholemia, but lacked an overt phenotype when fed standard chow. However, PSS/cholemic mice fed compositionally defined diets, developed BA- and cyclooxygenase-dependent liver injury, which was exacerbated and uniformly progressed to HCC when diets were enriched with the fermentable fiber inulin. Such progression to cholestatic HCC associated with exacerbated cholemia and an immunosuppressive milieu, both of which were required in that HCC was prevented by impeding BA biosynthesis or neutralizing interleukin-10 or programmed death protein 1. Analysis of human sera revealed that elevated BA was associated with future development of HCC.
PSS is relatively common in C57BL/6 mice and causes silent cholemia, which predisposes to liver injury and HCC, particularly when fed a fermentable fiber-enriched diet. Incidence of silent PSS/cholemia in humans awaits investigation. Regardless, measuring serum BA may aid HCC risk assessment, potentially alerting select individuals to consider dietary or BA interventions.
每年导致数百万人死亡的肝细胞癌（HCC）的发病机制了解甚少。迫切需要确定风险因素和可改变的决定因素，并了解它们如何影响 HCC。
我们在 C57BL/6 小鼠中寻找 HCC 的早期预后指标，发现当用富含可发酵纤维的饮食喂养时，这些小鼠容易发生这种疾病。这些标志物用于表型分析和研究 HCC 发展的各个阶段。使用前瞻性收集的 HCC/病例对照队列的血清来测试其与人类的相关性。
小鼠 HCC 的易感性取决于先天性门体分流（PSS）的存在，这导致血清胆汁酸（BA）显著升高。来自不同来源的大约 10％的小鼠存在 PSS/胆血症，但当用标准饲料喂养时，没有明显的表型。然而，用成分明确的饮食喂养 PSS/胆血症小鼠会导致 BA 和环氧化酶依赖性肝损伤，当饮食富含可发酵纤维菊粉时，这种损伤会加剧并均匀进展为 HCC。这种进展为胆汁淤积性 HCC 与加剧的胆血症和免疫抑制环境有关，这两者都需要阻止 BA 生物合成或中和白细胞介素-10 或程序性死亡蛋白 1，以防止 HCC 的发生。对人类血清的分析表明，BA 升高与 HCC 的未来发展有关。
PSS 在 C57BL/6 小鼠中较为常见，可导致无症状性胆血症，这会导致肝损伤和 HCC，尤其是当用富含可发酵纤维的饮食喂养时。在人类中，无症状性 PSS/胆血症的发生率有待研究。无论如何，测量血清 BA 可能有助于 HCC 风险评估，可能会提醒某些人考虑饮食或 BA 干预。
