Cholesterol Metabolism: A Double-Edged Sword in Hepatocellular Carcinoma.
Cholesterol Metabolism: A Double-Edged Sword in Hepatocellular Carcinoma.
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DOI：
10.3389/fcell.2021.762828
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发表时间：
2021
影响因子：
5.5
通讯作者：
Sun X
中科院分区：
文献类型：
--
作者：
Zhou F;Sun X
肝细胞癌（HCC）是全球癌症相关死亡的主要原因。近年来，代谢综合征及其肝脏表现，非酒精性脂肪性肝病（NAFLD）的发病率不断上升，已成为HCC增长最快的原因。胆固醇是细胞膜和脂蛋白颗粒的主要脂质成分，主要由肝脏产生和代谢。许多研究已经揭示了HCC中胆固醇生物合成和摄取增加，胆固醇输出和排泄减少，这些都有助于脂毒性，炎症和纤维化，已知的HCC风险因素。相反，一些临床研究表明，较高的胆固醇与HCC风险降低有关。这些相互矛盾的观察结果意味着胆固醇和HCC之间的关系比最初预期的要复杂得多。了解胆固醇的作用和破译HCC发展中的潜在分子事件与开发新疗法高度相关。在这里，我们讨论了目前对NAFLD相关HCC发病机制中胆固醇代谢的理解，以及潜在的机制，包括胆固醇在破坏特定细胞类型正常功能和信号转导中的作用。我们还回顾了胆固醇与HCC相关性的临床进展。还将总结降低胆固醇的治疗效果。我们还解释了不同临床前和人体研究中胆固醇在HCC中作用的矛盾观察结果的原因，旨在对胆固醇作为治疗靶点的潜力进行关键评估。
Hepatocellular carcinoma (HCC) represents a leading cause of cancer-related deaths globally. The rising incidence of metabolic syndrome and its hepatic manifestation, nonalcoholic fatty liver disease (NAFLD), have emerged as the fastest-growing cause of HCC in recent years. Cholesterol, a major lipid component of the cell membrane and lipoprotein particles, is primarily produced and metabolized by the liver. Numerous studies have revealed an increased cholesterol biosynthesis and uptake, reduced cholesterol exportation and excretion in HCC, which all contribute to lipotoxicity, inflammation, and fibrosis, known HCC risk factors. In contrast, some clinical studies have shown that higher cholesterol is associated with a reduced risk of HCC. These contradictory observations imply that the relationship between cholesterol and HCC is far more complex than initially anticipated. Understanding the role of cholesterol and deciphering the underlying molecular events in HCC development is highly relevant to developing new therapies. Here, we discuss the current understanding of cholesterol metabolism in the pathogenesis of NAFLD-associated HCC, and the underlying mechanisms, including the roles of cholesterol in the disruption of normal function of specific cell types and signaling transduction. We also review the clinical progression in evaluating the association of cholesterol with HCC. The therapeutic effects of lowering cholesterol will also be summarized. We also interpret reasons for the contradictory observations from different preclinical and human studies of the roles of cholesterol in HCC, aiming to provide a critical assessment of the potential of cholesterol as a therapeutic target.
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