a Division of Gastroenterology, Department of Medicine , Duke University Medical Center , Durham , NC , USA.
b Department of Gastroenterology , Hospital de Santa Maria, CHLN , Lisbon , Portugal.
Crit Rev Biochem Mol Biol. 2018 Jun;53(3):264-278. doi: 10.1080/10409238.2018.1448752. Epub 2018 Mar 20.
Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of obesity-associated liver diseases and it has become the major cause of cirrhosis in the Western world. The high prevalence of NAFLD-associated advanced liver disease reflects both the high prevalence of obesity-related fatty liver (hepatic steatosis) and the lack of specific treatments to prevent hepatic steatosis from progressing to more serious forms of liver damage, including nonalcoholic steatohepatitis (NASH), cirrhosis, and primary liver cancer. The pathogenesis of NAFLD is complex, and not fully understood. However, compelling evidence demonstrates that dysregulation of the hedgehog (Hh) pathway is involved in both the pathogenesis of hepatic steatosis and the progression from hepatic steatosis to more serious forms of liver damage. Inhibiting hedgehog signaling enhances hepatic steatosis, a condition which seldom results in liver-related morbidity or mortality. In contrast, excessive Hh pathway activation promotes development of NASH, cirrhosis, and primary liver cancer, the major causes of liver-related deaths. Thus, suppressing excessive Hh pathway activity is a potential approach to prevent progressive liver damage in NAFLD. Various pharmacologic agents that inhibit Hh signaling are available and approved for cancer therapeutics; more are being developed to optimize the benefits and minimize the risks of inhibiting this pathway. In this review we will describe the Hh pathway, summarize the evidence for its role in NAFLD evolution, and discuss the potential role for Hh pathway inhibitors as therapies to prevent NASH, cirrhosis and liver cancer.
非酒精性脂肪性肝病（NAFLD）包含了一系列与肥胖相关的肝脏疾病，已成为西方国家肝硬化的主要病因。NAFLD 相关晚期肝病的高患病率既反映了肥胖相关脂肪性肝病（肝脂肪变性）的高患病率，也反映了缺乏特定治疗方法来防止肝脂肪变性进展为更严重形式的肝损伤，包括非酒精性脂肪性肝炎（NASH）、肝硬化和原发性肝癌。NAFLD 的发病机制复杂，尚未完全阐明。然而，大量证据表明， hedgehog（Hh）通路的失调既参与了肝脂肪变性的发病机制，也参与了从肝脂肪变性向更严重形式的肝损伤的进展。抑制 hedgehog 信号通路会加重肝脂肪变性，而这种情况很少导致与肝脏相关的发病率或死亡率。相比之下，过度的 Hh 通路激活会促进 NASH、肝硬化和原发性肝癌的发展，这些是导致与肝脏相关的死亡的主要原因。因此，抑制过度的 Hh 通路活性是预防 NAFLD 进行性肝损伤的一种潜在方法。有多种抑制 Hh 信号通路的药物可用于癌症治疗，并且已经获得批准；还有更多的药物正在开发中，以优化抑制该通路的益处并降低风险。在这篇综述中，我们将描述 Hh 通路，总结其在 NAFLD 演变中的作用的证据，并讨论 Hh 通路抑制剂作为预防 NASH、肝硬化和肝癌的治疗方法的潜在作用。
