Orlistat (Xenical™), a US Food and Drug Administration (FDA)-approved anti-obesity drug, shows efficacy against multiple tumor types, including hepatocellular carcinoma (HCC), due to its ability to inhibit fatty acid synthase (FASN) activity. However, whether orlistat affects hepatocellular malignant transformation during hepatocarcinogenesis in vivo is unknown. This study assessed the antisteatotic and antitumorigenic efficacy of orlistat in a rapid HCC FVB/N mouse model established via hydrodynamic transfection of activated forms of AKT and c-Met proto-oncogenes. Human hepatoma cell lines were used for mechanical validation in vitro. Hematoxylin and eosin staining, immunohistochemistry, and immunoblotting were applied for the mechanistic investigation. The results revealed that when orlistat was administered in the early stage of AKT/c-Met-triggered hepatocarcinogenesis, it resulted in the elimination of hepatic tumor burden. Mechanistically, orlistat efficiently elevated PTEN expression and suppressed AKT/SREBP1/FASN signaling both in vivo and in vitro, impairing AKT/c-Met-driven de novo lipogenesis and aberrant proliferation. Altogether, this study demonstrates the antilipogenic and antiproliferative efficacy of orlistat in hepatocarcinogenesis, suggesting that orlistat may be beneficial for the treatment of HCC, especially in NAFLD-related HCCs featuring activated AKT/mTOR cascade and increased lipogenesis in livers.

中文翻译：

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奥利司他通过AKT和c-Met的肝共激活作用延缓小鼠肝癌的发生。

美国食品药品监督管理局（FDA）批准的Orlistat（Xenical™）抗肥胖药由于具有抑制脂肪酸合酶（FASN）活性的能力，因此对多种肿瘤类型（包括肝细胞癌（HCC））具有疗效。但是，奥利司他是否在体内影响肝癌发生期间是否影响肝细胞恶性转化。这项研究评估了奥利司他在快速HCC FVB / N小鼠模型中的抗脂肪变性和抗肿瘤作用，该模型通过流体动力学转染AKT和c-Met原癌基因的活化形式而建立。人肝癌细胞系用于体外机械验证。将苏木精和曙红染色，免疫组化和免疫印迹用于机理研究。结果表明，在AKT / c-Met触发的肝癌发生早期给予奥利司他，可以消除肝肿瘤负担。从机理上讲，奥利司他有效地提高了PTEN表达，并在体内和体外均抑制了AKT / SREBP1 / FASN信号传导，从而损害了AKT / c-Met驱动的新生脂肪生成和异常增殖。总而言之，这项研究证明了奥利司他在肝癌发生中的抗脂肪生成和抗增殖功效，这表明奥利司他对肝癌的治疗可能是有益的，尤其是在以活化AKT / mTOR级联反应和肝脏脂肪生成增加为特征的NAFLD相关HCC中。奥利司他在体内外有效地提高了PTEN的表达并抑制了AKT / SREBP1 / FASN信号传导，从而削弱了AKT / c-Met驱动的新生脂肪生成和异常增殖。总而言之，这项研究证明了奥利司他在肝癌发生中的抗脂肪生成和抗增殖功效，这表明奥利司他对肝癌的治疗可能是有益的，尤其是在以活化AKT / mTOR级联反应和肝脏脂肪生成增加为特征的NAFLD相关HCC中。奥利司他在体内外有效地提高了PTEN的表达并抑制了AKT / SREBP1 / FASN信号传导，从而削弱了AKT / c-Met驱动的新生脂肪生成和异常增殖。总而言之，这项研究证明了奥利司他在肝癌发生中的抗脂肪生成和抗增殖功效，这表明奥利司他对肝癌的治疗可能是有益的，尤其是在以活化AKT / mTOR级联反应和肝脏脂肪生成增加为特征的NAFLD相关HCC中。