Non-alcoholic fatty liver disease (NAFLD) leads to hepatocellular carcinoma (HCC). However, the underlying mechanism remains largely unclear. Here, we investigated the role of the tumor suppressor Zinc fingers and homeoboxes 2 (ZHX2) in the progression of NAFLD to HCC. ZHX2 expression was significantly decreased in fatty liver tissues, especially in the liver with NAFLD-HCC. ZHX2 overexpression disturbed lipid homeostasis of cultured HCC cells, and inhibited lipid deposition in hepatocytes both in vitro and in vivo. Moreover, ZHX2 inhibited uptake of exogenous lipids through transcriptional suppression of lipid lipase (LPL), leading to retarded proliferation of HCC cells. Importantly, LPL overexpression significantly reversed ZHX2-mediated inhibition of HCC cell proliferation, xenograft tumor growth, lipid deposition, and spontaneous liver tumor formation. Consistently, IHC staining demonstrated a negative correlation of ZHX2 with LPL in an HCC cohort. Collectively, ZHX2 protects hepatocytes from abnormal lipid deposition in NAFLD through transcriptional repression of LPL, which subsequently retards cell growth and NAFLD-HCC progression. These findings illustrate a novel mechanism of NAFLD progression into HCC.

中文翻译：

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肿瘤抑制因子ZHX2通过阻断LPL介导的脂质摄取来抑制NAFLD-HCC进程。

非酒精性脂肪肝疾病（NAFLD）导致肝细胞癌（HCC）。但是，基本机制仍不清楚。在这里，我们研究了抑癌锌指和同源盒2（ZHX2）在NAFLD到HCC进程中的作用。ZHX2表达在脂肪肝组织中显着降低，尤其是在患有NAFLD-HCC的肝脏中。ZHX2的过表达干扰了培养的HCC细胞的脂质稳态，并在体外和体内均抑制了肝细胞中脂质的沉积。此外，ZHX2通过转录抑制脂质脂肪酶（LPL）抑制外源脂质的摄取，从而导致HCC细胞增殖受阻。重要的是，LPL的过表达显着逆转了ZHX2介导的对HCC细胞增殖，异种移植肿瘤生长，脂质沉积，并自发形成肝肿瘤。一致地，在HCC队列中，IHC染色显示ZHX2与LPL呈负相关。总体而言，ZHX2通过LPL的转录阻滞保护肝细胞免受NAFLD中异常脂质沉积的影响，随后会阻滞细胞生长和NAFLD-HCC进程。这些发现说明了NAFLD发展成肝癌的新机制。