Department of Nutrition and Food Hygiene, School of Public Health, Guangxi Medical University, Nanning, 530021, China; Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning, 530021, China.
School of Basic Medical Sciences, Guangxi Medical University, Nanning, 530021, China.
Food Chem Toxicol. 2023 Sep;179:113986. doi: 10.1016/j.fct.2023.113986. Epub 2023 Aug 12.
Non-alcoholic fatty liver disease (NAFLD) is a progressive disorder of liver metabolism and has become the most common chronic liver disease worldwide. Benzo[a]pyrene (BaP) is recognized as a potent carcinogen, but the effect of low-dose BaP on the development of NAFLD has not been well-studied, and its molecular mechanism is still unknown. In this study, we demonstrated that low-dose BaP induced hepatic steatosis in a mouse model with a notable increase in hepatic lipid content. Interestingly, mRNA expression of genes related to fatty acids uptake or synthesis was not significantly altered after BaP exposure. Instead, we found that low-dose BaP promoted lipid deposition in primary mouse hepatocytes by inhibiting autophagy, which was regulated through Leucine carboxyl methyltransferase-1 (LCMT1) mediated Protein Phosphatases 2A subunit C (PP2Ac) methylation. The role of LCMT1 in BaP-induced steatosis was further validated in a liver-specific lcmt1 knockout (L-LCMT1 KO) mouse model. In this study, we provided evidence to support a novel mechanism by which BaP induces the development of hepatic steatosis through PP2Ac mediated autophagy inhibition. These findings provided new insight into the pathogenesis of NAFLD induced by environmental exposure to low-dose BaP.
非酒精性脂肪性肝病（NAFLD）是一种进行性肝脏代谢紊乱疾病，已成为全球最常见的慢性肝病。苯并[a]芘（BaP）被认为是一种强致癌剂，但低剂量 BaP 对 NAFLD 发展的影响尚未得到充分研究，其分子机制仍不清楚。在本研究中，我们证明了低剂量 BaP 可在小鼠模型中诱导肝脂肪变性，肝脂质含量明显增加。有趣的是，BaP 暴露后与脂肪酸摄取或合成相关的基因的 mRNA 表达没有明显改变。相反，我们发现低剂量 BaP 通过抑制自噬促进原代小鼠肝细胞中的脂质沉积，这是通过亮氨酸羧基甲基转移酶 1（LCMT1）介导的蛋白磷酸酶 2A 亚基 C（PP2Ac）甲基化来调节的。LCMT1 在 BaP 诱导的脂肪变性中的作用在肝特异性 lcmt1 敲除（L-LCMT1 KO）小鼠模型中得到了进一步验证。在这项研究中，我们提供了证据支持 BaP 通过 PP2Ac 介导的自噬抑制诱导肝脂肪变性的新机制。这些发现为环境暴露于低剂量 BaP 诱导的 NAFLD 发病机制提供了新的见解。
