p53 protects against alcoholic fatty liver disease via ALDH2 inhibition

The tumor suppressor p53 is critical for tumor suppression, but the regulatory role of p53 in alcohol-induced fatty liver remains unclear. Here, we show a role for p53 in regulating the ethanol metabolism via acetaldehyde dehydrogenase 2 (ALDH2), a key enzyme responsible for oxidization of alcohol. By repressing ethanol oxidization, p53 suppresses intracellular levels of acetyl-CoA and histone acetylation, leading to the inhibition of the stearoyl-CoA desaturase-1 (SCD1) gene expression. Mechanistically, p53 directly binds to ALDH2 and prevents the formation of its active tetramer, and indirectly limits the production of pyruvate that promotes the activity of ALDH2. Notably, p53 deficient mice exhibit increased lipid accumulation, which can be reversed by ALDH2 depletion. Moreover, liver-specific knockdown of SCD1 alleviates ethanol-induced hepatic steatosis caused by p53 loss. By contrast, overexpression of SCD1 in liver promotes ethanol-induced fatty liver development in wildtype mice, while it has a mild effect on p53-/- or ALDH2-/- mice. Overall, our findings reveal a previously unrecognized function of p53 in alcohol-induced fatty liver and uncover pyruvate as a natural regulator of ALDH2.

肿瘤抑制因子p53（tumor suppressor p53）在肿瘤抑制中发挥关键作用，但其在酒精诱导的肝脂肪变性中的调控机制仍不明确。本研究发现，p53可通过乙醛脱氢酶2（acetaldehyde dehydrogenase 2，ALDH2）调控乙醇代谢——ALDH2是介导乙醇氧化的关键酶。通过抑制乙醇氧化过程，p53可降低细胞内乙酰辅酶A（acetyl-CoA）水平与组蛋白乙酰化修饰水平，进而抑制硬脂酰辅酶A去饱和酶1（stearoyl-CoA desaturase-1，SCD1）的基因表达。从机制层面分析，p53可直接结合ALDH2并阻碍其活性四聚体的形成，同时间接限制可增强ALDH2活性的丙酮酸的产生。值得注意的是，p53基因敲除小鼠会出现脂质蓄积增加的表型，该表型可通过ALDH2基因敲除得以逆转。此外，肝脏特异性敲低SCD1可缓解p53缺失引发的乙醇诱导性肝脂肪变性。与之相反，在野生型小鼠肝脏中过表达SCD1会促进乙醇诱导的肝脂肪变性发生，而该效应在p53基因敲除或ALDH2基因敲除小鼠中仅表现出轻微影响。综上，本研究揭示了p53在酒精诱导肝脂肪变性中此前未被认知的功能，并明确了丙酮酸作为ALDH2天然调控因子的新角色。