Kohjima Motoyuki, Tsai Tsung-Huang, Tackett Bryan C, Thevananther Sundararajah, Li Lan, Chang Benny Hung-Junn, Chan Lawrence
Diabetes and Endocrinology Research Center and Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
J Hepatol. 2013 Dec;59(6):1246-54. doi: 10.1016/j.jhep.2013.07.025. Epub 2013 Aug 6.
BACKGROUND & AIMS: Adult hepatocytes undergo cell cycle progression and proliferation in response to partial hepatectomy (PH). Transient lipid accumulation within hepatocytes preceding the peak proliferative phase is a characteristic feature of regenerating livers. However, the molecular mediators and mechanisms responsible for lipid accumulation in regenerating livers are not well understood. Adipose differentiation related protein (ADRP; Plin2) regulates hepatic triglyceride storage and Plin2-deficient (Plin2(-/-)) mice have significantly reduced triglyceride (TG) content in the liver. We sought to determine the functional significance of PLIN2 in liver regeneration in response to PH and toxic liver injury and examined whether absence of Plin2 expression modulates hepatocyte proliferation and liver regeneration.
We subjected wild-type (WT) and Plin2(-/-) mice to 70% PH or acute carbon tetrachloride (CCL4) treatment and examined the hepatic lipid content, the expression profile of lipid metabolism-related genes, the rate of cellular proliferation and the dynamics of liver regeneration in the treated animals.
In response to PH, Plin2(-/-) mice showed decreased hepatic triglyceride accumulation and delayed cell cycle progression, which was associated with impaired liver regeneration. Fatty acid (FA) synthesis and lipid transfer gene expression profile were comparable between Plin2(-/-) and wild-type mice, while VLDL secretion rate was higher in the Plin2(-/-) mice. Downregulated β-oxidation and reduced cytosolic FA level in Plin2(-/-) mice may have contributed to the attenuation of the liver regeneration capacity in these animals. In parallel experiments, we also observed attenuated hepatic lipid accumulation and proliferation in response to CCl4-mediated acute toxic liver injury in Plin2(-/-) mice.
We conclude that PLIN2-mediated lipid accumulation and utilization by the liver is important for efficient liver regeneration in response to PH and toxic liver injury.
成年肝细胞在部分肝切除（PH）后会经历细胞周期进程和增殖。在增殖高峰期之前，肝细胞内短暂的脂质积累是再生肝脏的一个特征。然而，导致再生肝脏脂质积累的分子介质和机制尚未完全明确。脂肪分化相关蛋白（ADRP；Plin2）调节肝脏甘油三酯储存，Plin2基因缺陷（Plin2(-/-)）小鼠肝脏中的甘油三酯（TG）含量显著降低。我们试图确定PLIN2在PH和中毒性肝损伤后肝脏再生中的功能意义，并研究Plin2表达缺失是否会调节肝细胞增殖和肝脏再生。
我们对野生型（WT）和Plin2(-/-)小鼠进行70%肝切除或急性四氯化碳（CCL4）处理，并检测处理动物的肝脏脂质含量、脂质代谢相关基因的表达谱、细胞增殖率以及肝脏再生的动态变化。
在PH后，Plin2(-/-)小鼠肝脏甘油三酯积累减少，细胞周期进程延迟，这与肝脏再生受损有关。Plin2(-/-)小鼠和野生型小鼠之间脂肪酸（FA）合成和脂质转运基因表达谱相当，但Plin2(-/-)小鼠的极低密度脂蛋白（VLDL）分泌率较高。Plin2(-/-)小鼠中β-氧化下调和胞质FA水平降低可能导致了这些动物肝脏再生能力的减弱。在平行实验中，我们还观察到Plin2(-/-)小鼠在CCl4介导的急性中毒性肝损伤后肝脏脂质积累和增殖减弱。
我们得出结论，PLIN2介导的肝脏脂质积累和利用对于PH和中毒性肝损伤后的有效肝脏再生很重要。
