Shteyer Eyal, Liao Yunjun, Muglia Louis J, Hruz Paul W, Rudnick David A
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.
Hepatology. 2004 Dec;40(6):1322-32. doi: 10.1002/hep.20462.
The liver responds to injury with regulated tissue regeneration. During early regeneration, the liver accumulates fat. Neither the mechanisms responsible for nor the functional significance of this transient steatosis have been determined. In this study, we examined patterns of gene expression associated with hepatic fat accumulation in regenerating liver and tested the hypothesis that disruption of hepatic fat accumulation would be associated with impaired hepatic regeneration. First, microarray-based gene expression analysis revealed that several genes typically induced during adipocyte differentiation were specifically upregulated in the regenerating liver prior to peak hepatocellular fat accumulation. These observations suggest that hepatic fat accumulation is specifically regulated during liver regeneration. Next, 2 methods were employed to disrupt hepatocellular fat accumulation in the regenerating liver. Because exogenous leptin supplementation reverses hepatic steatosis in leptin-deficient mice, the effects of leptin supplementation on liver regeneration in wild-type mice were examined. The data showed that leptin supplementation resulted in suppression of hepatocellular fat accumulation and impairment of hepatocellular proliferation during liver regeneration. Second, because glucocorticoids regulate cellular fat accumulation during adipocyte differentiation, the effects of hepatocyte-specific disruption of the glucocorticoid receptor were similarly evaluated. The results showed that hepatic fat accumulation and hepatocellular proliferation were also suppressed in mice with liver specific disruption of glucocorticoid receptor. In conclusion, suppression of hepatocellular fat accumulation is associated with impaired hepatocellular proliferation following partial hepatectomy, indicating that hepatocellular fat accumulation is specifically regulated during and may be essential for normal liver regeneration.
肝脏通过调控组织再生来应对损伤。在早期再生过程中，肝脏会积累脂肪。这种短暂性脂肪变性的发生机制及其功能意义均尚未明确。在本研究中，我们检测了再生肝脏中与肝脂肪积累相关的基因表达模式，并验证了肝脂肪积累的破坏与肝再生受损相关这一假说。首先，基于微阵列的基因表达分析显示，在肝细胞脂肪积累达到峰值之前，再生肝脏中一些通常在脂肪细胞分化过程中被诱导的基因会特异性上调。这些观察结果表明，肝再生过程中肝脂肪积累受到特异性调控。接下来，我们采用两种方法来破坏再生肝脏中的肝细胞脂肪积累。由于外源性补充瘦素可逆转瘦素缺乏小鼠的肝脂肪变性，因此我们检测了补充瘦素对野生型小鼠肝脏再生的影响。数据显示，补充瘦素会导致肝脏再生过程中肝细胞脂肪积累受到抑制以及肝细胞增殖受损。其次，由于糖皮质激素在脂肪细胞分化过程中调控细胞脂肪积累，我们同样评估了肝细胞特异性破坏糖皮质激素受体的影响。结果显示，在糖皮质激素受体肝脏特异性破坏的小鼠中，肝脂肪积累和肝细胞增殖也受到抑制。总之，肝细胞脂肪积累的抑制与部分肝切除术后肝细胞增殖受损相关，这表明肝再生过程中肝细胞脂肪积累受到特异性调控，且可能对正常肝脏再生至关重要。
