Newberry Elizabeth P, Kennedy Susan M, Xie Yan, Luo Jianyang, Stanley Susan E, Semenkovich Clay F, Crooke Roseanne M, Graham Mark J, Davidson Nicholas O
Department of Medicine, School of Medicine, Washington University, St Louis, MO 63110, USA.
Hepatology. 2008 Oct;48(4):1097-105. doi: 10.1002/hep.22473.
Liver regeneration is impaired following partial hepatectomy (PH) in mice with genetic obesity and hepatic steatosis and also in wild-type mice fed a high-fat diet. These findings contrast with other data showing that liver regeneration is impaired in mice in which hepatic lipid accumulation is suppressed by either pharmacologic leptin administration or by disrupted glucocorticoid signaling. These latter findings suggest that hepatic steatosis may actually be required for normal liver regeneration. We have reexamined this relationship using several murine models of altered hepatic lipid metabolism. Liver fatty acid (FA) binding protein knockout mice manifested reduced hepatic triglyceride (TG) content compared to controls, with no effect on liver regeneration or hepatocyte proliferation. Examination of early adipogenic messenger RNAs revealed comparable induction in liver from both genotypes despite reduced hepatic steatosis. Following PH, hepatic TG was reduced in intestine-specific microsomal TG transfer protein deleter mice, which fail to absorb dietary fat, increased in peroxisome proliferator activated receptor alpha knockout mice, which exhibit defective FA oxidation, and unchanged (from wild-type mice) in liver-specific FA synthase knockout mice in which endogenous hepatic FA synthesis is impaired. Hepatic TG increased in the regenerating liver in all models, even in animals in which lipid accumulation is genetically constrained. However, in no model -- and over a >90-fold range of hepatic TG content -- was liver regeneration significantly impaired following PH.
Although hepatic TG content is widely variable and increases during liver regeneration, alterations in neither exogenous or endogenous lipid metabolic pathways, demonstrated to promote or diminish hepatic steatosis, influence hepatocyte proliferation.
在患有遗传性肥胖和肝脂肪变性的小鼠以及喂食高脂饮食的野生型小鼠中，部分肝切除（PH）后肝脏再生受损。这些发现与其他数据形成对比，其他数据表明，通过药物性给予瘦素或破坏糖皮质激素信号来抑制肝脏脂质积累的小鼠肝脏再生受损。后一组发现表明，肝脂肪变性实际上可能是正常肝脏再生所必需的。我们使用几种肝脏脂质代谢改变的小鼠模型重新审视了这种关系。与对照组相比，肝脏脂肪酸（FA）结合蛋白基因敲除小鼠的肝脏甘油三酯（TG）含量降低，对肝脏再生或肝细胞增殖没有影响。对早期脂肪生成信使核糖核酸的检测显示，尽管肝脏脂肪变性减少，但两种基因型的肝脏中诱导情况相当。PH后，肠道特异性微粒体TG转移蛋白缺失小鼠（其无法吸收膳食脂肪）的肝脏TG降低，过氧化物酶体增殖物激活受体α基因敲除小鼠（其表现出FA氧化缺陷）的肝脏TG增加，而肝脏特异性FA合酶基因敲除小鼠（其内源性肝脏FA合成受损）的肝脏TG与野生型小鼠相比无变化（即未改变）。在所有模型中，即使在脂质积累受到基因限制的动物中，再生肝脏中的肝脏TG也会增加。然而，在任何模型中——以及在肝脏TG含量超过90倍的范围内——PH后肝脏再生均未受到显著损害。
尽管肝脏TG含量变化很大且在肝脏再生过程中增加，但无论是促进还是减少肝脏脂肪变性的外源性或内源性脂质代谢途径的改变，均不影响肝细胞增殖。
