Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain.
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain; Department of Pathology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Brazil.
J Hepatol. 2014 Jan;60(1):87-95. doi: 10.1016/j.jhep.2013.07.041. Epub 2013 Aug 19.
BACKGROUND & AIMS: This study examined whether the regulation of resistin and visfatin could reduce damage and improve regeneration in both steatotic and non-steatotic livers undergoing partial hepatectomy under ischemia-reperfusion, a procedure commonly applied in clinical practice to reduce bleeding.
Resistin and visfatin were pharmacologically modulated in lean and obese animals undergoing partial hepatectomy under ischemia-reperfusion.
No evident role for these adipocytokines was observed in non-steatotic livers. However, obese animals undergoing liver surgery showed increased resistin in liver and plasma, without changes in adipose tissue, together with visfatin downregulation in liver and increment in plasma and adipose tissue. Endogenous resistin maintains low levels of visfatin in the liver by blocking its hepatic uptake from the circulation, thus regulating the visfatin detrimental effects on hepatic damage and regenerative failure. Indeed, the administration of anti-resistin antibodies increased hepatic accumulation of adipocyte-derived visfatin, exacerbating damage and regenerative failure. Interestingly, treatment with anti-visfatin antibodies protected steatotic livers, and similar results were obtained with the concomitant inhibition of resistin and visfatin. Thus, when visfatin was inhibited, the injurious effects of anti-resistin antibodies disappeared. Herein we show that upregulation of visfatin increased NAD levels in the remnant steatotic liver, whereas visfatin inhibition decreased them. These later observations suggest that visfatin may favour synthesis of NAD instead of DNA and induces alterations in amino acid metabolism-urea cycle and NO production, overall negatively affecting liver viability.
Our results indicate the clinical potential of visfatin blocking-based therapies in steatotic livers undergoing partial hepatectomy with ischemia-reperfusion.
本研究旨在探讨抵抗素和内脂素的调节是否可以减轻肝缺血再灌注损伤，并促进肝再生，肝部分切除术常采用该方法以减少术中出血。
在接受肝部分切除术的瘦素和肥胖动物中，通过药理学方法调节抵抗素和内脂素的表达。
在非脂肪变性肝脏中，这些脂肪细胞因子并未发挥明显作用。然而，接受肝手术的肥胖动物表现为肝脏和血浆中抵抗素增加，而脂肪组织中无变化，同时肝脏中内脂素下调，血浆和脂肪组织中内脂素增加。内源性抵抗素通过阻断其从循环中摄取肝脏，从而维持肝脏中低水平的内脂素，从而调节内脂素对肝损伤和再生失败的有害作用。事实上，给予抗抵抗素抗体增加了肝脏中脂肪细胞衍生的内脂素的蓄积，从而加重了损伤和再生失败。有趣的是，用抗内脂素抗体治疗可以保护脂肪变性的肝脏，同时抑制抵抗素和内脂素也可获得类似的结果。因此，当抑制内脂素时，抗抵抗素抗体的损伤作用消失。在此，我们发现内脂素的上调增加了残留脂肪变性肝脏中的 NAD 水平，而内脂素的抑制则降低了 NAD 水平。这些后续观察表明，内脂素可能有利于 NAD 的合成而不是 DNA 的合成，并诱导氨基酸代谢-尿素循环和 NO 产生的改变，从而整体上对肝脏的活力产生负面影响。
我们的研究结果表明，在接受肝缺血再灌注的肝部分切除术的脂肪变性肝脏中，内脂素阻断治疗具有潜在的临床应用价值。
