醛脱氢酶 1 a1 调节不同物种脂肪细胞中的能量代谢。
Aldehyde dehydrogenase 1 a1 regulates energy metabolism in adipocytes from different species.
机构信息
Department of Human Sciences, The Ohio State University, Columbus, OH, USA.
Department of Nutrition, School of Medical, Shanghai Jiao Tong University, Shanghai, China.
出版信息
Xenotransplantation. 2017 Sep;24(5). doi: 10.1111/xen.12318. Epub 2017 Jul 17.
BACKGROUND
Survival and longevity of xenotransplants depend on immune function and ability to integrate energy metabolism between cells from different species. However, mechanisms for interspecies cross talk in energy metabolism are not well understood. White adipose tissue stores energy and is capable of mobilization and dissipation of energy as heat (thermogenesis) by adipocytes expressing uncoupling protein 1 (Ucp1). Both pathways are under the control of vitamin A metabolizing enzymes. Deficient retinoic acid production in aldehyde dehydrogenase 1 A1 (Aldh1a1) knockout adipocytes (KO) inhibits adipogenesis and increases thermogenesis. Here we test the role Aldh1a1 in regulation of lipid metabolism in xenocultures.
METHODS
Murine wide-type (WT) and KO pre-adipocytes were encapsulated into a poly-L-lysine polymer that allows exchange of humoral factors <32kD via nanopores. Encapsulated murine adipocytes were co-incubated with primary differentiated canine adipocytes. Then, expression of adipogenic and thermogenic genes in differentiated canine adipocytes was detected by real-time polymerase chain reaction (PCR). The regulatory factors in WT and KO cells were identified by comparison of secretome using proteomics and in transcriptome by gene microarray.
RESULTS
Co-culture of encapsulated mouse KO vs WT adipocytes increased expression of peroxisome proliferator-activated receptor gamma (Pparg), but reduced expression of its target genes fatty acid binding protein 4 (Fabp4), and adipose triglyceride lipase (Atgl) in canine adipocytes, suggesting inhibition of PPARγ activation. Co-culture with KO adipocytes also induced expression of Ucp1 in canine adipocytes compared to expression in WT adipocytes. Cumulatively, murine KO compared to WT adipocytes decreased lipid accumulation in canine adipocytes. Comparative proteomics revealed significantly higher levels of vitamin A carriers, retinol binding protein 4 (RBP4), and lipokalin 2 (LCN2) in KO vs WT adipocytes.
CONCLUSIONS
Our data demonstrate the functional exchange of regulatory factors between adipocytes from different species for regulation of energy balance. RBP4 and LCN2 appear to be involved in the transport of retinoids for regulation of lipid accumulation and thermogenesis in xenocultures. While the rarity of thermogenic adipocytes in humans and dogs precludes their use for autologous transplantation, our study demonstrates that xenotransplantation of engineered cells could be a potential solution for the reduction in obesity in dogs and a strategy for translation to patients.
背景
异种移植物的存活和寿命取决于免疫功能和不同物种细胞之间能量代谢的整合能力。然而，种间能量代谢交流的机制尚不清楚。白色脂肪组织储存能量，并能够通过表达解偶联蛋白 1（Ucp1）的脂肪细胞动员和消耗能量产生热量（生热作用）。这两种途径都受到维生素 A 代谢酶的控制。醛脱氢酶 1A1（Aldh1a1）敲除脂肪细胞（KO）中视黄酸生成不足会抑制脂肪生成并增加生热作用。在这里，我们测试了 Aldh1a1 在调节异种培养物中脂质代谢中的作用。
方法
将鼠源 WT 和 KO 前脂肪细胞包裹在聚-L-赖氨酸聚合物中，该聚合物允许通过纳米孔交换小于 32kD 的体液因子。将包裹的鼠源脂肪细胞与原代分化的犬源脂肪细胞共孵育。然后，通过实时聚合酶链反应（PCR）检测分化的犬源脂肪细胞中脂肪生成和生热基因的表达。通过蛋白质组学比较 WT 和 KO 细胞的分泌组，通过基因微阵列比较转录组，鉴定 WT 和 KO 细胞中的调节因子。
结果
与 WT 脂肪细胞共培养的包裹鼠 KO 脂肪细胞增加了过氧化物酶体增殖物激活受体γ（Pparg）在犬源脂肪细胞中的表达，但降低了其靶基因脂肪酸结合蛋白 4（Fabp4）和脂肪甘油三酯脂肪酶（Atgl）的表达，表明 PPARγ 激活受到抑制。与 WT 脂肪细胞相比，与 KO 脂肪细胞共培养还诱导了犬源脂肪细胞中 Ucp1 的表达。累积起来，与 WT 脂肪细胞相比，鼠 KO 脂肪细胞减少了犬源脂肪细胞中的脂质积累。比较蛋白质组学显示，KO 脂肪细胞中维生素 A 载体视黄醇结合蛋白 4（RBP4）和脂联素 2（LCN2）的水平明显高于 WT 脂肪细胞。
结论
我们的数据表明，不同物种脂肪细胞之间的调节因子进行功能交换，以调节能量平衡。RBP4 和 LCN2 似乎参与了视黄醇的运输，以调节异种培养物中的脂质积累和生热作用。虽然人类和犬类中罕见的生热脂肪细胞不能用于自体移植，但我们的研究表明，工程细胞的异种移植可能是减少犬肥胖的一种潜在解决方案，也是将其转化为患者的一种策略。
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