Singh Shailendra P, Grant Ilana, Meissner Aliza, Kappas Attallah, Abraham Nader G
Department of Pharmacology, New York Medical College, NY, USA.
Department of Medicine, New York Medical College, NY, USA.
Horm Mol Biol Clin Investig. 2017 Aug 1;31(1):hmbci-2017-0027. doi: 10.1515/hmbci-2017-0027.
Background Hmox1 plays an important role in the regulation of mitochondrial bioenergetics and function by regulating cellular heme-derived CO and bilirubin. Previous studies have demonstrated that global disruption of HO-1 in humans and mice resulted in severe organ dysfunction. Methods We investigated the potential role of adipose-specific-HO-1 genetic ablation on adipose tissue function, mitochondrial quality control and energy expenditure by generating an adipo-HO-1 knockout mouse model (Adipo-HO-1-/-) and, in vitro, adipocyte cells in which HO activity was inhibited. Adiposity, signaling proteins, fasting glucose and oxygen consumption were determined and compared to adipocyte cultures with depressed levels of both HO-1/HO-2. Results Adipo-HO-1-/- female mice exhibited increased adipocyte size, and decreases in the mitochondrial fusion to fission ratio, PGC1, and SIRT3. Importantly, ablation of HO-1 in adipose tissue resulted in fat acquiring many properties of visceral fat such as decreases in thermogenic genes including pAMPK and PRDM16. Deletion of HO-1 in mouse adipose tissue led to complete metabolic dysfunction, an increase in white adipose tissue, a reduction of beige fat and associated increases in FAS, aP2 and hyperglycemia. Mechanistically, genetic deletion of HO-1 in adipose tissues decreased the mitochondrial fusion to fission ratio; disrupted the activity of the PGC1 transcriptional axis and thermogenic genes both in vitro and in vivo. Conclusion Ablation of adipose tissue-HO-1 abridged PGC1 expression promoted mitochondrial dysfunction and contributed to an increase of pro-inflammatory visceral fat and abrogated beige-cell like phenotype.
血红素加氧酶-1（Hmox1）通过调节细胞内源自血红素的一氧化碳（CO）和胆红素，在调节线粒体生物能量学和功能方面发挥重要作用。先前的研究表明，人类和小鼠中HO-1的整体缺失会导致严重的器官功能障碍。方法：我们通过构建脂肪特异性HO-1基因敲除小鼠模型（Adipo-HO-1-/-），并在体外抑制HO活性的脂肪细胞中，研究脂肪特异性HO-1基因缺失对脂肪组织功能、线粒体质量控制和能量消耗的潜在作用。测定肥胖程度、信号蛋白、空腹血糖和氧气消耗，并与HO-1/HO-2水平均降低的脂肪细胞培养物进行比较。结果：Adipo-HO-1-/-雌性小鼠的脂肪细胞大小增加，线粒体融合与分裂比率、过氧化物酶体增殖物激活受体γ共激活因子1（PGC1）和沉默调节蛋白3（SIRT3）降低。重要的是，脂肪组织中HO-1的缺失导致脂肪获得许多内脏脂肪的特性，如包括磷酸化腺苷酸活化蛋白激酶（pAMPK）和PR结构域蛋白16（PRDM16）在内的产热基因减少。小鼠脂肪组织中HO-1的缺失导致完全的代谢功能障碍、白色脂肪组织增加、米色脂肪减少以及脂肪酸合成酶（FAS）、脂肪细胞脂肪酸结合蛋白2（aP2）增加和高血糖。从机制上讲，脂肪组织中HO-1的基因缺失降低了线粒体融合与分裂比率；在体外和体内均破坏了PGC1转录轴和产热基因的活性。结论：脂肪组织HO-1的缺失缩短了PGC1的表达，促进了线粒体功能障碍，并导致促炎性内脏脂肪增加和消除米色细胞样表型。
