Dental Biochemistry, Faculty of Dentistry, University of Debrecen, Debrecen, Hungary.
Department of Biochemistry and Molecular Biology, Faculty of General Medicine, University of Debrecen, Debrecen, Hungary.
Cell Death Dis. 2019 Jun 5;10(6):439. doi: 10.1038/s41419-019-1677-z.
Transglutaminase 2 (TG2) is a multifunctional protein that promotes clearance of apoptotic cells (efferocytosis) acting as integrin β coreceptor. Accumulating evidence indicates that defective efferocytosis contributes to the development of chronic inflammatory diseases. Obesity is characterized by the accumulation of dead adipocytes and inflammatory macrophages in the adipose tissue leading to obesity-related metabolic syndrome. Here, we report that loss of TG2 from bone marrow-derived cells sensitizes for high fat diet (HFD)-induced pathologies. We find that metabolically activated TG2 null macrophages express more phospho-Src and integrin β, unexpectedly clear dying adipocytes more efficiently via lysosomal exocytosis, but produce more pro-inflammatory cytokines than the wild type ones. Anti-inflammatory treatment with an LXR agonist reverts the HFD-induced phenotype in mice lacking TG2 in bone marrow-derived cells with less hepatic steatosis than in wild type mice proving enhanced lipid clearance. Thus it is interesting to speculate whether LXR agonist treatment together with enhancing lysosomal exocytosis could be a beneficial therapeutic strategy in obesity.
转谷氨酰胺酶 2（TG2）是一种多功能蛋白，可作为整合素β辅助受体促进细胞凋亡（吞噬作用）。越来越多的证据表明，吞噬作用缺陷会导致慢性炎症性疾病的发展。肥胖症的特征是脂肪组织中堆积的死脂肪细胞和炎症性巨噬细胞，导致与肥胖相关的代谢综合征。在这里，我们报告骨髓来源细胞中 TG2 的缺失会使高脂肪饮食（HFD）诱导的病变敏感。我们发现，代谢激活的 TG2 缺失巨噬细胞表达更多的磷酸化Src 和整合素β，出人意料地通过溶酶体胞吐作用更有效地清除凋亡的脂肪细胞，但产生的促炎细胞因子比野生型细胞更多。用 LXR 激动剂进行抗炎治疗可逆转骨髓来源细胞中缺乏 TG2 的 HFD 诱导表型，与野生型小鼠相比，肝脏脂肪变性更少，证明了脂质清除增强。因此，推测 LXR 激动剂治疗联合增强溶酶体胞吐作用是否可能成为肥胖症的一种有益治疗策略是很有趣的。
