Exploring the signal-dependent transcriptional regulation involved in the liver pathology of type 2 diabetes
Exploring the signal-dependent transcriptional regulation involved in the liver pathology of type 2 diabetes
复制标题
探索 2 型糖尿病肝脏病理学中涉及的信号依赖性转录调控
DOI：
10.1007/s13340-022-00610-0
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发表时间：
2022
影响因子：
2.2
通讯作者：
Sakai Mashito
中科院分区：
文献类型：
--
作者：
T. Oshimoto;H. Watanabe;N. Loew;M. Motosuke;T. Mikawa;I. Shitanda;and M. Itagaki;Sakai Mashito
糖尿病患者中胰高血糖素活性过高通过促血管生成基因诱导增加肝脏葡萄糖生成，从而加重高血糖症。胰高血糖素受体激活的cAMP依赖性蛋白激酶A（PKA）通过cAMP反应元件结合蛋白（CREB）调节的转录辅激活因子2（CRTC 2）途径诱导增殖物激活受体γ辅激活因子1 α（PGC-1α）表达。转录共激活因子PGC-1α随后共激活转录因子，如叉头盒O 1（FoxO 1）和肝细胞核因子4 α（HNF 4 α），以诱导致凋亡基因。本文首先综述了转录辅因子CBP和p300激活的反式激活因子（CITED 2）通过调控PGC-1α和氨基酸合成蛋白5-like 2（GCN 5）激活胚胎发生的机制。2型糖尿病与非酒精性脂肪肝（NAFLD）密切相关。10%至20%的NAFLD进展为非酒精性脂肪性肝炎（NASH），这可能导致肝硬化，也可能导致肝细胞癌。认为肝巨噬细胞与NASH中观察到的炎症和纤维化相关。本文综述了NASH中肝脏巨噬细胞分化和髓样细胞多样化机制的肝源性信号。
Excess glucagon activity in diabetes increases hepatic glucose production via gluconeogenic gene induction, thus exacerbating hyperglycemia. Glucagon receptor-activated cAMP-dependent protein kinase A (PKA) induces proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) expression via the cAMP response element-binding protein (CREB)-regulated transcription coactivator 2 (CRTC2) pathway. Transcriptional coactivator PGC-1α subsequently coactivates transcription factors, such as forkhead box O1 (FoxO1) and hepatocyte nuclear factor 4 alpha (HNF4α), to induce gluconeogenic genes. The current review first summarizes the mechanism by which transcriptional cofactor CBP and p300-activated transactivator with glutamic acid and aspartic acid-rich COOH-terminal domain 2 (CITED2) activates gluconeogenesis via the regulation of PGC-1α and general control of amino acid synthesis protein 5-like 2 (GCN5). Type 2 diabetes is closely linked with non-alcoholic fatty liver disease (NAFLD). Between 10 and 20% of NAFLD progresses to non-alcoholic steatohepatitis (NASH), which can cause liver cirrhosis and can also lead to hepatocellular carcinoma. Liver macrophages are considered to be related to inflammation and fibrosis observed in NASH. This review outlines liver-derived signals underlying the differentiation of liver macrophages and the mechanism of myeloid cell diversification in NASH.