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Exploring the signal-dependent transcriptional regulation involved in the liver pathology of type 2 diabetes

Journal

DIABETOLOGY INTERNATIONAL
Volume 14, Issue 1, Pages 15-20

Publisher

SPRINGER JAPAN KK
DOI: 10.1007/s13340-022-00610-0

Keywords

Transcriptional regulation; Gluconeogenesis; Non-alcoholic steatohepatitis; Macrophage

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Excess glucagon activity in diabetes leads to increased hepatic glucose production, exacerbating hyperglycemia. Additionally, type 2 diabetes is closely associated with non-alcoholic fatty liver disease (NAFLD), which can progress to non-alcoholic steatohepatitis (NASH), causing liver cirrhosis and hepatocellular carcinoma.
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-1 alpha) expression via the cAMP response element-binding protein (CREB)-regulated transcription coactivator 2 (CRTC2) pathway. Transcriptional coactivator PGC-1 alpha subsequently coactivates transcription factors, such as forkhead box O1 (FoxO1) and hepatocyte nuclear factor 4 alpha (HNF4 alpha), 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-1 alpha 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.

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