The Regulatory Effect of SIRT1 on Extracellular Microenvironment Remodeling

Abstract

The sirtuins family is well known by its unique nicotinamide adenine dinucleotide (NAD⁺)-dependent deacetylase function. The most-investigated member of the family, Sirtuin 1 (SIRT1), accounts for deacetylating a broad range of transcription factors and coregulators, such as p53, the Forkhead box O (FOXO), and so on. It serves as a pivotal regulator in various intracellular biological processes, including energy metabolism, DNA damage response, genome stability maintenance and tumorigenesis. Although the most attention has been focused on its intracellular functions, the regulatory effect on extracellular microenvironment remodeling of SIRT1 has been recognized by researchers recently. SIRT1 can regulate cell secretion process and participate in glucose metabolism, neuroendocrine function, inflammation and tumorigenesis. Here, we review the advances in the understanding of SIRT1 on remodeling the extracellular microenvironment, which may provide new ideas for pathogenesis investigation and guidance for clinical treatment.

Keywords: SIRT1; cell secretion; endocrine; inflammation; microenvironment remodeling; tumorigenesis.

Figure 1

SIRT1 modulates glucose metabolism through regulating cell secretion. (A) SIRT1 suppresses UCP2 expression to upregulate insulin secretion. (B) SIRT1 enhances insulin secretion through DDAH2/secretagogin pathway. (C) SIRT1 increases FABP4 secretion to regulate hepatic glucose production and glucose-stimulated insulin secretion. (D) SIRT1 inhibits PPARγ activity to downregulate Ero1-L α expression, and suppresses adiponectin secretion.

Figure 2

SIRT1 regulates neuroendocrine secretion. (A) SIRT1 upregulates S100β release. (B) AGEs bind to RAGE and inactivates SIRT1/NRF2 pathway, and decreases TH secretion. (C) SIRT1 deacetylates PIP5Kγ to increase TSH release, and stimulates TH secretion.

Figure 3

SIRT1 mediates inflammatory microenvironment remodeling by deacetylating HMGB1 to reduce its secretion. Released HMGB1 forms complex with CXCL12 and CXCR4 to induce the recruitment of mononuclear cells. HMGB1 also binds to TLR2, TLR4 and RAGE to mediate cytokines or chemokines secretion of immune cells.

Figure 4

SIRT1 increases the expression of ATP6V1A to maintain pH level of lysosomes. Down-regulation of SIRT1 promotes MVBs formation and enhancing protein cargos released by exosomes to dissolve the cell matrix of tumor microenvironment.