Biomolecules, Vol. 12, Pages 1755: Protein Targeting to Glycogen (PTG): A Promising Player in Glucose and Lipid Metabolism

The liver plays a major role in maintaining normal glucose homeostasis by controlling the balance between hepatic glucose production and storage [15]. During fasting, an increase in circulating glucagon triggers the gluconeogenesis by activating the cAMP pathway [65]. It has been reported that norepinephrine could stimulate PTG expression in mouse cortical astrocytes via the cAMP pathway [66]. PTG was significantly up-regulated during 3T3-L1 adipocyte differentiation, which involved the cAMP signaling pathway [67]. FoxA2, a transcriptional regulator of hepatic gluconeogenesis genes, mediates cAMP-stimulated PTG transcription by binding to promoters in hepatocytes [41]. Recent studies have found that the phosphorylation/dephosphorylation of related signaling molecules plays a key role in the regulation of hepatic gluconeogenesis, which is mainly regulated by phosphorylase and dephosphorylase. Various hormones can regulate glucose metabolism by affecting the phosphorylation and dephosphorylation status of liver enzymes [68]; glucagon activates adenylate cyclase to produce cAMP, which, on the one hand, activates the cAMP-dependent protein kinase, which causes the phosphorylation of pyruvate kinase to inhibit the effect of pyruvate kinase, and on the other hand, it can also promote the phosphorylation of fructose 2,6-bisphosphatase, which in turn inhibits the glycolytic pathway, stimulates gluconeogenesis, and promotes glucose production, while insulin exhibits the opposite effect [6,69]. In addition, glucagon can also activate peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) to dephosphorylate. Dephosphorylated PGC-1α will be transferred to the nucleus and combined with hepatocyte nuclear factor 4α (HNF4α) to form a complex to activate it. In this way, the transcription of G6Pase and PEPCK-encoding genes is initiated, which affects gluconeogenesis [65,69]. Previous studies also found that glucagon can promote the nuclear translocation and stability of FOXO1 through cAMP-dependent and protein kinase α-dependent phosphorylation of FOXO1, thereby affecting gluconeogenesis [70]. Uebi et al. [71] found that PP1 can dephosphorylate and activate the Ser171 site of CREB-regulated transcriptional coactivator 2 (TORC2). Phosphorylated TORC2 remains inactive in the cytosol, while dephosphorylated TORC2 is translocated to the nucleus. It binds with phosphorylated cAMP response element binding protein (CREB) to form a CREB-TORC2 complex, which increases the expression of key gluconeogenesis enzymes such as G6Pase and PEPCK. Qi et al. [72] found that follicle-stimulating hormone can promote the membrane translocation of G protein-coupled receptor kinase 2 (GRK2), resulting in the phosphorylation of serine 485 of AMPK α and the dephosphorylation of threonine 172. In the nucleus, it promotes gluconeogenesis, while TORC2 translocates into the nucleus and promotes gluconeogenesis. As a member of the PP1 family, PTG has a dephosphorylation effect, suggesting that PTG may be closely related to hepatic gluconeogenesis. Ji et al. [73] found that overexpression of PTG in primary mouse hepatocytes or wild-type mouse liver promoted hepatic glucose production and expression of gluconeogenesis genes. Conversely, PTG knockout reduced hepatic gluconeogenesis and suppressed cAMP-stimulated gluconeogenic gene expression and TORC2 dephosphorylation. Animal studies showed that PTG knockdown in the liver of db/db mice significantly improved blood glucose levels and reduced the expression of key genes of gluconeogenesis (Figure 2). However, other researchers constructed PTGOE hybridized mice with PTG overexpression. The results showed that, compared with normal mice, PTGOE mice showed decreased liver gluconeogenesis and increased glycolysis, and PGC1 α and PEPCK expression levels decreased, further reducing the blood glucose level of the mice [58]. The possible reason for the difference is that, first of all, the models of the two research teams are from different strains of mice, and the differences in genetic background may lead to abnormal results. Secondly, the methods of overexpression and knockdown of PTG adopted by the two groups were inconsistent, which may also be the reason for the difference in the results. In addition, the influence of living environment and intestinal flora on the results cannot be ruled out. Previous studies have shown that hepatic glycogen synthesis is closely related to the process of gluconeogenesis, and that, in addition to glucose uptake, hepatic gluconeogenesis flux also determines the amount of glycogen formed, especially in the fasted state [1,74,75]. Overexpression of PTG in the liver stimulates glycogen synthesis mainly from gluconeogenic precursors through an indirect pathway. The roles and mechanisms of PTG in gluconeogenesis have not been fully elucidated, and more in-depth studies are still needed.

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