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  • Expression and translocation of GLUT are regulated by variou

    2022-05-21

    Expression and translocation of GLUT4 are regulated by various mechanisms including protein kinase C isoforms (PKCs) and mitogen-activated protein kinase (MAPK) signals [22], [23], but the real mechanism that statins alter expression and function of GLUT4 has not been fully identified. It is generally accepted that statins show their clinical efficacy on hypercholesterolemia through inhibiting cholesterol synthesis. A report demonstrated that atorvastatin significantly decreased expression of ATP-binding cassette (ABC) and solute carrier (SLC)transporters, which were positively correlated with plasma cholesterol levels [24]. Furthermore, cholesterol depletion with methyl-β-cyclodextrin (MβCD) was also reported to decrease activity of breast cancer resistance protein [25]. In contrast, the elevated cholesterol levels markedly increased P-glycoprotein activity [26]. These results gave a clue that expression and function of GLUT4, one isoform of SLCtransporter family, may be regulated by cellular cholesterol levels.
    Methods and materials
    Results
    Discussion Growing evidences have demonstrated that statins may increase the risk of incident diabetes, exact mechanism of which is not fully understood. In general, skeletal muscle has a critical role in glycemic control and metabolic homeostasis, which accounts for about 80% of glucose disposal in body [42]. Here, the aim of the study was to investigate whether atorvastatin impaired glucose utilization in skeletal muscle. C2C12, a muscle cell line widely used in the study of insulin resistance [43], [44], [45], [46], was used as an in vitro model to investigate the effect of atorvastatin on glucose metabolism in myocytes. The present study indicated that atorvastatin inhibited glucose consumption and uptake in C2C12 7ACC1 (Fig. 1A and B), but little affected mRNA and protein expression of HXKII and its activity (Fig. 1D, F and H). Generally, glucose uptake by peripheral tissues is dependent on the expression and translocation of GLUT4 [47]. In adipocytes, atorvastatin and simvastatin were reported to decrease glucose uptake via inhibiting expression of GLUT4 protein [19]. Then, we investigated whether atorvastatin impaired glucose uptake via suppressing expression of GLUT4 protein in C2C12 cells. It was contrast to our expectation that atorvastatin did not affect total mRNA and protein expression of GLUT4 in C2C12 cells (Fig. 1C and E). Further study demonstrated that atorvastatin showed a mild but significant decrease in GLUT4 translocation (Fig. 1G), as well as a marked less distribution on membrane of the C2C12 cells (Fig. 3A), which may be a reason that atorvastatin impaired glucose utilization in C2C12 cells. Interestingly, pravastatin was found to mildly increase glucose uptake (Fig. 1B) without affecting the GLUT4 translocation (Fig. 1G), indicating that other factors may be involved in the increase in glucose uptake induced by pravastatin. Several reports suggested that pravastatin improved glucose uptake through increasing adiponectin receptor expression and adiponectin production [48], [49]. Besides GLUT4, other membrane receptors, such as insulin receptor (IR), insulin receptor substrate 1 (IRS-1) and protein kinase B (Akt), may also be sensitive to statins and cholesterol levels [50], [51], which may also be contributed to the impaired glucose utilization induced by statins. It is widely accepted that statins including atorvastatin exhibit their therapeutic effects via inhibiting synthesis of cholesterol. Some reports demonstrated that activities of breast cancer resistance protein [25] and P-glycoprotein [26] were associated with contents of cholesterol in plasma membrane of cells. It was also reported that decreases in expression of some ABC and SLC transporters by atorvastatin might be involved in a decrease in cholesterol levels [24]. Moreover, free (non-esterified) cholesterol is a major component of the cell membranes, which is believed to influence the function of lipid rafts [52] and aid in anchor of transmembrane proteins [53]. All these suggested that the atorvastatin-induced GLUT4 translocation inhibition may be attributed to the inhibition of cholesterol synthesis by atorvastatin. Thus, a series of experiments were designed to verify the hypothesis. The measurement showed that the impairment of glucose consumption and glucose uptake, as well as GLUT4 translocation and GLUT4 distribution on membrane of C2C12 cells by atorvastatin were alleviated by restoration of cellular cholesterol or mevalonic acid (Fig. 2A, B, E and 3A). Depletion of cholesterol with MβCD led to similar inhibitory effects to atorvastatin, which could be partly mitigated by supplement of cholesterol (Fig. 2C, D, E and 3B). Moreover, a high degree of correlations between free cholesterol concentrations and glucose consumption, as well as GLUT4 translocation in C2C12 cells (Fig. 4B–E) further confirmed the contribution of decreased cholesterol level to the impairment of GLUT4 function and translocation. All these results indicated that the decrease in GLUT4 translocation by atorvastatin was, at least, partly attributed to the inhibition of cholesterol synthesis. However, several reports showed that cholesterol depletion increased GLUT4 on the cell surface in adipose cells [54], [55], indicating that roles of cholesterol in GLUT4 translocation were tissue-dependent. Moreover, GLUT4 translocation was involved in several processes such as tethering, docking, fusion and endocytosis [56]. The contribution of cholesterol to these processes needs to be further investigated.