Fig 2: Human cellular expression of SGLT1. A Uniform manifold approximation and projection (UMAP) of snRNA-seq data of human heart cells from Koenig et al. 14 distinct cell types were identified, including cardiomyocytes. B SGLT1 expression (left UMAP) is enriched in cardiomyocytes. Conversely, SGLT2 expression (right UMAP) is scant. C UMAP of snRNA-seq data human cardiomyocytes (top UMAP) from Tucker et al. The bottom UMAP represents stratification of cardiomyocytes into the four chambers, with atrial and ventricular cardiomyocytes resolving separately. Analysis of the relative expression of SGLT1 in atrial versus ventricular cardiomyocytes (D)

Fig 3: Ang II causes a redox-sensitive up-regulation of SGLT1 and 2 promoting their own expression in ECs. ECs are incubated with either (a, b) N-acetyl cysteine (NAC, an antioxidant, 1 mM) for 2 h, VAS-2870 (VAS, a NADPH oxidase inhibitor, 1 µM), indomethacin (INDO, a cyclooxygenase inhibitor, 30 µM) or myxothiazol (0.5 µM) + KCN (1 µM) + rotenone (1 µM; MKR, mitochondrial respiratory chain inhibitors) for 30 min, and (c, d) sotagliflozin (SOTA, 100 nM) or empagliflozin (EMPA, 100 nM) for 30 min before the addition of Ang II and the subsequent assessment of the expression level of SGLT1 and SGLT2 by Western blot analysis. Results are shown as representative immunoblots (upper panels) and corresponding cumulative data (lower panels). Data are expressed as mean ± SEM of n = 3. *P < 0.05 vs. control and #P < 0.05 vs. Ang II

Fig 4: Downregulation of MYBBP1A induces direct activation of PGC1α. (A) Downregulation of MYBBP1A by the expression of a specific shRNA. Cell lines were transfected with MYBBP1A shRNA (sh) or a scramble vector (V). After selection, cells were grown to 80% confluence, and proteins were extracted. The figure shows the western blot results of MYBBP1A expression in all cell lines and the quantification of MYBBP1A expression in cells expressing MYBBP1A shRNA (sh) related to the scramble vector (V). (B) PGC1α, SGLT1, p38, and p‐p38 (T180/Y182) levels at high‐ (4500 mg·L−1) and low‐glucose (100 mg·L−1) media were measured by WB. (C) A498, 786‐O, ACHN, and CaKi‐1 cells expressing the scramble vector (V) or MYBBP1A shRNA (sh) were cultured in low‐glucose (100 mg·L−1) media. SGLT1 and GLUT4 mRNA levels were measured by Q‐RT‐PCR. Graphs show mRNA levels of cells with reduced levels of MYBBP1A (sh) related to control cells (V).(D) A498, 786‐O, ACHN, and CaKi‐1 cells expressing the scramble vector (V) or MYBBP1A shRNA (sh) were cultured in low‐glucose (100 mg·L−1) media. HK2, PFKM, GAPDH, PGK1, PGAM1, and PKM mRNA levels were measured by Q‐RT‐PCR. Graphs show mRNA levels of cells with reduced levels of MYBBP1A (sh) related to control cells (V). (E) Quantification of HK2 and LDHA levels from xenografted tumors (N = 4) by Q‐RT‐PCR. Graphs show mRNA levels of cells with reduced levels of MYBBP1A (sh) related to control cells (V). (C, D) Graphs show the mean ± SD of three independent experiments performed in triplicate. (C–E) Statistical test: unpaired Student’s t‐test with Welch’s correction, *P < 0.05; **P < 0.01; ***P < 0.001.

Fig 5: Correlation between SGLT-1 (SLC5A1) and prognosis in PC. A and B Kaplan–Meier analysis of OS for patients with high vs. low SGLT-1 expression in IHC. C Kaplan–Meier analysis of OS for patients with high vs. low SGLT-1 (SLC5A1) mRNA expression using GEPIA. D Kaplan–Meier analysis of DFS for patients with high vs. low SGLT-1 (SLC5A1) mRNA expression using GEPIA. E Kaplan–Meier analysis of OS for patients with high vs. low SGLT-1 (SLC5A1) mRNA expression based on data downloaded from TCGA. F Kaplan–Meier analysis of PFS for patients with high vs. low SGLT-1 (SLC5A1) mRNA expression based on data downloaded from TCGA. (* for P < 0.05, ** for P < 0.01)