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, 2002) or (b) experimentally induced insulin resistance (due to liver-specific deletion of insulin receptor IRS1, IRS2, or both IRS1 and IRS2) in the absence of obesity ( Guo et?al., 2009?and?Biddinger et?al., 2008). Similarly, muscle-specific insulin resistance, even with superimposed hyperglycemia, does not alter Sfrs10 expression ( Yechoor et?al., 2004). Additionally, exposure of HepG2 hepatoma cells and C2C12 myotubes to palmitate or elevated glucose did not affect SFRS10 expression. However, overnight incubation with 10?nM insulin decreased SFRS10 expression ( Figure?S1), supporting a potential role for chronic insulin exposure in contributing to decreased SFRS10 expression. To assess the functional consequences of decreased splicing factor gene expression, we NU7441 molecular weight experimentally reduced SFRS10 expression in HepG2 cells. siRNA-mediated knockdown of SFRS10 led to a 50%�C70% decrease in mRNA and protein levels (Figure?2A). Given that decreased expression of several RNA processing genes was associated with increased hepatic lipid content in human subjects, we examined the effects of reducing SFRS10 on lipid metabolism in hepatic cells. Indeed, SFRS10 knockdown in HepG2 cells induced a 1.5- to 2-fold increase in lipogenic genes, including SREBP1c, FASN, ACC1, and DGAT2 ( Figure?2B). While we observed trends for SFRS10 knockdown to increase expression of SREBP1a and PCK1 ATP7A (PEPCK), expression of other genes influencing lipid or glucose metabolism, including ESR1 (ERR��), NR1H3 (LXR��), NR1H2 (LXR��), NR1H4 (FXR), PPARA, PPARG, PPARD, PPARGC1A (PGC-1��), and PPARGC1B (PGC-1��), did not differ following SFRS10 knockdown ( Table S5). Notably, SFRS10 knockdown-mediated increases in lipogenic gene expression were accompanied by a 1.6-fold increase in lipogenesis, as measured by [14C]-acetate incorporation into the lipid fraction (p?Antiinfection Compound Library cell line (TAG) (p?