Obesity is associated with the risk of cardiovascular disease, and non-nutritive sweetener, such as acesulfame potassium (AceK) has been used to combat obesity. However, the effects of AceK on cardiovascular disease are still unclear. In this study, high cholesterol diet (HCD)-fed ApoE^−/− mice had dysregulated plasma lipid profile, and developed atherosclerosis, determined by atherosclerotic plaque in the aorta. Supplement of AceK in HCD worsened the dyslipidemia and increased atherosclerotic plaque, as compared with HCD-fed ApoE^−/− mice. Since treatment of AceK in RAW264.7 macrophages showed no significant effects on inflammatory cytokine expressions, we then investigated the impacts of AceK on lipid metabolism. We found that AceK consumption enhanced hepatic lipogenesis and decreased β-oxidation in ApoE^−/− mice. In addition, AceK directly increased lipogenesis and decreased β-oxidation in HepG2 cells. Taken together, a concurrent consumption of AceK exacerbated HCD-induced dyslipidemia and atherosclerotic lesion in ApoE^−/− mice, and AceK might increase the risk of atherosclerosis under HCD.

Sugar substitutes have been recommended to be used for weight and glycemic control. However, numerous studies indicate that consumption of artificial sweeteners exerts adverse effects on glycemic homeostasis. Although sucralose is among the most extensively utilized sweeteners in food products, the effects and detailed mechanisms of sucralose on insulin sensitivity remain ambiguous. In this study, we found that bolus administration of sucralose by oral gavage enhanced insulin secretion to decrease plasma glucose levels in mice. In addition, mice were randomly allocated into three groups, chow diet, high-fat diet (HFD), and HFD supplemented with sucralose (HFSUC), to investigate the effects of long-term consumption of sucralose on glucose homeostasis. In contrast to the effects of sucralose with bolus administration, the supplement of sucralose augmented HFD-induced insulin resistance and glucose intolerance, determined by glucose and insulin tolerance tests. In addition, we found that administration of extracellular signal-regulated kinase (ERK)-1/2 inhibitor reversed the effects of sucralose on glucose intolerance and insulin resistance in mice. Moreover, blockade of taste receptor type 1 member 3 (T1R3) by lactisole or pretreatment of endoplasmic reticulum stress inhibitors diminished sucralose-induced insulin resistance in HepG2 cells. Taken together, sucralose augmented HFD-induced insulin resistance in mice, and interrupted insulin signals through a T1R3-ERK1/2-dependent pathway in the liver.

Background: The oncogenic Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation was reported to be the signature genetic event in most cases of pancreatic ductal adenocarcinoma (PDAC). Hepassocin (HPS/FGL1) is involved in regulating lipid metabolism and the progression of several cancer types; however, the underlying mechanism of HPS/FGL1 in the KRAS mutant PDAC cells undergoing eicosapentaenoic acid (EPA) treatment remains unclear. Methods: We measured HPS/FGL1 protein expressions in a human pancreatic ductal epithelial (HPNE) normal pancreas cell line, a KRAS-wild-type PDAC cell line (BxPC-3), and KRAS-mutant PDAC cell lines (PANC-1, MIA PaCa-2, and SUIT-2) by Western blot methods. HEK293T cells were transiently transfected with corresponding KRAS-expressing plasmids to examine the level of HPS expression with KRAS activation. We knocked-down HPS/FGL1 using lentiviral vectors in SUIT-2 cells and measured the cell viability by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and clonogenicity assays. Furthermore, a lipidomic analysis was performed to profile changes in lipid metabolism after HPS/FGL1 knockdown. Results: We found that the HPS/FGL1 level was significantly upregulated in KRAS-mutated PDAC cells and was involved in KRAS/phosphorylated (p)-signal transduction and activator of transcription 3 (STAT3) signaling, and the knockdown of HPS/FGL1 in SUIT-2 cells decreased cell proliferation through increasing G₂/M cell cycle arrest and cyclin B1 expression. In addition, the knockdown of HPS/FGL1 in SUIT-2 cells significantly increased omega-3 polyunsaturated fatty acids (PUFAs) and EPA production but not docosahexaenoic acid (DHA). Moreover, EPA treatment in SUIT-2 cells reduced the expression of de novo lipogenic protein, acetyl coenzyme A carboxylase (ACC)-1, and decreased p-STAT3 and HPS/FGL1 expressions, resulting in the suppression of cell viability. Conclusions: Results of this study indicate that HPS is highly expressed by KRAS-mutated PDAC cells, and HPS/FGL1 plays a crucial role in altering lipid metabolism and increasing cell growth in pancreatic cancer. EPA supplements could potentially inhibit or reduce ACC-1-involved lipogenesis and HPS/FGL1-mediated cell survival in KRAS-mutated pancreatic cancer cells.