Despite enormous efforts to improve therapeutic options, pancreatic cancer remains a fatal disease and is expected to become the second leading cause of cancer-related deaths in the next decade. Previous research identified lipid metabolic pathways to be highly enriched in pancreatic ductal adenocarcinoma (PDAC) cells. Thereby, cholesterol uptake and synthesis promotes growth advantage to and chemotherapy resistance for PDAC tumor cells. Here, we demonstrate that high-density lipoprotein (HDL)–mediated efficient cholesterol removal from cancer cells results in PDAC cell growth reduction and induction of apoptosis in vitro. This effect is driven by an HDL particle composition–dependent interaction with SR-B1 and ABCA1 on cancer cells. AAV-mediated overexpression of APOA1 and rHDL injections decreased PDAC tumor development in vivo. Interestingly, plasma samples from pancreatic-cancer patients displayed a significantly reduced APOA1-to-SAA1 ratio and a reduced cholesterol efflux capacity compared with healthy donors. We conclude that efficient, HDL-mediated cholesterol depletion represents an interesting strategy to interfere with the aggressive growth characteristics of PDAC.

Decreasing circulating low-density lipoprotein (LDL) cholesterol levels leads to decreased risk of cardiovascular diseases. Natural compounds are capable of lowering LDL-cholesterol even on top of lifestyle modification or medication. To identify novel plant-derived compounds to lower plasma LDL cholesterol levels, we performed high-content screening based on the transcriptional activation of the promoter of the LDL receptor (LDLR). The identified hits were thoroughly validated in human hepatic cell lines in terms of increasing LDLR mRNA and protein levels, lowering cellular cholesterol levels and increasing cellular LDL uptake. By means of this incremental validation process in vitro, aqueous extracts prepared from leaves of lingonberries (Vaccinium vitis-idaea) as well as blackberries (Rubus fruticosus) were found to have effects comparable to lovastatin, a prototypic cholesterol-lowering drug. When applied in vivo in mice, both extracts induced subtle increases in hepatic LDLR expression. In addition, a significant increase in high-density lipoprotein (HDL) cholesterol was observed. Taken together, aqueous extracts from lingonberry or blackberry leaves were identified and characterized as strong candidates to provide cardiovascular protection.

Background/Objectives: Individuals with special metabolic demands are at risk of deficiencies in fat-soluble vitamins, which can be counteracted via supplementation. Here, we tested the ability of micellization alone or in combination with selected natural plant extracts to increase the intestinal absorption and bioefficacy of fat-soluble vitamins. Methods: Micellated and nonmicellated vitamins D3 (cholecalciferol), D2 (ergocalciferol), E (alpha tocopheryl acetate), and K2 (menaquionone-7) were tested in intestinal Caco-2 or buccal TR146 cells in combination with curcuma (Curcuma longa), black pepper (Piper nigrum), or ginger (Zingiber officinale Roscoe) plant extracts. The vitamin uptake was quantified via HPLC-MS, and bioefficacy was assessed via gene expression analyses or the Griess assay for nitric oxide generation. Results: Micellization increased the uptake of vitamin D into buccal and intestinal cells, with vitamin D3 being more efficient than vitamin D2 in increasing the expression of genes involved in calcium transport. The micellization of vitamin E acetate increased its uptake and conversion into biologically active free vitamin E in intestinal cells only. The vitamin K2 uptake into buccal and intestinal cells was increased via micellization. Plant extracts increased the uptake of select micellated vitamins, with no plant extract being effective in combination with all vitamins. The curcuma extract increased the uptake of vitamins D2/D3 but not their bioefficacy. Black pepper and ginger extracts increased the uptake of vitamin E acetate into intestinal cells but failed to increase its conversion into free vitamin E. The ginger extract augmented the uptake of vitamin K2 and increased NO generation additively. Conclusions: Our data substantiate the positive effects of micellization on fat-soluble vitamin absorption and bioefficacy in vitro. While the application of plant extracts in addition to micellization to further increase bioefficacy is an interesting approach, further studies are warranted to understand vitamin-specific interactions and translation into increased bioefficacy.