Circulating Human Metabolites Resulting from TOTUM-070 Absorption (a Plant-Based, Polyphenol-Rich Ingredient) Improve Lipid Metabolism in Human Hepatocytes: Lessons from an Original Ex Vivo Clinical Trial

• Published in: Nutrients 2023-04, Vol.15 (8), p.1903
• Main Authors: Wauquier, Fabien, Boutin-Wittrant, Line, Krisa, Stéphanie, Valls, Josep, Langhi, Cedric, Otero, Yolanda F, Sirvent, Pascal, Peltier, Sébastien, Bargetto, Maxime, Cazaubiel, Murielle, Sapone, Véronique, Bouchard-Mercier, Annie, Roux, Véronique, Macian, Nicolas, Pickering, Gisèle, Wittrant, Yohann
• Format: Article
• Language: English
• Subjects: Atherosclerosis; Biological activity; Body weight; Care and treatment; Cholesterol; Chromatography; Chromatography, Liquid; Clinical trials; Complications and side effects; Diet; Diet, High-Fat; Ethics; Fatty acids; Fatty-acid synthase; Health aspects; Hepatocytes; High density lipoprotein; High fat diet; Humans; Hydroxymethylglutaryl-CoA reductase; Hyperlipidemia; Ingestion; Life Sciences; Lipid Metabolism; Lipids; Liver - metabolism; Mass spectrometry; Medicine, Botanic; Medicine, Herbal; Metabolism; Metabolites; Nutrition research; Palmitic acid; Physiological aspects; Plant extracts; Polyphenols; Polyphenols - metabolism; Polyphenols - pharmacology; Proteomics; Reductases; Scientific imaging; Tandem Mass Spectrometry; Triglycerides; Veins & arteries
• ISSN: 2072-6643; 2072-6643
• DOI: 10.3390/nu15081903

TOTUM-070 is a patented polyphenol-rich blend of five different plant extracts showing separately a latent effect on lipid metabolism and potential synergistic properties. In this study, we investigated the health benefit of such a formula. Using a preclinical model of high fat diet, TOTUM-070 (3 g/kg of body weight) limited the HFD-induced hyperlipemia with a reduction in triglyceride (-32% after 6 weeks; -20.3% after 12 weeks) and non-HDL cholesterol levels (-21% after 6 weeks; -38.4% after 12 weeks). To further investigate such a benefit and its underlying mechanisms in humans, we designed an ex vivo clinical approach to collect the circulating bioactives resulting from TOTUM-070 ingestion and to determine their biological activities on human hepatocytes. Human serum was obtained from healthy subjects before and after intake of TOTUM-070 (4995 mg). The presence of circulating metabolites was assessed by UPLC-MS/MS. Serum containing metabolites was further incubated with hepatocytes cultured in a lipotoxic environment (palmitate, 250 µM). RNA sequencing analyses show that lipid metabolism was one of the most impacted processes. Using histologic, proteomic, and enzymatic assays, the effects of human TOTUM-070 bioactives on hepatocyte metabolism were characterized by (1) the inhibition of lipid storage, including both (2) triglycerides (-41%, < 0.001) and (3) cholesterol (-50%, < 0.001) intracellular content, (4) a reduced de novo cholesterol synthesis (HMG-CoA reductase activity -44%, < 0.001), and (5) a lowered fatty acid synthase protein level ( < 0.001). Altogether, these data support the beneficial impact of TOTUM-070 on lipid metabolism and provide new biochemical insights in human mechanisms occurring in liver cells.