Pharmaco-nutraceutical improvement of the response to obeticholic acid with omega-3 polyunsaturated fatty acids.

Abstract

Obeticholic acid (OCA) is the second line therapy for primary biliary cholangitis. While efficient in promoting BA detoxification and limiting liver fibrosis, its clinical use is restricted by severe dose-dependent side effects. We tested the hypothesis that adding n-3 polyunsaturated fatty acids, eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids to OCA may improve the therapeutic effect of the low drug dosage. Several liver cell lines were exposed to vehicle, low or high OCA dose (1-20μM) in the presence or absence of EPA/DHA for 24H. To induce ER stress, apoptosis, and fibrosis, HepG2 cells were exposed to a 400μM BA mixture or to 2ng/mL TGF-β. For inflammation analyses, THP-1 cells were activated with 100ng/mL LPS. The impact OCA+EPA/DHA was assessed using transcriptomic (qRT-PCR), proteomic (ELISA, caspase-3), and metabolomic (LC-MS/MS) approaches. The addition of EPA/DHA reinforced the ability of low OCA dose to down-regulate the expression of genes involved in BA synthesis (CYP7A1, CYP8B1) and uptake (NTCP) and to up-regulate MRP2 & 3 genes expression. EPA/DHA also enhanced the anti-inflammatory response of the drug by reducing the expression of the LPS-induced cytokines: TNFα, IL-6, IL-1β and MCP-1 in THP-1 macrophages. OCA+EPA/DHA decreased the expression of BIP, CHOP and COL1A1 genes and the caspase-3 activity. EPA+DHA potentiate the response to low OCA doses on BA toxicity, and provide additional benefits on ER stress, apoptosis, inflammation and fibrosis. These observations support the idea that adding n-3 polyunsaturated fatty acids to the drug may reduce the risk of dose-related side effects in patients treated with OCA.