BOSTON, MA—Fenofibrate has the potential to reduce hepatic inflammation by decreasing production of pro-inflammatory cytokines and may “exert human anti-cholestatic actions through its anti-inflammatory mechanisms,” a presentation at The Liver Meeting® 2016 has found.
“Fenofibrate protected human hepatocytes against bile acid toxicity and improved liver biochemistries associated with cholestatic liver disease,” noted Nisanne Ghonem, PharmD, PhD, department of biomedical and pharmaceutical sciences, University of Rhode Island, Kingston, RI.
Characterized by inflammation, cholestasis—primary biliary cholangitis and primary sclerosing cholangitis—causes intracellular retention of toxic bile acids. Currently, the only therapy available is ursodeoxycholic acid; however, many patients have a subtherapeutic response and the agent does not improve survival in primary sclerosing cholangitis.
“Alternative therapies are urgently needed,” she noted. Recently, “fenofibrate, a PPARα ligand and FDA-approved therapy for dyslipidemia, has shown anti-cholestatic effects for patients with primary biliary cholangitis and primary sclerosing cholangitis; however, the mechanism of fenofibrate’s actions remains unknown.”
To determine the mechanism by which fenofibrate exerts anti-cholestatic and anti-inflammatory actions, the investigators measured cell viability, IL-8 production, and alkaline phosphatase activity in HepaRG cells treated with chenodeoxycholic acid (CDCA, 100–1000μM) for 24 hours ± 2 hours of pretreatment with fenofibrate (5–250μM) by colorimetric assays. The positive control was Wy-14,643 (50μM).
THP-1, a human leukemia monocyte cell line, differentiates into a macrophage-like phenotype when treated with phorbol-12-myristate-13-acetate (5ng/mL). The pro-inflammatory cytokines TNFα, IL-1β, and IL-8 were measured in HepaRG and THP-1 cells treated with lipopolysaccharide (10ng/mL) for 0–24 hours ± pretreatment with fenofibrate (5-250μM), Wy-14,643 (50μM), or DMSO (vehicle control) by ELISA.
They found that in the HepaRG cells, CDCA 500 and 1000μM significantly reduced cell viability to 52% and 31% ± 7% of control, respectively (both P<0.001).
In HepaRG cells, pretreatment with fenofibrate 5, 25, 50, and 125μM significantly improved cell viability in a dose-dependent manner compared with lipopolysaccharide alone. In addition, pretreatment with fenofibrate 50 and 125μM significantly reduced lipopolysaccharide-stimulated alkaline phosphatase activity compared to CDCA treatment as well as significantly attenuated CDCA-stimulated pro-inflammatory cytokine IL-8 production.
In THP-1 cells, treatment with lipopolysaccharide 10ng/mL for 24 hours stimulated peak cytokine concentrations of TNFα (2,224pg/mL), IL-1β (1,234pg/mL), and IL-8 (1,206pg/mL). Pretreatment with fenofibrate 50–125μM significantly reduced TNFα, IL-1β, and IL-8 production in a dose-dependent manner by approximately 65% to 90% (P<0.001), 50% to 90% (P<0.001), and 40% to 60% (P<0.01), respectively.
Fenofibrate 125–250μM reduced lipopolysaccharide-induced nuclear p65 and p50 subunit activity, “suggesting PPARα treatment directly inhibited NK-κB activation,” she concluded.