Fenofibrate Downregulates NF-κB Signaling to Inhibit Pro-inflammatory Cytokine Secretion in Human THP-1 Macrophages and During Primary Biliary Cholangitis

Chronic liver diseases, e.g., cholestasis, are negatively impacted by inflammation, which further aggravates liver injury. Pharmacotherapy targeting the peroxisome proliferator-activated receptor alpha (PPAR alpha), e.g., fenofibrate, has recently become an off-label therapeutic option for patients with refractory cholestasis. Clinical studies show that fibrates can reduce some pro-inflammatory cytokines in primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC); however, its anti-inflammatory mechanisms have not been established. Numerous cytokines are regulated by the transcription factor nuclear receptor kappa B (NF-kappa B), and PPAR alpha has been shown to interfere with NF-kappa B signaling. This study investigates the anti-inflammatory mechanism of fenofibrate by inhibiting NF-kappa B signaling in human macrophages and clinical outcomes in patients with PBC. For adult patients with PBC and an incomplete biochemical response to ursodiol (13-15 mg/kg/day), the addition of fenofibrate (145-160 mg/day) reduced serum levels of TNF-alpha, IL-17A, IL-1 beta, IL-6, IL-8, and MCP-1 and increased IL-10. In THP-1 cells, pretreatment with fenofibrate (125 mu M) reduced LPS-stimulated peak concentrations of IL-1 beta (- 63%), TNF-alpha (- 88%), and IL-8 (-54%), in a PPAR alpha-dependent manner. Treatment with fenofibrate prior to LPS significantly decreased nuclear NF-kappa B p50 and p65 subunit binding by 49% and 31%, respectively. Additionally, fenofibrate decreased nuclear NF-kappa B p50 and p65 protein expression by 66% and 55% and increased cytoplasmic levels by 53% and 54% versus LPS alone, respectively. Lastly, fenofibrate increased I kappa B alpha levels by 2.7-fold (p < 0.001) vs. LPS. These data demonstrate that fenofibrate reduces pro-inflammatory cytokines section by inhibiting in NF-kappa B signaling, which likely contribute to its anti-inflammatory effects during chronic liver diseases.

Automated summary

Fenofibrate has anti-inflammatory effects in chronic liver diseases by inhibiting NF-kappa B signaling and reducing the secretion of pro-inflammatory cytokines.