A Fibroblast Growth Factor 21–Pregnane X Receptor Pathway Downregulates Hepatic CYP3A4 in Nonalcoholic Fatty Liver Disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) alters drug response. We previously reported that NAFLD is associated with reduced in vivo CYP3A drug-metabolism activity and hepatic CYP3A4 expression in humans as well as mouse and human hepatoma models of the disease. Here, we investigated the role of the lipidand glucose-modulating hormone fibroblast growth factor 21 (FGF21) in the molecular mechanism regulating CYP3A4 expression in NAFLD. In human subjects, mouse and cellular NAFLD models with lower CYP3A4 expression, circulating FGF21, or hepatic FGF21 mRNA levels were elevated. Administration of recombinant FGF21 or transient hepatic overexpression of FGF21 resulted in reduced liver CYP3A4 luciferase reporter activity in mice and decreased CYP3A4 mRNA expression and activity in cultured Huh7 hepatoma cells. Blocking canonical FGF21 signaling by pharmacological inhibition of MEK1 kinase in Huh7 cells caused de-repression of CYP3A4 mRNA expression with FGF21 treatment. Mice with high-fat dietinduced simple hepatic steatosis and lipid-loaded Huh7 cells had reduced nuclear localization of the pregnane X receptor (PXR), a key transcriptional regulator of CYP3A4. Furthermore, decreased nuclear PXR was observed in mouse liver and Huh7 cells after FGF21 treatment or FGF21 overexpression. Decreased PXR binding to the CYP3A4 proximal promoter was found in FGF21-treated Huh7 cells. An FGF21-PXR signaling pathway may be involved in decreased hepatic CYP3A4 metabolic activity in NAFLD.

Histone Methyltransferase G9a Regulates Expression of Nuclear Receptors and Cytochrome P450 Enzymes in HepaRG Cells at Basal Level and in Fatty Acid Induced Steatosis

“…The transcription factor, nuclear factor interleukin 3 (NFIL3), also known as E4BP4, interacts with G9a to increase H3K9me2 at the FGF21 promoter to repress FGF21 gene expression (Tong et al, 2013). Previously, it was observed that treatment of Huh-7 cells with recombinant FGF21 protein resulted in decreased nuclear transport of PXR leading to decreased CYP3A4 transcription (Woolsey et al, 2016).…”

Review article: drug‐induced liver injury in the context of nonalcoholic fatty liver disease – a physiopathological and clinical integrated view

“…Impairment of CYP3A activity due to reduced protein levels was reported in diabetic patients, a factor likely associated with the occurrence of NAFLD in these subjects. 273 Downregulation of CYP3A4 by the cytokinemediated activation of the "Janus kinase" (JAK)/"signal transducer and activator of transcription" (STAT) signalling pathway in the course of the inflammatory response, 274 or by the "fibroblast growth factor 21" (FGF21)-mediated activation of the "mitogen-activated protein kinase" (MAPK) pathway, 275 has been proposed. BESSONE ET AL.…”

Non-alcoholic fatty liver disease (NAFLD) – pathogenesis, classification, and effect on drug metabolizing enzymes and transporters

“…The cytokine-mediated down-regulation of CYP3A4 (Werk and Cascorbi, 2014) in the course of the inflammatory response via the JAK/STAT (Janus kinase/Signal Transducer and Activator of Transcription) pathway (Jover et al , 2002 ) seem to be clinically relevant in NAFLD and diabetic patients due to circulating cytokines. Additionally, it has been suggested that the hepatic CYP3A4 expression is probably down-regulated by FGF21 (fibroblast growth factor 21) through the receptor-mitogen-activated protein kinase (MAPK) pathway which leads to reduced gene transcription (Woolsey et al , 2016). …”