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A Fibroblast Growth Factor 21 – Pregnane X Receptor Pathway Downregulates Hepatic Cytochrome P450 3A4 in Nonalcoholic Fatty Liver Disease

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A Fibroblast Growth Factor 21 – Pregnane X Receptor Pathway Downregulates Hepatic Cytochrome P450 3A4 in Nonalcoholic Fatty Liver Disease Molecular Pharmacology Fast Forward. Published on August 1, 2016 as DOI: 10.1124/mol.116.104687 This article has not been copyedited and formatted. The final version may differ from this version. MOL #104687 A Fibroblast Growth Factor 21 – Pregnane X Receptor Pathway Downregulates Hepatic Cytochrome P450 3A4 in Nonalcoholic Fatty Liver Disease Sarah J. Woolsey, Melanie D. Beaton, Sara E. Mansell, Matilde Leon-Ponte, Janice Yu, Christopher L. Pin, Paul C. Adams, Richard B. Kim, and Rommel G. Tirona Downloaded from Department of Physiology and Pharmacology (S.J.W., J.Y., C.L.P., R.B.K., R.G.T); Division of molpharm.aspetjournals.org Gastroenterology, Department of Medicine (M.D.B, P.C.A.); Division of Clinical Pharmacology, Department of Medicine (S.J.W., S.E.M., M.L-P., J.Y., R.B.K., R.G.T.); Department of Paediatrics (C.L.P.); and Department of Oncology (R.B.K, C.L.P.), Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada at ASPET Journals on September 27, 2021 1 Molecular Pharmacology Fast Forward. Published on August 1, 2016 as DOI: 10.1124/mol.116.104687 This article has not been copyedited and formatted. The final version may differ from this version. MOL #104687 Running Title: FGF21-PXR pathway downregulates CYP3A4 in NAFLD Corresponding Author: Dr. Rommel G. Tirona Departments of Physiology & Pharmacology and Medicine The University of Western Ontario 339 Windermere Road. Downloaded from London, Ontario Canada N6A 5A5 E-mail: [email protected] Telephone: 519-685-8500 x32102 molpharm.aspetjournals.org Number of Text Pages: 30 Number of Tables: 0 Number of Figures: 7 at ASPET Journals on September 27, 2021 Number of References: 61 Abstract: 218 words Introduction: 535 words Discussion: 1273 words Abbreviations: NAFLD, nonalcoholic fatty liver disease; CYP3A4, cytochrome P450 3A4; FGF21, Fibroblast Growth Factor 21; PXR, pregnane X receptor; NASH, nonalcoholic steatohepatitis; FGFR, fibroblast growth factor receptor; MAPK, mitogen-activated protein kinases; ND, normal diet; HFD, high fat diet; ER, endoplasmic reticulum; MEK, mitogen activated protein kinase; ERK, extracellular signal regulated kinases 2 Molecular Pharmacology Fast Forward. Published on August 1, 2016 as DOI: 10.1124/mol.116.104687 This article has not been copyedited and formatted. The final version may differ from this version. MOL #104687 Abstract Nonalcoholic fatty liver disease (NAFLD) alters drug response. We previously reported that NAFLD is associated with reduced in vivo cytochrome P450 3A (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 lipid- and glucose-modulating hormone, Fibroblast Growth Factor 21 (FGF21), in the molecular mechanism regulating Downloaded from 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 molpharm.aspetjournals.org 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 at ASPET Journals on September 27, 2021 mRNA expression with FGF21 treatment. Mice with high fat diet-induced 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. 3 Molecular Pharmacology Fast Forward. Published on August 1, 2016 as DOI: 10.1124/mol.116.104687 This article has not been copyedited and formatted. The final version may differ from this version. MOL #104687 Introduction Nonalcoholic fatty liver disease (NAFLD) is considered the liver manifestation of metabolic syndrome, characterized as triglyceride accumulation within hepatocytes in the absence of significant alcohol consumption (Marchesini et al., 2003). NAFLD affects approximately one third of the western adult population with high prevalence in obesity and Type 2 diabetes (Browning et al., 2004). It is a disease spectrum that includes simple steatosis Downloaded from and nonalcoholic steatohepatitis (NASH), a progressive stage involving inflammation and hepatocyte ballooning. NASH is associated with increased risk for hepatic fibrosis, cirrhosis and hepatocellular carcinoma (Angulo, 2002). molpharm.aspetjournals.org Current management strategies for NAFLD, and in particular NASH, focus on weight reduction and pharmacotherapy to treat comorbidities such as hypertension, dyslipidemia and diabetes. Many medications used by patients with NAFLD are eliminated from the body by the at ASPET Journals on September 27, 2021 intestinal and hepatic enzyme cytochrome P450 3A4 (CYP3A4) (Guengerich, 1999). We reported that in vivo CYP3A activity in subjects with biopsy-proven NAFLD was reduced in both simple steatosis and NASH and that CYP3A4 mRNA levels were lower in NASH liver biopsies than normal liver (Woolsey et al., 2015). Furthermore, we found similar reductions in CYP3A4 expression in mouse and cultured human hepatoma models of the disease (Woolsey et al., 2015). However, the underlying molecular mechanisms involved had yet to be determined. A direct transcriptional regulator of CYP3A4 is the xenosensing, nuclear hormone receptor, pregnane X receptor (PXR) (Kliewer et al., 1998; Tirona et al., 2003). Exposure to PXR-activating dietary and xenobiotic ligands induces hepatic CYP3A4 drug metabolism activity. Interestingly, PXR is also involved in energy homeostasis and consequently, PXR signaling has been implicated in hepatic steatosis. Indeed, studies in transgenic mice have 4 Molecular Pharmacology Fast Forward. Published on August 1, 2016 as DOI: 10.1124/mol.116.104687 This article has not been copyedited and formatted. The final version may differ from this version. MOL #104687 revealed involvement of PXR in hepatic lipogenesis and fatty acid oxidation (He et al., 2013) (Zhou et al., 2008) (Nakamura et al., 2007). Moreover, PXR was found to promote steatosis in cultured primary human hepatocytes (Bitter et al., 2014) (Li et al., 2015). In addition, genetic polymorphisms in the PXR gene (NR1I2) are associated with disease severity in NAFLD (Sookoian et al., 2010). These findings offer an intriguing link between PXR signaling in the development of NAFLD with the observed reduction in CYP3A4 activity. Downloaded from Fibroblast Growth Factor 21 (FGF21) is a hormone secreted largely by the liver that acts as a potent regulator of carbohydrate and lipid metabolism (Kharitonenkov et al., 2005). In molpharm.aspetjournals.org NAFLD, both circulating FGF21 and hepatic FGF21 mRNA levels are elevated as a protective response to metabolic dysregulation (Li et al., 2010; Yilmaz et al., 2010). Indeed, pharmacological treatment with FGF21 reduces hepatic steatosis and weight, improves triglyceride and lipoprotein profiles, and increases insulin sensitivity in rodents and non-human at ASPET Journals on September 27, 2021 primates (Kharitonenkov et al., 2007; Xu et al., 2009). Such beneficial metabolic actions are the motivation for the development of FGF21 mimetic drugs, which in Phase I studies, had favorable effects on serum cholesterol and triglycerides in humans with Type 2 diabetes (Dong et al., 2015; Gaich et al., 2013). Given the diverse metabolic effects and upreglation in NAFLD, we explored whether FGF21 was a contributor to reduced CYP3A4 drug metabolism. In this report, we demonstrate that hepatic CYP3A4 mRNA expression is downregulated by FGF21 through a receptor-mitogen activated protein kinase (MAPK) pathway leading to reduced nuclear PXR localization and CYP3A4 gene transcription. 5 Molecular Pharmacology Fast Forward. Published on August 1, 2016 as DOI: 10.1124/mol.116.104687 This article has not been copyedited and formatted. The final version may differ from this version. MOL #104687 Materials and Methods Human Tissue Samples. Studies were approved by the Human Subjects Research Ethics Board at the University of Western Ontario and all study participants provided written informed consent. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki. Liver biopsy samples and fasting plasma were collected from patients with biopsy- Downloaded from proven NAFLD as reported by Beaton and colleagues (Beaton et al., 2013). NAFLD disease staging into simple steatosis and NASH were defined using histological NAFLD activity score molpharm.aspetjournals.org (NAS) as described previously (Woolsey et al., 2015). Normal human liver samples were obtained through the Liver Tissue Cell Distribution System (Minneapolis, Minnesota; funded by NIH Contract #N01-DK-7-0004 / HHSN267200700004C). Livers were considered normal after histological assessment for steatosis by Oil Red O staining. Plasma was obtained from normal at ASPET Journals on September 27, 2021 healthy control subjects as detailed previously (Woolsey et al., 2016). Total RNA of normal human
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