title: Nuclear receptors and nonalcoholic fatty liver disease.
abstract: Nuclear receptors are transcription factors which sense changing environmental or hormonal signals and effect transcriptional changes to regulate core life functions including growth, development, and reproduction. To support this function, following ligand-activation by xenobiotics, members of subfamily 1 nuclear receptors (NR1s) may heterodimerize with the retinoid X receptor (RXR) to regulate transcription of genes involved in energy and xenobiotic metabolism and inflammation. Several of these receptors including the peroxisome proliferator-activated receptors (PPARs), the pregnane and xenobiotic receptor (PXR), the constitutive androstane receptor (CAR), the liver X receptor (LXR) and the farnesoid X receptor (FXR) are key regulators of the gut:liver:adipose axis and serve to coordinate metabolic responses across organ systems between the fed and fasting states. Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease and may progress to cirrhosis and even hepatocellular carcinoma. NAFLD is associated with inappropriate nuclear receptor function and perturbations along the gut:liver:adipose axis including obesity, increased intestinal permeability with systemic inflammation, abnormal hepatic lipid metabolism, and insulin resistance. Environmental chemicals may compound the problem by directly interacting with nuclear receptors leading to metabolic confusion and the inability to differentiate fed from fasting conditions. This review focuses on the impact of nuclear receptors in the pathogenesis and treatment of NAFLD. Clinical trials including PIVENS and FLINT demonstrate that nuclear receptor targeted therapies may lead to the paradoxical dissociation of steatosis, inflammation, fibrosis, insulin resistance, dyslipidemia and obesity. Novel strategies currently under development (including tissue-specific ligands and dual receptor agonists) may be required to separate the beneficial effects of nuclear receptor activation from unwanted metabolic side effects. The impact of nuclear receptor crosstalk in NAFLD is likely to be profound, but requires further elucidation. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie.
authors.affiliation: Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Louisville School of Medicine, Louisville, KY 40202, USA; Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY 40202, USA; Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, USA; The Robley Rex Veterans Affairs Medical Center, Louisville, KY 40206, USA; The KentuckyOne Health Jewish Hospital Liver Transplant Program, Louisville, KY 40202, USA. Electronic address: matt.cave@louisville.edu.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Cave
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY 40202, USA.
authors.forename: Heather B
authors.initials: HB
authors.lastname: Clair
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY 40202, USA.
authors.forename: Josiah E
authors.initials: JE
authors.lastname: Hardesty
authors.affiliation: Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Louisville School of Medicine, Louisville, KY 40202, USA.
authors.forename: K Cameron
authors.initials: KC
authors.lastname: Falkner
authors.affiliation: Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Louisville School of Medicine, Louisville, KY 40202, USA; Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, USA.
authors.forename: Wenke
authors.initials: W
authors.lastname: Feng
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY 40202, USA.
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Clark
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY 40202, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Sidey
authors.affiliation: Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, USA.
authors.forename: Hongxue
authors.initials: H
authors.lastname: Shi
authors.affiliation: Department of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Scottsdale, AZ 85054, USA.
authors.forename: Bashar A
authors.initials: BA
authors.lastname: Aqel
authors.affiliation: Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Louisville School of Medicine, Louisville, KY 40202, USA; Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, USA; The Robley Rex Veterans Affairs Medical Center, Louisville, KY 40206, USA; The KentuckyOne Health Jewish Hospital Liver Transplant Program, Louisville, KY 40202, USA.
authors.forename: Craig J
authors.initials: CJ
authors.lastname: McClain
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY 40202, USA.
authors.forename: Russell A
authors.initials: RA
authors.lastname: Prough
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000090702:Constitutive Androstane Receptor; D015507:Drugs, Investigational / Q000008:administration & dosage / Q000009:adverse effects; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000071518:Liver X Receptors / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D000077297:Pregnane X Receptor; D020239:Receptor Cross-Talk / Q000187:drug effects; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D011987:Receptors, Steroid / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D015262:Xenobiotics / Q000008:administration & dosage / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000090702:Constitutive Androstane Receptor; D015507:Drugs, Investigational; D000071518:Liver X Receptors; D047492:Peroxisome Proliferator-Activated Receptors; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D015262:Xenobiotics; D000099150:Receptor, Farnesoid X-Activated
keywords: CAR; FXR; LXR; NAFLD; NASH; PCBs; PPAR; PXR; TAFLD; TASH