Role of Nuclear Receptors in Lipid Dysfunction and Obesity-Related Diseases

Abstract

This article is a report on a symposium sponsored by the American Society for Pharmacology and Experimental Therapeutics and held at the Experimental Biology 12 meeting in San Diego, CA. The presentations discussed the roles of a number of nuclear receptors in regulating glucose and lipid homeostasis, the pathophysiology of obesity-related disease states, and the promise associated with targeting their activities to treat these diseases. While many of these receptors (in particular, constitutive androstane receptor and pregnane X receptor) and their target enzymes have been thought of as regulators of drug and xenobiotic metabolism, this symposium highlighted the advances made in our understanding of the endogenous functions of these receptors. Similarly, as we gain a better understanding of the mechanisms underlying bile acid signaling pathways in the regulation of body weight and glucose homeostasis, we see the importance of using complementary approaches to elucidate this fascinating network of pathways. The observation that some receptors, like the farnesoid X receptor, can function in a tissue-specific manner via well defined mechanisms has important clinical implications, particularly in the treatment of liver diseases. Finally, the novel findings that agents that selectively activate estrogen receptor b can effectively inhibit weight gain in a high-fat diet model of obesity identifies a new role for this member of the steroid superfamily. Taken together, the significant findings reported during this symposium illustrate the promise associated with targeting a number of nuclear receptors for the development of new therapies to treat obesity and other metabolic disorders.

Drug Metabolism by the Host and Gut Microbiota: A Partnership or Rivalry?

“…The gut microbiota plays an extensive role in bile acid metabolism and in this manner contributes to the health of the host via its impact on the absorption of lipids and lipid-soluble vitamins and maintenance of intestinal barrier function (Li and Jia, 2013;Swanson et al, 2013;Klaassen and Cui, 2015). Whereas the liver is the major source of primary bile acid synthesis, the intestinal bacteria are largely responsible for the production of secondary bile acids.…”

Bile acid detoxifying enzymes limit susceptibility to liver fibrosis in female SHRSP5/Dmcr rats fed with a high-fat-cholesterol diet

“…These observations warrant further studies to determine whether estrogen influences Fxr and Shr mRNA and protein expressions. Swanson et al [49] showed that the intestinal FXR/FGF15 pathway was critical for suppressing the expression of Cyp7a1 and Cyp8b1 genes, whereas the liver FXR/SHP pathway was important for suppressing Cyp8b1 gene expression and played a minor role in suppressing Cyp7a1 gene expression in mice. Because the influences of HFC-diet feeding on the expression of both Cyp genes are dimorphic, investigations of the intestinal FXR/FGF15 pathway may provide clear indications of gender differences.…”

Bile acid activated receptors are targets for regulation of integrity of gastrointestinal mucosa

“…Several major signaling networks are activated by bile acids [1][2][3][4][5]. Thus, bile acids are known ligands for at least four members of the nuclear receptor (NR) superfamily (Figs.…”

“…1, 2), i.e., farnesoid X receptor (FXR; also known as NR1H4), constitutive androstane receptor (also known as NR1H3), pregnane X receptor (also known as NR1H2) and vitamin D receptor (also known as NR1H1) [1][2][3][4][5][6]. In addition, secondary bile acids activate G-protein-coupled receptors, including G-proteincoupled bile acid receptor 1 (GP-BAR1; also known as M-BAR, TGR5, or BG37) and muscarinic receptors [1][2][3][4][5][6]. Further, primary and secondary bile acids activate voltageand calcium-gated potassium channels (BKCa or KCa1.1).…”

“…The FXRretinoid X receptor heterodimer binds DNA sequences on target genes composed of two inverted repeats separated by one nucleotide, and can be activated by ligands for both receptors (bile acids and/or 9-cis-retinoic acid). On ligand binding, FXR undergoes conformational changes to release corepressors such as NCor (a nuclear corepressor) and recruits coactivators such as steroid receptor coactivator 1, protein arginine methyltransferase 1, coactivatorassociated arginine methyltransferase 1, peroxisome-proliferator-activated receptor c coactivator 1a, and vitamin D receptor interacting protein 205 [1][2][3][4][5][6]. In hepatocytes, a rise in intracellular bile acid concentrations results in the transcriptional activation of FXR (Fig.…”