Showing papers by "Ronald M. Evans published in 2018"

Visible light reduces C. elegans longevity.

Abstract: The transparent nematode Caenorhabditis elegans can sense UV and blue-violet light to alter behavior. Because high-dose UV and blue-violet light are not a common feature outside of the laboratory setting, we asked what role, if any, could low-intensity visible light play in C. elegans physiology and longevity. Here, we show that C. elegans lifespan is inversely correlated to the time worms were exposed to visible light. While circadian control, lite-1 and tax-2 do not contribute to the lifespan reduction, we demonstrate that visible light creates photooxidative stress along with a general unfolded-protein response that decreases the lifespan. Finally, we find that long-lived mutants are more resistant to light stress, as well as wild-type worms supplemented pharmacologically with antioxidants. This study reveals that transparent nematodes are sensitive to visible light radiation and highlights the need to standardize methods for controlling the unrecognized biased effect of light during lifespan studies in laboratory conditions. The nematode C. elegans is known to alter its behavior in response to UV light. Here, the authors show that visible light triggers photo-oxidative stress and a wider stress response in C. elegans, suggesting that light exposure during routine laboratory handling may influence the outcome of lifespan experiments.

Corepressor SMRT is required to maintain Hox transcriptional memory during somitogenesis

Abstract: Nuclear hormone receptors (NRs), such as retinoic acid receptors (RARs), play critical roles in vertebrate development and homeostasis by regulating target gene transcription. Their activity is controlled by ligand-dependent release of corepressors and subsequent recruitment of coactivators, but how these individual receptor modes contribute to development are unknown. Here, we show that mice carrying targeted knockin mutations in the corepressor Silencing Mediator of Retinoid and Thyroid hormone receptor (SMRT) that specifically disable SMRT function in NR signaling (SMRTmRID), display defects in cranial neural crest cell-derived structures and posterior homeotic transformations of axial vertebrae. SMRTmRID embryos show enhanced transcription of RAR targets including Hox loci, resulting in respecification of vertebral identities. Up-regulated histone acetylation and decreased H3K27 methylation are evident in the Hox loci whose somitic expression boundaries are rostrally shifted. Furthermore, enhanced recruitment of super elongation complex is evident in rapidly induced non-Pol II-paused targets in SMRTmRID embryonic stem cells. These results demonstrate that SMRT-dependent repression of RAR is critical to establish and maintain the somitic Hox code and segmental identity during fetal development via epigenetic marking of target loci.

Ligand-Dependent Corepressor (LCoR) Is a Rexinoid-Inhibited Peroxisome Proliferator-Activated Receptor γ-Retinoid X Receptor α Coactivator.

Abstract: The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is an essential regulator of placental development. To gain deeper insights into placental PPARγ signaling, we dissected its regulation of the Muc1 promoter. We find that, unlike prototypic target activation by heterodimeric receptors, which is either stimulated by or refractory to retinoid X receptor (RXR) ligands (rexinoids), the induction of Muc1 by liganded PPARγ requires RXRα but is inhibited by rexinoids. We demonstrate that this inhibition is mediated by the activation function 2 (AF2) domain of RXRα and that Muc1 activation entails altered AF2 structures of both PPARγ and RXRα. This unique regulation of Muc1 reflects specific coactivation of PPARγ-RXRα heterodimers by the transcription cofactor ligand-dependent corepressor (LCoR), corroborated by significant downregulation of Muc1 in Lcor-null placentas. LCoR interacts with PPARγ and RXRα in a synergistic fashion via adjacent noncanonical protein motifs, and the AF2 domain of ligand-bound RXRα inhibits this interaction. We further identify the transcription factor Kruppel-like factor 6 (KLF6) as a critical regulator of placental development and a component of Muc1 regulation in cooperation with PPARγ, RXRα, and LCoR. Combined, these studies reveal new principles and players in nuclear receptor function in general and placental PPARγ signaling in particular.

Hepatic Nuclear Receptor Expression Associates with Features of Histology in Pediatric Nonalcoholic Fatty Liver Disease.

Abstract: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in children and adults. This study examined the relationship between hepatic nuclear receptor (NR) expression and histologic features of NAFLD. Drugs targeting a variety of NRs for nonalcoholic steatohepatitis (NASH) are in clinical trials. Liver messenger RNA was isolated from 40 children (10-19 years) undergoing end-of-treatment biopsy in the Treatment of NAFLD in Children (TONIC) trial. High-throughput quantitative polymerase chain reaction assayed NR messenger RNA. Cluster analysis was used to group 36 NRs, and NR levels were related to histologic measures of specific NAFLD features. Cluster analysis determined five groupings of NRs. Significant (P < 0.05) differential expressions of specific NRs associated with histologic measures include farnesoid X receptor alpha and retinoic acid receptor (RARβ and RARβ) for steatosis; estrogen receptor alpha (ERα) and peroxisome proliferator-activated receptor gamma 3 (PPARγ3) for hepatocellular ballooning; ER and PPARγ2 for lobular inflammation; PPARα/δ/γ1/γ2, ERα, constitutive androstane receptor, chicken ovalbumin upstream promoter transcription factor 1, RARα, RARβ1, retinoid X receptor, pregnane X receptor, thyroid hormone receptors α and β, and nuclear receptor related-1 for fibrosis; and ERα and RARβ/β1/α for diagnosis of NASH. Conclusion: Differential expression of specific NRs correlates with histologic severity of specific NAFLD features. These NRs are pleiotropic transactivators regulating basal metabolic functions and inflammatory responses. Derangement of activity of these receptors in NAFLD provides a rationale for exploiting their ability with receptor-specific ligands to ameliorate NASH and its consequences.

Rational application of macrophage-specific LXR agonists avoids the pitfalls of SREBP-induced lipogenesis

Abstract: While 92 million Americans are currently estimated to have some form of cardiovascular disease (CVD), nearly one-half of adults in the United States are projected to develop CVD by 2030, annually eclipsing all other causes of death for the past century (1). Coronary heart disease, which confers a plurality of CVD etiologies resulting in death, is exceptional in its ties to insufficient cholesterol transfer from peripheral sites to the liver and subsequent disposal (1, 2). As a mediator of inflammation, a source of peripheral cholesterol, and a cell type integral to the deposition of vascular fatty lesions, the macrophage has been cast to play a leading role in atherosclerosis. Each of these contributors to atherogenesis are regulated by the liver X receptor (LXR) (3). In PNAS, Muse et al. (4) manipulate ligand-induced LXR activities to accentuate a transcriptional program that promotes cholesterol efflux gene expression specifically in the macrophage. The LXR family of nuclear receptors is implicated in a reciprocal coordination of gene products involved in lipid homeostasis and inflammation (3). While lipids bearing oxidative modifications not only underlie excessive neutral lipid accumulation and inflammatory gene expression, they also agonize LXR. Therefore, this nuclear receptor family is a uniquely suited drug target to mitigate vascular lesion development (5). LXR performs these functions by … [↵][1]1To whom correspondence should be addressed. Email: evans{at}salk.edu. [1]: #xref-corresp-1-1

A SU2C catalyst randomized phase II trial of pembrolizumab with or without paricalcitol in patients with stage IV pancreatic cancer who have been placed in best possible response.

Abstract: TPS4154Background: Pancreatic cancer remains a deadly disease and despite advances in chemotherapy treatment, survival for most patients is still less than one year. Refractory pancreatic cancer ha...

Author Correction: Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity.

Abstract: In this Article, the sentence: “After 7 months of HFD, MUP-uPA mice developed HCC15, which contained numerous (usually 50–100 per tumour) non-recurrent coding mutations in pathways that are mutated in human HCC (Fig. 2d and Extended Data Fig. 6a).”, should have read: “After 7 months of HFD, MUP-uPA mice developed HCC15, which contained numerous (usually 50–100 per tumour) non-recurrent mutations in pathways that are mutated in human HCC (Fig. 2d and Extended Data Fig. 6a).”. This has been corrected online. In Extended Data Fig. 6a and b, which show the number of point mutations identified per sample and the mutational signatures, all sequence variants (including non-coding mutations) are shown. Fig. 2d also presents all variants compared to human mutations. In the Supplementary Information to this Amendment, we now provide the comparisons of all variants and coding variants to human mutations.

Use of fibroblast growth factor 1 (fgf1)-vagus nerve targeting chimeric proteins to treat hyperglycemia

Abstract: The present disclosure provides FGF1 mutant proteins, which include an N-terminal deletion, point mutation(s), or combinations thereof, as well as FGF1-vagus targeting chimeric proteins which include an FGF1 portion (e.g., native FGF1 or mutant FGF1) and a portion that targets the chimera to the vagus nerve (e.g., GLP or exendin-4). Also provided are nucleic acid molecules that encode such proteins, and vectors and cells that include such nucleic acids. The disclosed FGF1 mutants and FGF1-vagus targeting chimeric proteins can reduce blood glucose in a mammal, and in some examples are used to treat a metabolic disorder.