Sex-Dependent Hepatoprotective Role of IL-22 Receptor Signaling in Non-Alcoholic Fatty Liver Disease-Related Fibrosis.

Background & Aims: Nonalcoholic fatty liver disease (NAFLD) is a major health problem with complex pathogenesis. Although sex differences in NAFLD pathogenesis have been reported, the mechanisms underlying such differences remain understudied. Interleukin (IL)22 is a pleiotropic cytokine with both protective and/or pathogenic effects during liver injury.

The Tetracycline-Controlled Transactivator (Tet-On/Off) System in β-Cells Reduces Insulin Expression and Secretion in Mice.

Controllable genetic manipulation is an indispensable tool in research, greatly advancing our understanding of cell biology and physiology. However in β-cells, transgene silencing, low inducibility, ectopic expression, and off-targets effects are persistent challenges. In this study, we investigated whether an inducible Tetracycline (Tet)-Off system with β-cell-specific mouse insulin promoter (MIP)-itTA-driven expression of tetracycline operon (TetO)-Cre could circumvent previous issues of specificity and efficacy.

Loss of in β-Cells Induces an mTORC1-ATF4 Anabolic Pathway That Leads to β-Cell Dysfunction.

FURIN is a proprotein convertase (PC) responsible for proteolytic activation of a wide array of precursor proteins within the secretory pathway. It maps to the PRC1 locus, a type 2 diabetes susceptibility locus, but its specific role in pancreatic β-cells is largely unknown. The aim of this study was to determine the role of FURIN in glucose homeostasis.

PGC-1α isoforms coordinate to balance hepatic metabolism and apoptosis in inflammatory environments.

Objective: The liver is regularly exposed to changing metabolic and inflammatory environments. It must sense and adapt to metabolic need while balancing resources required to protect itself from insult. Peroxisome proliferator activated receptor gamma coactivator-1 alpha (PGC-1α) is a transcriptional coactivator expressed as multiple, alternatively spliced variants transcribed from different promoters that coordinate metabolic adaptation and protect against inflammation.

Peptide-based sequestration of the adaptor protein Nck1 in pancreatic β cells enhances insulin biogenesis and protects against diabetogenic stresses.

One feature of diabetes is the failure of pancreatic β cells to produce insulin, but the molecular mechanisms leading to this failure remain unclear. Increasing evidence supports a role for protein kinase R-like endoplasmic reticulum kinase (PERK) in the development and function of healthy pancreatic β cells. Previously, our group identified the adaptor protein Nck1 as a negative regulator of PERK.

The pancreas: Bandmaster of glucose homeostasis.

The pancreas is a centralized organ vital for whole body metabolic control. Recent advances in the field of metabolism have reinforced its importance for orchestrating endocrine hormone secretion in response to several nutrients including glucose, lipids and amino acids, in addition to hormones and inflammatory signals. Cell types within the pancreas, in particular the insulin-producing β cells, control nutrient breakdown and energy production and are essential to maintain not only efficient hormone secretion, but also cell integrity, survival, and the ability to sense and adapt to changing metabolic environments.

Searching for the β-Cell Fountain of Youth.

Aging affects every species and tissue but not in equal ways. Human pancreatic β-cells lose their ability to replicate, regenerate, and secrete insulin as one gets older. This natural process increases risk of developing diabetes as you age and is a concern for donor islets and stem cells obtained from older subjects destined for transplantation or emerging regenerative therapies.

PGC-1 coactivators in β-cells regulate lipid metabolism and are essential for insulin secretion coupled to fatty acids.

Objectives: Peroxisome proliferator-activated receptor γ coactivator 1 (PPARGCA1, PGC-1) transcriptional coactivators control gene programs important for nutrient metabolism. Islets of type 2 diabetic subjects have reduced PGC-1α expression and this is associated with decreased insulin secretion, yet little is known about why this occurs or what role it plays in the development of diabetes. Our goal was to delineate the role and importance of PGC-1 proteins to β-cell function and energy homeostasis.

Phenotypic Characterization of MIP-CreERT1Lphi Mice With Transgene-Driven Islet Expression of Human Growth Hormone.

There is growing concern over confounding artifacts associated with β-cell-specific Cre-recombinase transgenic models, raising questions about their general usefulness in research. The inducible β-cell-specific transgenic (MIP-CreERT(1Lphi)) mouse was designed to circumvent many of these issues, and we investigated whether this tool effectively addressed concerns of ectopic expression and disruption of glucose metabolism. Recombinase activity was absent from the central nervous system using a reporter line and high-resolution microscopy.

Humanized mice for the study of infectious diseases.

Many of the pathogens that cause human infectious diseases do not infect rodents or other mammalian species. Small animal models that allow studies of the pathogenesis of these agents and evaluation of drug efficacy are critical for identifying ways to prevent and treat human infectious diseases. Immunodeficient mice engrafted with functional human cells and tissues, termed 'humanized' mice, represent a critical pre-clinical bridge for in vivo studies of human pathogens.

RNA polymerase II degradation in response to rapamycin is not mediated through ubiquitylation.

In Saccharomyces cerevisiae, the immunosuppressor rapamycin engenders the degradation of excessive RNA polymerase II leading to growth arrest but the regulation of this process is not known yet. Here, we show that this mechanism is dependent on the peptidyl prolyl cis/trans isomerase Rrd1. Strikingly this degradation is independent of RNA polymerase II polyubiquitylation and does not require the elongation factor Elc1.

Rrd1 isomerizes RNA polymerase II in response to rapamycin.

Background: In Saccharomyces cerevisiae, the immunosuppressant rapamycin engenders a profound modification in the transcriptional profile leading to growth arrest. Mutants devoid of Rrd1, a protein possessing in vitro peptidyl prolyl cis/trans isomerase activity, display striking resistance to the drug, although how Rrd1 activity is linked to the biological responses has not been elucidated.

Results: We now provide evidence that Rrd1 is associated with the chromatin and it interacts with RNA polymerase II.

Human glyceraldehyde-3-phosphate dehydrogenase plays a direct role in reactivating oxidized forms of the DNA repair enzyme APE1.

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has diverse biological functions including its nuclear translocation in response to oxidative stress. We show that GAPDH physically associates with APE1, an essential enzyme involved in the repair of abasic sites in damaged DNA, as well as in the redox regulation of several transcription factors. This interaction allows GAPDH to convert the oxidized species of APE1 to the reduced form, thereby reactivating its endonuclease activity to cleave abasic sites.