METABOLISM - New mechanism explains the role of growth hormone in fatty liver
Non-alcoholic fatty liver disease (NAFLD) is a common condition that is linked to obesity and insulin resistance. If left untreated, this build up of fat deposits within the liver cells can lead to fibrosis and scarring of the organ. Although not completely understood, aberrant growth hormone (GH) signaling is thought to contribute to the development of this disorder, as genetic deletion of the GH receptor in the livers of mice results in the development of fatty liver.
In new research, Ethan J. Weiss and colleagues, of the University of California, San Francisco, further investigated the role of GH signaling in NAFLD by generating mice in which JAK2- the intracellular mediator of GH signaling- was genetically deleted in the liver. They found that these mutant mice had increased serum GH which was responsible for the breakdown of fats into free fatty acids. In addition, the livers of mutant mice had increased expression of the transcription factor PPARĪ³ and its target the fatty acid transporter Cd36. Remarkably, treating the mutant mice with an inhibitor of PPARĪ³ improved the fatty liver phenotype. This work explains the mechanism by which disrupted GH signaling leads to NAFLD, as well as raises important questions regarding the safety of JAK2 inhibitors- currently used as therapeutics in some blood cancers- in human patients.
TITLE: Abrogation of growth hormone secretion rescues fatty liver in mice with hepatocyte-specific deletion of JAK2
ONCOLOGY - New therapy could stress out cancer cells
The rapid growth of cancer cells is due, in part, to successful adaptation to stressful environments. Cells respond to stresses, such as the accumulation of misfolded protein, by activating genes that help the cell restore homeostasis and survive, but paradoxically, they may also promote apoptosis if the stress is unresolved. This so-called unfolded protein response (UPR) functions in multiple cellular locations, including the endoplasmic reticulum and the mitochondria.
In this paper, researchers led by Dario Altieri, at the Wistar Institute Cancer Center in Philadelphia, investigated the role of UPR-modulating factors called heat shock proteins (specifically the HSP90 family) in the mitochondria. They found that treating brain tumor cells with a pharmacological inhibitor of mitochondrial HSP90s induced mitochondrial UPR signaling followed by cell death via a process called autophagy. Furthermore, inhibition of mitochondrial HSP90 sensitized several different kinds of tumor cells (including breast and prostate) to an apoptosis-inducing agent that currently being investigated as a cancer therapeutic. The researchers believe that these studies suggest that targeting the mitochondrial UPR pathway may be broadly beneficial in cancer therapy.
TITLE: Exploiting the mitochondrial unfolded protein response for cancer therapy in mice and human cells
ONCOLOGY - Mouse model explains the role of cancerous protein in blood stem cells
Acute promyelocytic leukemia (APL) is a blood cancer that is most common in young adults; untreated, it has a 100% mortality rate. Most cases of APL are caused by a chromosomal translocation that results in the fusion of the promyelocytic leukemia gene with the retinoic receptor alpha gene generating the novel protein PML-RARA. This fusion protein is thought to inhibit the differentiation of some types of blood cells, but how its expression results in cancer is not fully understood.
In this paper, Timothey Ley and colleagues, at Washington University in St. Louis recapitulated the human disease in mice by expressing PML-RARA from the endogenous PML locus. The researchers noted an expansion of hematopoietic cells in these mice, suggesting that the fusion protein promoted continuous self-renewal of these cells. Furthermore, cells expressing the mutant protein had a competitive growth advantage, which predisposed them to acquire the secondary mutations necessary for the progression to cancer. The researchers believe that this mouse model provides new insights into the pathophysiology of APL in humans.
TITLE: PML-RARA can increase hematopoietic self-renewal without causing a myeloproliferative disease in mice
INFECTIOUS DISEASE - Tuberculosis bacteria uses membrane vesicles to modulate immune responses
The World Health Organization estimates that one third of the world population is infected with the bacteria that cause TB, Mycobacterium tuberculosis (Mtb), though only a small percentage of those actually become ill. The immune response to Mtb in the host is mediated by signaling through toll-like receptors (TLRs); the bacteria secrete lipoproteins and glycolipids that bind to the TLRs, activating immune cells to kill the invading bacteria. However, activation of TLR2 within macrophages has also been implicated in allowing Mtb to inhibit the innate immune response. In addition, how these bacteria release the TLR ligands is unknown.
Some pathogenic bacteria deliver ligands to host cells using membrane vesicles (MVs), which can also contain toxins and other molecules important for pathogenesis. In this paper, Dr. Arturo Casadevall and his team at the Albert Einstein College of Medicine in the Bronx, New York found that Mtb and other related mycobacterium species also release MVs. Analysis of the proteins within these vesicles revealed that only the MVs from virulent bacteria contain TLR2 agonists, and the researchers found that MVs triggered immune responses in mice in a TLR2-dependent manner. The researchers hope that their findings may reveal new pathways to target in the development of tuberculosis therapeutics and vaccines.
TITLE: Mycobacteria release active membrane vesicles that modulate immune responses in a TLR2-dependent manner in mice
DEVELOPMENTAL BIOLOGY - Eya1 and Six1 help you put your best face forward
Deletions in chromosome 22 are a rare congenital condition that result in characteristic craniofacial malformations and heart defects, collectively called del22q11 syndromes. One of the genes deleted in del22q11 patients is T-box transcription factor 1 (Tbx1), which is required for the proliferation of muscle cells during heart and craniofacial development. In fact, the genes required for normal heart muscle development also contribute to the differentiation of the muscles that control facial expressions and jaw movement, suggesting that that disruption of a single pathway may explain the spectrum of defects observed in these patients. Fibroblast growth factor 8 (FGF8) is not deleted in this disease, but aberrant FGF8 signaling has been linked to the associated developmental abnormalities.
In new research, Sean Li and colleagues, at Children's Hospital in Boston, investigated the role of another transcription factor Six 1, and its coactivator Eya1 in cardiac and craniofacial development. They found that the Six1 and Eya1 genes were required for normal patterning of the heart in mice, and that genetic deletion of either of them resulted a developmental phenotype that was similar to that seen in mice lacking Tbx1 or Fgf8. Furthermore, they found that Six1 and Eya1 cooperate to activate transcription of the Fgf8 gene, and that Tbx1 acts genetically upstream of Six1 and Eya1. The researchers believe that these findings reveal a new genetic pathway involved in cardiac and craniofacial development, and indicate that dysregulation of Six1 and Eya1 may contribute to the pathogenesis of del22q11 syndromes.
TITLE: A Tbx1-Six1/Eya1-Fgf8 genetic pathway controls mammalian cardiovascular and craniofacial morphogenesis
HEPATOLOGY - Heavy metal does mitochondrial damage in Wilson Disease
Wilson Disease (WD) is a rare, fatal genetic disorder in which mutations in a copper transporter gene result in massive copper overload in the liver. It is not clear how the accumulation of copper in liver cells (hepatocytes) leads to liver failure, but it has been previously reported that the mitochondria in hepatocytes from WD patients are structurally abnormal.
In new research, Hans Zischka and colleagues, of the Helmholtz center in Munich, Germany, investigated the effect of copper accumulation on mitochondria in a rat model of WD. They found that high copper levels induced structural changes in mitochondria that preceded liver failure, and that oxidative damage- previously thought to be one of primary determinants of WD- was undetectable before animals displayed disease symptoms. Copper overload resulted in crosslinking of mitochondrial membrane proteins, and importantly, this effect was reversible when rats were treated with copper chelating agents. The researchers believe that these studies more clearly define the molecular pathology of WD.
TITLE: Liver mitochondrial membrane crosslinking and destruction in a rat model of Wilson disease
HEPATOLOGY - A microRNA is critical for iron homeostasis
Iron is critical for the transport of oxygen in the blood, and thus the system that maintains iron homeostasis is highly regulated. Disturbance of this system leads to serious illness including anemia and iron overload syndromes such as hereditary hemochromatosis. Most of the body's iron stores are in the liver, and that organ also produces the hormone hepcidin, which maintains iron homeostasis by inhibiting iron absorption in the intestine and iron release from macrophages.
In this paper, scientists from the laboratories of Martina U. Muckenthaler of the University of Heidelberg, Germany and Matthias W. Hentze, of the European Molecular Biology Laboratory in Heidelberg, investigated new mechanisms that might regulate hepcidin. They found that a microRNA, miR-122, was an important regulator of hepcidin levels, and functioned by targeting known activators of hepcidin expression. Inhibiting miR-122 in mice resulted in increased hepcidin levels and liver and plasma iron deficiency. This work is the first to implicate a miRNA in iron homeostasis, and the researchers believe miR-122 may be a viable therapeutic target in human diseases of this system.
TITLE: The liver-specific microRNA miR-122 controls systemic iron homeostasis in mice
HEMATOLOGY - NKp46 marks the spot in T-LGL leukemia
T cell large granular lymphocyte (T-LGL) and NK leukemias are rare forms of blood cancer. IL-15 is a cytokine required for the normal survival and expansion of some immune cells including NK cells and memory T cells, and its overexpression is implicated in the development of both of these diseases. Mice that overexpress IL-15 spontaneously develop NK or T-LGL leukemia.
To investigate the mechanism of this process, Michael A. Caligiuri, Jianhua Yu and their team at Ohio State University in Columbus, Ohio examined the T cell populations in these mutant mice. They found that mice expressing excess IL-15 had an expanded population of T cells that express the cytoxicity receptor NKp46, an NK cell marker, and that all of the leukemic cells in mice with T-LGL leukemia expressed NKp46. These NKT cells were more active and more responsive to cytokine simulation, and further studies suggested that it was malignant transformation of this small population that accounted for the development of disease. Remarkably, treatment of IL-15 expressing mice with an antibody that targeted this T-cell subset prevented the development of leukemia. The researchers also identified a similar subset of T-cells in human samples, and believe that this work identifies a unique subset of immune cells that are susceptible to cancerous transformation in the presence of high levels of IL-15. They hope that these data may help in the design and targeting of new drugs for this as yet incurable disease.
TITLE: NKp46 identifies an NKT cell subset susceptible to leukemic transformation in mouse and human
Source:
Karen Honey
Journal of Clinical Investigation