The researchers find that accumulated liver lipids come from serum fatty acids, newly made fatty acids within the liver, and dietary fatty acids. These fats build up in NAFLD because the liver is unable to regulate changes in fat metabolism that normally occur when one alternates between fasted and fed states. In an accompanying commentary, Shinji Tamura and Iichiro Shimomura write, "In light of these findings, it seems possible that the reduction of oxidative stress as well as the use of insulin-sensitizing agents…may prove to be successful treatments for NAFLD."
TITLE: Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease
AUTHOR CONTACT:
Elizabeth Parks
University of Minnesota, St. Paul, MN USA
Phone: (612) 625-1785; Fax: (612) 625-5272; E-mail: eparks@umn.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=23621
ACCOMPANYING COMMENTARY:
TITLE: Contribution of adipose tissue and de novo lipogenesis to nonalcoholic fatty liver disease
AUTHOR CONTACT:
Shinji Tamura
Osaka University, Osaka, Japan
Phone: 81-6-6879-3732; Fax: 81-6-6879-3739; E-mail: tamuras@imed2.med.osaka-u.ac.jp
View the PDF of this article at: https://www.the-jci.org/article.php?id=24930
EDITORS' PICK
Liver metabolism goes to pot
Endocannabinoids are natural cannabis-like proteins that can stimulate appetite and regulate fat metabolism by binding to receptors called CB1. Drugs that block these receptors may be useful for treating obesity by suppressing appetite and food intake. In a new study appearing in the May 2 print issue of The Journal of Clinical Investigation, George Kunos and colleagues from the NIH examine the possible role of the liver as a target of the metabolic actions of endocannabinoids.
The authors find that liver cells express CB1 and when stimulated, these cells activate a signaling pathway that ultimately increases fatty acid synthesis. The cellular proteins that are activated in the liver upon CB1 stimulation are the same as those known to be activated in the brain and thus may be a common molecular target for metabolic regulation and appetite control.
In an accompanying commentary, Aron Lichtman and Benjamin Cravatt write, "A particularly provocative implication of the work…is that endocannabinoid-mediated modulation of lipogenesis in the liver may contribute to the development of fatty liver and obesity. Targeting these pathways could promote sustained weight loss and favorable serum lipid profiles in obese patients"
TITLE: Endocannabinoid action at hepatic CB1 receptors regulates fatty acid synthesis: role in diet-induced obesity
AUTHOR CONTACT:
George Kunos
National Institute on Alcohol Abuse and Alcoholism, Rockville, MD USA
Phone: (301) 443-2069; Fax: (301) 480-0257; E-mail: gkunos@mail.nih.gov
View the PDF of this article at: https://www.the-jci.org/article.php?id=23057
ACCOMPANYING COMMENTARY:
TITLE: Food for thought: endocannabinoid modulation of lipogenesis
AUTHOR CONTACT:
Aron H. Lichtman
Virginia Commonwealth University, Richmond, VA USA
Phone: (804) 828-8480; Fax: (804) 828-2117; E-mail: alichtma@hsc.vcu.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=25076
METABOLIC DISEASE
Liver insulin receptors left out of hepatic glucose production
Patients with type 2 diabetes show insulin resistance in the muscle, fat, and liver. Mice with mutations in the insulin receptor (Insr) have been used to study insulin resistance previously. In a new study appearing in the May 2 print issue of The Journal of Clinical Investigation, Luciano Rossetti and colleagues from Albert Einstein Collage of Medicine now show that Insr knockout mice also have defective insulin signaling in the hypothalamus of the brain but display normal insulin signaling in the liver. Surprisingly, restoring Insr expression and signaling in the liver was not sufficient to rescue normal in vivo responses to insulin. This restoration did not affect the ability of insulin to inhibit liver glucose production, suggesting that the indirect effects of insulin on the liver determine hepatic glucose production in mice.
A companion paper by members of the same group supports the claim by showing that downregulation of liver insulin receptor expression by up to 95% does not alter liver insulin action. Here, the authors used antisense technology to block insulin receptor expression in mice, but this approach did not modify rates of glucose production by the liver.
An accompanying commentary by Alan Cherrington discusses both papers. Cherrington writes, "taken at face value, these results suggest that the role of hepatic insulin receptors in the control of hepatic glucose production in mice is limited and that the indirect mechanisms of insulin-mediated hepatic glucose production are dominant. The combined papers make a compelling case for the role of indirect mechanisms in the control of hepatic glucose production in mice."
TITLE: Restoration of liver insulin signaling in Insr knockout mice fails to normalize hepatic insulin action
AUTHOR CONTACT:
Luciano Rossett
Albert Einstein College of Medicine, Bronx, NY USA
Phone: (718) 430-4118; Fax: (718) 430-4215; E-mail: rossetti@aecom.yu.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=23096
TITLE: Severe impairment in liver insulin signaling fails to alter hepatic insulin action in conscious mice
AUTHOR CONTACT:
Luciano Rossett
Albert Einstein College of Medicine, Bronx, NY USA
Phone: (718) 430-4118; Fax: (718) 430-4215; E-mail: rossetti@aecom.yu.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=23109
ACCOMPANYING COMMENTARY:
TITLE: The role of hepatic insulin receptors in the regulation of glucose production
AUTHOR CONTACT:
Alan D. Cherrington
Vanderbilt University School Of Medicine, Nashville, TN USA
Phone: (615) 322-7013; Fax: (615) 343-0490; E-mail: alan.cherrington@vanderbilt.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=25152
PHYSIOLOGY
Caffey disease is in the genes
Caffey disease is a disorder in infants characterized by abnormally accelerated bone formation, painful swelling, and fever. In a new study appearing in the May 2 print issue of The Journal of Clinical Investigation, Harald Juppner and colleagues from Massachusetts General Hospital conducted genetic linkage studies to determine the genes responsible for the disease.
The researchers find that affected individuals and carriers of the disease in a large family had a mutation in a gene that encodes for type 1 collagen. The same mutation was found in 2 smaller families with Caffey disease but not in healthy individuals. Cells from these patients had abnormal collagen patterns. In an accompanying commentary, Francis Glorieux writes that these data "represent an important step forward in the understanding of the pathology of an elusive disorder."
TITLE: Novel COL1A1 mutation in infantile cortical hyperostosis (Caffey disease) expands the spectrum of collagen-related disorders
AUTHOR CONTACT:
Harald Jueppner
Massachusetts General Hospital, Boston, MA USA
Phone: (617) 726-3966; Fax: (617) 726-7543; E-mail: jueppner@helix.mgh.harvard.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=22760
ACCOMPANYING COMMENTARY:
TITLE: Caffey disease: an unlikely collagenopathy
AUTHOR CONTACT:
Francis H. Glorieux
Mc Gill University Shriners Hospital, Montreal, Quebec Canada
Phone: (514) 842-5964; Fax: (514) 842-5581; E-mail: glorieux@shriners.mcgill.ca
View the PDF of this article at: https://www.the-jci.org/article.php?id=25148
PHYSIOLOGY
A breath of fresh air for bronchiolitis obliterans syndrome
After lung transplantation, development of bronchiolitis obliterans syndrome (BOS) can lead to destruction of the airways and transplant rejection. In a new study appearing in the May 2 print issue of The Journal of Clinical Investigation, John Belperio and colleagues from UCLA investigate whether abnormal formation of new blood vessels, called angiogenesis, contributes to the pathogenesis of BOS.
The authors find that lung biopsies from BOS patients have increased vascular remodeling and increased angiogenic activity. The latter was due to elevated levels of proteins called chemokines, namely CXC chemokines. Blocking CXC chemokine action by inhibiting receptor interactions was beneficial in mice and reduced BOS.
In an accompanying commentary, Ivor Douglas and Mark Nicolls write that this study "firmly establishes that neovascularization is an important contributor to the process of fibroproliferation in airway fibrosis" and that this aids in the potential design of therapies that can halt BOS.
TITLE: Vascular remodeling during the pathogenesis of broncholitis obliterans syndrome: the role of CXCR2/CXCR2 ligands
AUTHOR CONTACT:
John Belperio
University of California Los Angeles, Los Angeles, CA USA
Phone: (310) 794-1999; Fax: (310) 794-1998; E-mail: jbelperio@mednet.ucla.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=24233
ACCOMPANYING COMMENTARY:
TITLE: Chemokine-mediated angiogenesis: an essential link in the evolution of airway fibrosis?
AUTHOR CONTACT:
Ivor S. Douglas
Denver Health Medical Center, Denver, CO USA
Phone: (303) 436-5905; Fax: (303) 436-7249; E-mail: idouglas@dhha.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=25193
VIROLOGY
Herpesviruses plan the great escape from T cells
The immune system must recognize a viral infection in order to control it. Many of the immune cells that participate in this process can effectively recognize and kill infected cells and release antiviral proteins known as cytokines. Many types of cells are involved in this response, including T cells restricted by CD1 antigen-presenting molecules. These cells help control bacterial infections but it was not understood how these T cells recognized virus-infected cells. In a new study appearing in the May 2 print issue of The Journal of Clinical Investigation, Don Ganem and colleagues from UCSF infect cells with Kaposi sarcoma-associated herpesvirus (KSHV) and show that this causes downregulation of CD1d on the cell surface, a process that benefits the virus in a novel immune evasion strategy.
This decrease of CD1d impairs T cell activation and reveals a potentially important role for these T cells in the control of herpesvirus infection. In an accompanying commentary, Nagendra Hegde and David Johnson write, "these results are especially interesting because, as the authors point out, they reinforce the notion that CD1d in virus-infected cells can signal directly to T cells. Otherwise, why would KSHV infection pull CD1d off the cell surface, a process that can only benefit the virus in infected cells?"
TITLE: Regulation of CD1d display and function by a herpesvirus infection
AUTHOR CONTACT:
Donald E. Ganem
University of California, San Francisco, CA USA
Phone: (415) 476-2826; Fax: (415) 476-0939; E-mail: ganem@cgl.ucsf.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=24041
ACCOMPANYING COMMENTARY:
TITLE: A seek and hide game between Cd1-restricted T cells and herpesviruses
AUTHOR CONTACT:
David C. Johnson
Oregon Health and Science University, Portland, OR USA
Phone: (503) 494-0384; Fax: (503) 494-6862; E-mail: johnsoda@ohsu.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=25000
VIROLOGY
How HTLV-1 handles Treg function
HTLV-1 is a virus that chronically infects T cells. Most individuals remain lifelong carriers without any symptoms, but 2-3% of infected people develop adult T cell leukemia (ATL) and another small percentage of people develop an inflammatory disease of the central nervous system called HAM/TSP. In a new study appearing in the May 2 print issue of The Journal of Clinical Investigation, Steven Jacobson and colleagues examine a specific population of cells in HAM/TSP patients called CD4+ CD25+ T cells, the main reservoir for the HTLV-1 virus.
The authors find that these cells have abnormal protein expression of FOXP3, a factor necessary for these cells to function properly. The resulting defective function of the cells allows them to proliferate abnormally causing the HTLV-1 associated disorders. In an accompanying commentary, Robert Fujinami also points out that "the lack of suppression of these autoreactive cells could lead to an autoimmune component of HTLV-1 infection."
TITLE: Virus induced dysfunction of CD4+CD25+ T cells in patients with HTLV-I associated neuroimmunological disease
AUTHOR CONTACT:
Steven Jacobson
NIH/NINDS, Bethesda, MD USA
Phone: (301) 496-0519; Fax: (301) 402-0373; E-mail: jacobsons@ninds.nih.gov
View the PDF of this article at: https://www.the-jci.org/article.php?id=23913
ACCOMPANYING COMMENTARY:
TITLE: A tax on luxury: HTLV-1 infection of CD4+CD25+ regulatory T cells
AUTHOR CONTACT:
Robert Fujinami
University Of Utah School Of Medicine, Salt Lake City, UT USA
Phone: (801) 585-3305; Fax: (801) 585-3311; E-mail: robert.fujinami@hsc.utah.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=25130
Journal
Journal of Clinical Investigation