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News From The Journal Of Clinical Investigation: Dec. 21, 2012

The X-factor in liver metabolism

After you eat, your liver switches from producing glucose to storing it. At the same time, a cellular signaling pathway known as the unfolded protein response (UPR) is transiently activated, but it is not clear how this pathway contributes to the liver’s metabolic switch. In this issue of the Journal of Clinical Investigation, researchers led by Phillip Scherer at the University of Texas Southwestern Medical Center report that activation of the UPR triggers the expression of Xbp1s, a protein that regulates genes needed for the metabolic switch. Scherer and colleagues found that they could induce changes in liver metabolism just by increasing expression of Xbps1. These results suggest that Xbps1 could play a role in metabolic disease.

TITLE: The Xbp1s/GalE axis links ER stress to postprandial hepatic metabolism

Low iron levels increase the risk of H. pylori-associated gastric cancer

H. pylori frequently causes gastric ulcers and is also one of the greatest risk factors for gastric cancer. H. pylori infection is also associated with another gastric cancer risk factor, iron deficiency. In this issue of the Journal of Clinical Investigation, researchers led by Richard Peek at Vanderbilt University investigated the influence of iron on H. pylori-induced gastric cancer. Peek and colleagues found that low iron accelerated the development of H. pylori-associated cancerous lesions in gerbils. Further, H. pylori strains isolated from a human population at high risk for gastric cancer were more virulent and produced greater inflammation if they came from patients with low iron levels. In an accompanying article, El-Omar Emad of Aberdeen University discusses how iron levels could be used to identify patients that are at a higher risk for gastric cancer after H. pylori infection.

TITLE: Iron deficiency accelerates Helicobacter pylori-induced carcinogenesis in rodents and humans

ACCOMPANYING ARTICLE TITLE: Iron deficiency and H. pylori-induced gastric cancer: too little, too bad

A critical genetic regulator of brown fat functionality

Obesity is a direct consequence of prolonged positive energy balance that occurs when energy intake (ie. calories) exceeds energy expenditure. In mammals, brown fat plays a critical role in energy metabolism due to its ability to burn energy by dissipating heat, a process known as thermogenesis. Therapeutics that target brown fat could possibly increase metabolism and correct the imbalance that leads to obesity. In this issue of the Journal of Clinical Investigation, researchers led by Matthias Tschöp identified a protein in mice, p62, that is required for brown fat thermogenesis. Mice that did not express p62 in fat cells became obese and developed glucose intolerance, key features of metabolic syndrome in humans. These findings indicate that p62 is an important regulator of metabolism and energy balance and is could potentially serve as a therapeutic target for the treatment of metabolic syndrome.

TITLE: p62 links beta-adrenergic input with mitochondrial function

Dendritic cells play a protective role in atherosclerosis

Atherosclerosis is characterized by a chronic inflammatory immune response that increases the formation atherosclerotic plaques and lesions that could trigger atherothrombosis. Dendritic cells (DCs) are a type of immune cell that have been shown to play a complex role in atherosclerosis. In this issue of the Journal of Clinical Investigation, researchers led by Ira Tabas and Manikandan Subramanian at Columbia University used atherosclerosis-prone mice to elucidate the role of DCs in atherosclerosis. Tabas, Subramanian, and colleagues found that a protein known as MYD88 is required for the activation of DCs, which in turn activate another group of immune cells that protect against inflammation. These results demonstrate that MYD88-mediated DC activation is protective and could be a useful therapeutic target for the treatment of atherosclerosis.

TITLE: Treg-mediated suppression of atherosclerosis requires MYD88 signaling in dendritic cells

Getting to the heart of thyroid hormone function

Thyroid hormone has profound effects on cardiovascular function and metabolism, regulating heart rate, blood pressure, food intake, and metabolic rate. Originally, thyroid hormone was thought to act directly on the target tissues; however, several recent studies have suggested that thyroid hormones effects are mediated by the central nervous system (CNS). In this issue of the Journal of Clinical Investigation, researchers led by Jens Mittag at the Karolinska Institute in Stockholm, Sweden identified a population of neurons in the hypothalamus that are required for thyroid hormone regulation of blood pressure and heart rate. Loss of these neurons in mice resulted in elevated blood pressure and heart rate. These findings demonstrate an important role for the hypothalamus in the regulation of cardiovascular function and indicate a connection between thyroid disease and cardiovascular disorders. In an accompanying commentary, Jürgen Wess of the National Institute of Diabetes and Digestive and Kidney Diseases discusses the link between developmental hypothyroidism and cardiovascular disease.

TITLE: Thyroid hormone is required for hypothalamic neurons regulating cardiovascular functions

ACCOMPANYING ARTICLE TITLE: A heartfelt response: new thyroid hormone-sensitive neurons in the hypothalamus

Immune system-associated protein regulates metabolism

Hyperglycemia results from impaired insulin activity and is a hallmark of diabetes. In this issue of the Journal of Clinical Investigation, researchers led by Chih-Hao Li at Harvard University identified IL-13, a protein more commonly associated with the immune system, as a regulator of blood glucose levels. Mice lacking IL-13 had higher blood sugar and lipid levels compared with normal mice, and exhibited glucose intolerance and insulin resistance. Treatment with recombinant IL-13 reversed these effects. Li and colleagues found that IL-13 repressed glucose production in the liver, contributing to lower blood sugar levels. These findings suggest that IL-13 is an important regulator of metabolism and is a potential therapeutic target in the treatment of diabetes. In a companion commentary, Anna Mae Diehl and colleagues discuss how IL-13 connects inflammation and glucose homeostasis.

TITLE: Direct control of hepatic glucose production by interleukin-13

ACCOMPANYING ARTICLE TITLE: The Benefits of Restraint: Pivotal Role for IL13 in Hepatic Glucose Homeostasis

Cyclin D1b is a genetic reprogrammer that drives cancer progression

Cyclin D1b is a protein that is induced during cancer progression; however, it’s exact function in cancer is poorly understood. In this issue of the Journal of Clinical Investigation, researchers led by Karen Knudsen at Thomas Jefferson University’s Kimmel Cancer Center examined the role of cyclin D1b in prostate cancer. Using a mouse model of the disease, they found that cyclin D1b promoted the expression of genes that allow the cancer to grow and metastasize. Additionally, Knudsen and colleagues demonstrated that cyclin D1b’s effects were dependent on androgen receptor signaling. These findings identify cyclin D1b as an important regulator of prostate cancer progression and suggest that this pathway is a potential therapeutic target in the treatment of prostate cancer.

TITLE: Convergence of oncogenic and hormone receptor pathways promotes pro-metastatic phenotypes

A new framework for ovarian cancer

Ovarian cancer is one of the most deadly cancers. It has a five year survival rate below 30% and a high rate of recurrence. It is a variable disease, with many different biological underpinnings that make it difficult to treat. In this issue of the Journal of Clinical Investigation, researchers led by Roel Verhaak at MD Anderson Cancer Center examined gene expression patterns in ovarian cancer tumor samples to identify gene expression signatures that correlated with patient prognosis. Using these data, they developed a model, Classification of Ovarian Cancer (CLOVAR), that could accurately classify ovarian cancer subtypes and predict patient outcomes. This new classification system may be useful in determining which treatments will be most effective for a given patient.

TITLE: Prognostically relevant gene expression signatures of high grade serous ovarian carcinoma


Journal of Clinical Investigation