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News From The Journal Of Clinical Investigation: October 1, 2012

Sphingolipid metabolism contributes to diabetes-associated heart disease

Patients with type 2 diabetes are subject to a number of major health risks, including a greatly increased risk of heart failure. This is due in part to the development of diabetic cardiomyopathy (DbCM), a condition that significantly impairs heart function. In this issue of the Journal of Clinical Investigation, Ashley Cowart and colleagues at the Medical University of South Carolina report that an increase in specific types of saturated fatty acids (SFAs) and fatty acid metabolic pathways cause lipid overload and symptoms of DbCM in mice. Mice fed a diet high in SFAs developed alterations in the walls of the heart and heartbeat that are characteristic cardiomyopathy symptoms in humans. This study reveals the underlying metabolic mechanisms of DbCM and successfully models diabetes-associated heart disease in mice without genetic manipulation.

TITLE: Ceramide Synthase 5 mediates lipid-induced autophagy and hypertrophy in cardiomycoytes


Altered triglyceride metabolism in mice causes non-alcoholic fatty liver disease

Non-Alcoholic Fatty Liver Disease (NAFLD) is a condition in which triglycerides accumulate in liver cells. Individuals who develop NAFLD frequently have a mutation in a protein known as PNPLA3. In this issue of the Journal of Clinical Investigation, researchers led by Helen Hobbs at the University of Texas Southwestern Medical Center report on the contribution of this mutation to NAFLD in mice. Mice overexpressing mutant PNPLA3 did not metabolize triglycerides as well as normal mice indicating that mutation of PNPLA3 and the subsequent loss of appropriate triglyceride metabolism may underlie human NAFLD.

TITLE: Chronic overexpression of PNPLA3I148M in mouse liver causes hepatic steatosis


Researchers identify inflammatory mediators in pancreatic cancer

Pancreatic ductal adenocarcinoma is an aggressive cancer that feeds off inflammation in the tumor microenvironment. Current research is directed at determining how the tumor interacts with the surrounding tissue to drive inflammation and tumor growth. In this issue of the Journal of Clinical Investigation researchers led by George Miller at the New York University School of Medicine report that pancreatic cancer is driven by activation of a pro-inflammatory cell surface receptor known as TLR7. In a mouse model of pancreatic cancer, TLR7 activation accelerated tumor progression and drove the activation of oncogenic pathways. TLR7-deficient mice or mice that had been treated with a drug to block TLR7 activation had lower levels of inflammation and did not develop pancreatic cancer. These findings suggest that therapeutics targeting TLR7 may be an effective treatment for human pancreatic cancer.

TITLE: Toll-Like Receptor 7 regulates pancreatic carcinogenesis in mice and humans


Putting a ‘HEX’ on muscle regeneration

A complex genetic regulatory network mediates the regeneration of adult skeletal muscles. In this issue of the Journal of Clinical Investigation, researchers at the State University of New York Downstate Medical Center in Brooklyn report that HEXIM1, a protein that regulates gene transcription, is important for skeletal muscle regeneration in mice. M.A.Q. Saddiqui and colleagues found that HEXIM1 blocks gene expression that is required for muscle regeneration after injury. Mice with a 50% reduction in HEXIM1 exhibited greater muscle mass and function after injury compared to mice with a normal amount of the gene. These results indicate that HEXIM1 may be a therapeutic target in degenerative muscle diseases.

TITLE: HEXIM1 controls satellite cell expansion to regulate skeletal muscle regeneration


Untangling the cause of congenital lung disease

Alveolar Capillary Dysplasia (ACD) is a rare, lethal congenital malformation of the small blood vessels surrounding the alveoli of the lungs. Newborns with this disease develop respiratory distress and pulmonary hypertension within minutes to hours after birth. In this issue of the Journal of Clinical Investigation researchers led by Parviz Minoo at the University of Southern California report that loss of the protein Pten causes an ACD-like disease in mice. Mice pups that did not express Pten in the lung could not oxygenate their blood supply and died shortly after birth. Analysis of the lung cells showed that these mice did not develop the cells required for formation of the blood vessels that mediate gas exchange. These studies demonstrate a role for Pten in the development of alveoli-associated capillaries and suggest that Pten-mutant mice could serve as a model of human ACD.

TITLE: Mesodermal Pten inactivation leads to alveolar capillary dysplasia-like phenotype


Seeing the light: researchers track oncogenesis in the liver bile ducts

Intrahepatic cholangiocarcinoma (ICC) is a highly malignant liver cancer originating in the bile ducts. Based on studies of tumor tissue, ICC was originally classified as a cancer of the cells that line the bile ducts, known as cholangiocytes; however, ICC frequently co-occurs in patients with chronic hepatitis C infections, suggesting that ICC originates in liver cells (hepatocytes). To determine how ICC begins, In this issue of the Journal of Clinical Investigation, researchers led by Atsushi Suzuki at Kyushu University in Japan studied ICC progression in a mouse with fluorescently labeled liver cells. They demonstrated that ICC can arise from hepatocytes and identified signaling pathways that were required for oncogenesis in this cell type. This study will help define the pathology of ICC and, eventually, the design of new and more effective therapies.

TITLE: Intrahepatic cholangiocarcinoma can arise from Notch-mediated conversion of hepatocytes


ACCOMPANYING ARTICLE TITLE: Cholangiocarcinomas can originate from hepatocytes in mice


In myelofibrosis, it’s all about location

In myelofibrosis (MF), hematopoietic stem cells become malignant. As the HSCs begin to grow out of control, they produce immature blood cells and fibrous tissue that destroy the bone marrow. Because the blood cells made in the marrow are of poor quality, HSCs in other organs such as the liver and spleen begin making blood cells to compensate. HSC behavior is determined by intrinsic properties as well as their environment. In a study published in the Journal of Clinical Investigation, Ronald Hoffman and colleagues at the Mount Sinai School of Medicine used HSCs isolated from the spleens and peripheral blood (PB) of human MF patients to determine how location influences HSC behavior. By transplanting the MF patient HSCs into mice, Hoffman and colleagues found that splenic HSCs were able to generate red and white blood cells for a prolonged period of time and behaved similarly to the normal HSCs found in bone marrow. In contrast, HSCs isolated from PB were not able to produce the full complement of white blood cells. These results suggest that the environment in the spleen may lead to the production of a greater number of malignant blood cells and contribute to disease progression.

TITLE: Spleens of myelofibrosis patients contain malignant hematopoietic stem cells



Journal of Clinical Investigation