ChREBP refines the hepatic response to fructose to protect the liver from injury

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Abstract

Overconsumption of fructose and other sugars has been linked to nonalcoholic fatty liver disease (NAFLD); however, the sugar-associated effects that lead to disease are poorly defined. In this issue of the JCI, Zhang and colleagues show that the carbohydrate response element–binding protein (ChREBP) coordinates an adaptive response to a high-fructose diet in mice and that loss of this transcription factor leads to hepatic inflammation and early signs of fibrosis. Intriguingly, ChREBP-dependent effects were due to an exaggerated activation of the proapoptotic arms of the endoplasmic reticulum stress response that is probably secondary to inappropriate derepression of cholesterol biosynthesis. These findings suggest that a previously unknown link exists between ChREBP and the regulation of cholesterol synthesis that affects liver injury.

Authors

Angela M. Hall, Brian N. Finck

HIV persistence: clonal expansion of cells in the latent reservoir

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Abstract

While antiretroviral therapy (ART) can reduce HIV-1 to undetectable levels, the virus generally reappears if treatment is stopped. Resurgence of the virus is due to the reactivation of T cells harboring latent integrated provirus, and recent studies indicate that proliferation of these latently infected cells helps maintain the HIV-1 reservoir. In this issue of the JCI, Lee et al. evaluated CD4+ T cell subsets to determine whether certain populations are more likely to harbor full-length, replication-competent provirus. The authors identified an enrichment of clonally expanded Th1 cells containing intact HIV-1 proviruses, suggesting that this polarized subset contributes to the persistence of the reservoir. Strategies to target these provirus-harboring cells need to be considered for future therapies aimed toward HIV-1 cure.

Authors

Kyungyoon J. Kwon, Robert F. Siliciano

The brains of the bones: how osteocytes use WNT1 to control bone formation

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Abstract

WNT proteins drive the development and maintenance of many tissues, including bone. It is less clear which of the many WNT proteins act on bone or where these WNTs act in the skeleton; however, loss-of-function mutations in WNT1 cause bone fragility in children and adults. In this issue of the JCI, Joeng and colleagues demonstrate that bone formation is under the control of WNT1 produced by osteocytes, the cells that reside deep in the bone matrix and form dendritic networks. The implication of WNT1 in the control of bone formation identifies a potential new target for the treatment of low bone mass disorders, such as osteoporosis.

Authors

Frank Rauch

The many ways of osteoclast activation

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Abstract

Osteoclasts are the cells responsible for bone resorption, a process that is essential for the maintenance of healthy bones. Bone diseases, such as osteoporosis, which are characterized by high rates of bone resorption and loss of bone mass, may benefit from treatments that inhibit osteoclast formation and/or function. The RANKL/RANK pathway is critical for both osteoclast formation and function, and these effects are thought to be mediated by the transcription factor nuclear factor of activated T cells, cytoplasmic 1 (NFATc1). In this issue of the JCI, Bae et al. challenge the convention that NFATc1 is the sole critical regulator of RANKL/RANK-dependent osteoclast activation. Specifically, the authors show that MYC drives metabolic reprogramming in osteoclasts and that MYC induces estrogen receptor–related receptor α (ERRα) to regulate osteoclastogenesis. Importantly, both loss of MYC and pharmacological inhibition of ERRα attenuated bone loss in a mouse model of osteoporosis. Together, the results of this study suggest that the MYC/ERRα pathway should be further explored as a drug target for bone diseases.

Authors

Joseph Lorenzo

Sugar makes neutrophils RAGE: linking diabetes-associated hyperglycemia to thrombocytosis and platelet reactivity

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Abstract

Diabetes mellitus is associated with an increased risk for cardiovascular disease, but the link between hyperglycemia and atherothrombotic disease is not completely understood. Patients with diabetes often show hyporesponsiveness to antiplatelet therapies, and it has been suggested that hyperreactive reticulated platelets underlie this altered therapeutic response. In this issue of the JCI, Kraakman et al. uncover a previously unknown link between hyperglycemia and enhanced platelet production and reactivity. The authors demonstrate that high blood glucose levels trigger neutrophil release of S100 calcium-binding protein A8/A9 (S100A8/A9), which binds to the receptor for advanced glycation end products (RAGE) on Kupffer cells, ultimately leading to increased thrombopoietin (TPO) production in the liver. TPO causes megakaryocyte proliferation and increased platelet production. This study demonstrates the importance of glycemic control and identifies potential therapeutic targets in the normalization of platelet numbers and function in diabetes.

Authors

Robert H. Lee, Wolfgang Bergmeier

The SO(H)L(H) “O” drivers of oocyte growth and survival but not meiosis I

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Abstract

The spermatogenesis/oogenesis helix-loop-helix (SOHLH) proteins SOHLH1 and SOHLH2 play important roles in male and female reproduction. Although previous studies indicate that these transcriptional regulators are expressed in and have in vivo roles in postnatal ovaries, their expression and function in the embryonic ovary remain largely unknown. Because oocyte differentiation is tightly coupled with the onset of meiosis, it is of significant interest to determine how early oocyte transcription factors regulate these two processes. In this issue of the JCI, Shin and colleagues report that SOHLH1 and SOHLH2 demonstrate distinct expression patterns in the embryonic ovary and interact with each other and other oocyte-specific transcription factors to regulate oocyte differentiation. Interestingly, even though there is a rapid loss of oocytes postnatally in ovaries with combined loss of Sohlh1 and Sohlh2, meiosis is not affected and proceeds normally.

Authors

T. Rajendra Kumar

A SMAP in the face for cancer

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Abstract

Observed deficits in protein phosphatase 2A (PP2A) function in a variety of human cancers have stimulated drug discovery efforts aimed at restoring PP2A function to inhibit tumor growth. Work published by Sangodkar et al. in this issue of the JCI describes the characterization of orally available small molecule activators of PP2A (SMAPs). These SMAPs attenuated mitogenic signaling and triggered apoptosis in KRAS-mutant lung cancer cells and inhibited tumor growth in murine models. Tumors with mutations in the SMAP-binding site of the PP2A A subunit displayed resistance to SMAPs. Future studies that identify the PP2A-regulated events targeted by SMAPs should guide critical decisions about which cancers might be best treated with these molecules. This study provides encouraging evidence in favor of SMAPs as potential anticancer drugs.

Authors

Shirish Shenolikar

Defects in DNA replication hit NK cells and neutrophils

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Abstract

Patients who present with unique immunological phenotypes provide an opportunity to better understand defect-driving mutations. In this issue of the JCI, Cottineau and colleagues characterize 5 individuals who exhibited growth restriction, facial deformities, and a history of bacterial and viral infection. Further characterization revealed that these patients were neutropenic and NK cell deficient. These phenotypes were unexpectedly linked to mutations in the gene encoding a subunit of the Go-Ichi-Ni-San (GINS) complex, which is essential for DNA replication prior to cell division. Together, the results of this study lay the groundwork for future studies to explore the role of DNA replication in immune cell generation and function.

Authors

Klaus Ley

An indirect route to repetitive actions

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Abstract

It is increasingly evident that there is a genetic contribution to autism spectrum disorders (ASDs) and other neural disorders involving excessive repetition of action sequences. Among the implicated genes in these disorders are those encoding postsynaptic scaffolding proteins with roles in synaptic transmission and plasticity. Several mouse models harboring synonymous mutations have shown alterations in synaptic transmission within the striatum, which has key roles in controlling actions and action sequences. In this issue of the JCI, Wang and coworkers show that glutamatergic synaptic transmission onto striatal projection neurons is weakened in mutant mice lacking the SH3 and multiple ankyrin repeat domains 3 (SHANK3B) scaffolding protein, defective expression of which has been implicated in ASDs. This synaptic alteration gives rise to stronger activity in the indirect pathway accompanied by decreased dendritic spines on the indirect pathway medium spiny projection neuron, indicative of decreased numbers of glutamatergic synapses. Selectively enhancing activity in this pathway reduced excessive repetitive grooming in the mutant mice. Changes in glutamatergic input to striatal projection neurons have been observed in several other murine ASD models and associated disorders. Thus, manipulation of the function of the striatal indirect pathway may be a useful therapeutic target for treating disorders characterized by excessive repetitive behaviors.

Authors

David M. Lovinger

Access granted: iRGD helps silicasome-encased drugs breach the tumor barrier

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Abstract

In this issue of the JCI, Liu et al. use irinotecan-loaded nanoparticles to treat pancreatic adenocarcinomas in mice. Encapsulating drugs into nanoparticles has distinct advantages: it can improve the pharmacokinetics of the drug, enhance efficacy, and reduce unwanted side effects. A drawback is that the large size of nanoparticles restricts their access to the tumor interior. Liu and colleagues show that the cyclic tumor-penetrating peptide iRGD, reported to be capable of enhancing tumor penetration by drugs, can overcome this limitation to a substantial degree when administered together with the nanoparticles. Pancreatic adenocarcinoma is a challenging malignancy to treat and in desperate need for improved treatments; therefore, advances like this are most welcome.

Authors

Erkki Ruoslahti