From the journals: September 2019

Picking cancerous mutations out of the crowd

Mutations that drive cancerous behavior may be candidates for targeted therapy, but differentiating them from the thousands of inconsequential mutations in cancer tissues has remained a challenge. Deepankar Chakroborty and an international team of researchers devised a new screening method to show cancer-associated mutations. They used the ability of Ba/F3 lymphoid cells to overcome their dependence on interleukin 3 with activated epidermal growth factor receptors, or EGFRs, which are perennially turned on in many cancers. By introducing random mutations into EGFRs and starving cells of IL-3, only those with EGFR-activating mutations survived.

This technique, presented in the Journal of Biological Chemistry, offers a simple means of identifying EGFR variants that potentially drive cancerous activity and merit further investigation.

Fat in muscle linked to insulin resistance

Diets high in saturated fat are associated with metabolic diseases. Insulin resistance caused by fat depletion, known as lipodystrophy, is rare but has become a focus of research, including studies of associations between accumulation of fats stored in muscle, known as intramyocellular lipids, and insulin-resistant or insulin-sensitive states. The amount of intramyocellular lipid has been associated with both states (known as the athlete’s paradox).

David B. Savage, Alison Sleigh and researchers from the U.K. and Switzerland write in the Journal of Lipid Research that they used magnetic resonance spectroscopy to compare the fatty acid composition in calf muscles of insulin-resistant lipodystorphic women with age- and gender-matched healthy controls and athletes. They hypothesized that differences in composition of the intramyocellular lipid pool might explain the athlete’s paradox. They found that the intramyocellular lipid pool was more saturated in the lipodystrophic women compared with controls and athletes. Measures of the accumulation of saturated intramyocellular lipid were more strongly associated with measures of insulin sensitivity than the total amount of intramyocellular lipid.

A strong correlation in athletes and healthy controls between maximum oxygen used during exercise and relatively unsaturated intramyocellular pools suggests exercise and diet can help decrease the amount of saturated fat within muscles associated with insulin resistance.

Potential drug target for Parkinson’s

Research suggests that chemicals in the brain similar to the neurotoxin MPTP may induce or enhance the progression of Parkinson’s disease. In 2013, a team of researchers from Vanderbilt University and the University of Pennsylvania found that the enzyme cytochrome P450 2D6, or CYP2D6, in the mitochondria metabolizes MPTP into a toxic form. The same team recently used dopamine neuron-mimicking cells and mice with the Cyp2d6 gene knocked out to show that the conversion of MPTP-mimicking chemicals produced in the brain by CYP2D6 induces neuronal degeneration. The results, published in the Journal of Biological Chemistry, suggest that CYP2D6 may be a promising target for treating Parkinson’s disease.

How smoking triggers changes in Reinke’s edema

Among the negative effects of smoking is Reinke’s edema, or RE, where swelling of the vocal cords causes breathing and voice problems. Treatment involves surgical stripping of vocal cord layers in a section called the lamina propia, which often results in permanent damage. In the search for better treatment options, vocal fold fibroblasts, or VFFs, the main cellular component of the lamina propia, have become a focus of RE research. To better understand the effect of smoking on these cells, Markus Gugatschka and his colleagues at the Medical University of Graz exposed VFFs to cigarette smoke and monitored the subsequent protein changes.

In a paper published in the journal Molecular & Cellular Proteomics, the researchers write that they found increased levels of the inflammation-promoting polysaccharide hyaluronan and antioxidative stress proteins as well as lower levels of the rigid structural protein collagen. The researchers hypothesize that the loss of collagen, increase of hyaluronan and increased VFF cell death from oxidative stress could combine to facilitate the formation of edema, thus leading to RE. Future research to evaluate this hypothesis could provide potential targets for treatments to combat RE.

A hormonal link between diet and obesity

Previous studies in mice have implicated the hormone adropin in metabolic homeostasis, but its role in the metabolism of humans is unknown. To gain a better understanding of adropin activity, Andrew Butler and colleagues at multiple institutions in the U.S. used the transcriptome atlas of a nonhuman primate to profile the expression of the adropin-encoding gene ENHO. A second nonhuman primate model of high-sugar diet indicated that low circulating adropin is predictive of increased weight gain and prediabetes. The authors suggest that the data, published in the Journal of Biological Chemistry, warrant the investigation of adropin administration to promote metabolic health.

Brain over binge: Unlocking metabolic obesity-related gender disparities

Diet-induced obesity is a global problem. Hypothalamic regulation, responsible for metabolic processes, and its relationship to obesity have become a promising avenue for research. The endocannabinoid system, found in the hypothalamus, also plays a role in metabolic functions, working like locks and keys, where cannabinoid receptors are the locks and the endocannabinoid proteins behave as keys, creating a positive feedback loop regulating energy homeostasis.

In a paper in the Journal of Lipid Research, Cristina Miralpeix and a team of researchers in Spain write that they have found a link between specific endocannabinoids and diet-induced obesity in mice while noting disparities between genders. Groups of male and female mice were put on a high-fat diet and observed over time. Endocannabinoid levels of all the mice increased four to six times as compared with initial levels after short-term changes in diet. The increase of transient endocannabinoids affected metabolic functions such as body heat and weight gain. Furthermore, female mice became obese later than males, and their hypothalamic endocannabinoids showed higher levels, suggesting not only differences between sexes but also an inverse relationship between weight and endocannabinoid levels. The results also showed a striking rise in endocannabinoids after a short-term high-fat diet in all the mice that leveled off when a high-fat diet was maintained long-term.

This study could add insight into the relationship between hypothalamic regulation and obesity, and the results support claims of differences in male and female metabolic tendencies.

How disease and diet influence transcription

The Mediator complex is a multiprotein assembly and transcriptional coactivator that connects transcription factors to RNA polymerase II. Past research suggested that the Mediator complex can come in two sizes, but it has not been clear what determines the form of the assembly. Dou Yeon Youn and researchers from Albert Einstein College of Medicine and Rutgers Robert Wood Johnson Medical School found that the large complex exists in the livers of fasted mice and that, after feeding, nutrient activation of the mTORC1 pathway converts the complex into a smaller form. They also found that insulin-resistant mice in the fasted state exhibited increased expression of the small Mediator complex. Taken together, these findings, published in the Journal of Biological Chemistry, demonstrate the dynamic regulation of the Mediator complex under physiological and pathophysiological conditions.

Boosting essential and versatile coenzyme NAD+

Recent work has indicated that increased concentrations of the coenzyme nicotinamide adenine dinucleotide, or NAD+, may provide an assortment of health benefits, including protection from liver disease and neurodegeneration. As such, there has been a surge of interest in agents that can raise NAD+ concentrations. Several NAD+ precursors have been identified, but high doses are required to obtain health benefits in animal models.

Yue Yang and colleagues at Weill Cornell Medical College investigated the ability of dihydronicotinamide riboside, or NRH, a likely NAD+ precursor, to enhance NAD+ concentrations.

The researchers report in the Journal of Biological Chemistry that, compared with two well-studied NAD+ precursors, NRH was more effective at raising NAD+ concentration in mammalian cells and in mice.

A model for the proteomics of plant defense

Just as animal bodies repair themselves after injuries, so too do plants. Previous research has identified the protein systemin as a key driver for plant defense and wound healing. Systemin exerts its effects by binding to receptors on plant cell membranes and signaling for initiation of a defensive response, but the specifics of this process are poorly understood. A new study by Fatima Haj Ahmad and colleagues at the University of Hohenheim, published in the journal Molecular & Cellular Proteomics, helps elucidate systemin’s downstream effects.

Ahmad and her team treated tomato cells with systemin or an inactive systemin mutant and compared how the prevalence of phosphate groups in various proteins changed with time. By tracking these changes, the researchers identified over 50 kinases (phosphate adders) and phosphatases (phosphate removers) specifically affected by systemin signaling. This enabled them to create the most advanced model to date for the downstream effects of systemin and the defensive response in plants. This research provides a baseline for further elucidation of the systemin pathway and could provide crucial insights for botanists and farmers to help ensure plant health and defenses against damage and disease.