Analyzing zits: Researchers study fats in sebum

May 31, 2016 § Leave a comment

Researchers analyzed some of fat molecules in acne.

Researchers analyzed some of fat molecules in acne. Photo by Thirteen Of Clubs and used by the Creative Commons license.

One of the many insults of adolescence is pimple-speckled skin. Sebum, an oily skin secretion, plays a major role in causing zits. But “the knowledge of what exactly in sebum is responsible for the occurrence of acne is rather limited,” says Emanuela Camera at the San Gallicano Dermatologic Institute in Italy.

 

In a paper recently published in the Journal of Lipid Research, Camera and colleagues described their analysis of the lipids in sebum and report a clue as to how sebum composition might correlate with the severity of acne.

 

The lipids in sebum “are highly complex and unique,” notes Camera. The lipids in human sebum are so diverse that some aren’t found in other oily substances in the body or even in other species. The complexity of sebum lipids make them hard to analyze. Researchers are unsure of what they are and how they contribute to skin disorders, such as acne.

 

For their study, Camera and colleagues, with the help of dermatologists, recruited 61 teenagers. They grouped adolescents, who were almost evenly split between male and female, into those who had acne and those who didn’t. The acne group was further subdivided into mild, moderate and severe groups. They asked all the teenagers to stick a special tape onto their foreheads to absorb sebum.

 

Camera and colleagues then took those tapes and analyzed them by mass spectrometry to see what lipids collected on them. To avoid going on a wild fishing expedition, the investigators focused on the neutral lipids in sebum. Their data suggested that diacylglycerols were the predominant species among the lipids in acne sebum. There also were fatty acyls, sterols and prenols. Notably, the investigators discovered that higher amounts of diacylglycerols correlated with the more acute cases of acne.

 

Given that more severe forms of acne can be disfiguring, it’s important to understand what causes the skin disorder. Acne can look different from person to person, such as in “white and black heads, papules, pustules, or as a miscellany of them.” Camera says that the different ways acne can manifest itself and its varying severity “calls for a personalized approach. Thus, biomarkers of acne and acne severity can be instrumental in the definition of acne pathogenic mechanisms and indicate novel drug targets.”

 

 

A mouse model for childhood obesity

September 18, 2014 § 1 Comment

 

Images of fetal and adult human adipose tissue grafted onto kidneys of immunodeficient mice. Photos were taken at the time of explantation at 14, 30 and 60 days  after transplantation. Yellow arrows indicate the position of grafts of human tissue. Scale bars are 2mm in length.

Images of fetal and adult human adipose tissue grafted onto kidneys of immunodeficient mice. Photos were taken at the time of explantation at 14, 30 and 60 days
after transplantation. Yellow arrows indicate the position of grafts of human tissue. Scale bars are 2mm in length.

Over the past 30 years, childhood obesity has more than doubled and teenage obesity has quadrupled. Researchers want to identify and understand the molecular triggers that set off children down the obesity path.  “There is considerable evidence that the prenatal environment can predispose the offspring to obesity. This is most clearly seen in children born to mothers who are overweight during pregnancy,” says Philip Gruppuso at Brown University. “However, there is not a suitable model to study human fat development.”

So to come up with such a model, Gruppuso, along with Jennifer Sanders at Brown University, led a team to create mice that carry human fetal fat tissue. As they report in a paper just out in the Journal of Lipid Research, these mice can be used to study human fat development.

The investigators took mid-gestation human fetal adipose tissue and implanted it into mice that were immunodeficient. This way, they avoided the problem of the animals rejecting the foreign tissue. The investigators were helped by Kim Boekelheide, also at Brown University, who developed the implantation technique.

Following a two-week period of latency after implantation, the transplanted human fat tissue began to develop steadily over two months. The tissue expressed genes associated with fat cell differentiation and development.

The investigators tried to do the same experiment with adult human fat tissue, but found that they couldn’t get the tissues to graft. The investigators suspect that the fetal tissue grew in the mice because the tissues were already programmed to develop new fat tissue and blood vessels.

The ultimate aim with these animals to is tease out which molecular factors trigger obesity to take hold in children. “Our goal is to manipulate the rodent hosts, for example with an altered diet or exposure to environmental toxicants, to examine the effect on the transplanted human tissue,” explains Gruppuso.

Vitamin A: From past to present

August 28, 2013 § Leave a comment

Vitamin A and its fellow fat-soluble vitamins were discovered a century ago, but knowledge about vitamin A goes back to ancient times. For example, 3,500-year-old Egyptian papyri recorded the role of vitamin A.  These writings describe how an eye disease, which is now thought to refer to night blindness, was caused by vitamin A deficiency.  These ancient medical texts suggested that eating roasted ox liver, which is a rich source of vitamin A, was an effective treatment for this eye disease, says William Blaner at Columbia University,  an expert in vitamin A’s biochemistry and molecular biology.

The Inuit people also understood the properties of vitamin A.  Among the Inuit, it is a taboo to eat or even touch livers from polar bears or Arctic fish, says Blaner. He adds that the livers of these animals are so rich in vitamin A that, if they were consumed as the main portion of a meal, they would induce acute vitamin A toxicity. “Presumably, the Inuit taboo against eating liver from these Arctic animals reflects an understanding of the adverse consequences of this action,” Blaner explains.

Earlier this month, Blaner did a G+ Hangout on Air with me and ASBMB’s public outreach coordinator, Geoff Hunt, to discuss the history and current understanding of vitamin A research. The springboard for the discussion was a recent thematic review series that ran in the Journal of Lipid Research. Blaner, an editorial board member of JLR, was the coordinating editor for the review series on vitamin A.

Check out the highlights of the broadcast in this video!

(Video editing credit goes to Andrew Harmon, ASBMB’s science web publishing expert)

Gut bacteria may be a source of male steroid hormones

June 25, 2013 § Leave a comment

Cortisol tuns on genes to make an enzyme that converts glucocorticoids into androgens by Clostridium scindens in the gut.

Cortisol tuns on genes to make an enzyme that converts glucocorticoids into androgens by Clostridium scindens in the gut.

Looks like there is more than one fount for male steroid hormones in the body. In a paper recently out in the Journal of Lipid Research, researchers show that a bacterial species converts glucocorticoids into androgens, a group of male steroid hormones. The implication is that the host endocrine system may not be the only source of androgens and other regulatory molecules: The gut microbiome may be another.

Phillip Hylemon at the Virginia Commonwealth University explains that there has been evidence since the 1960s that secondary bile acids, which are microbial products made from the primary bile acids secreted by the gallbladder, are associated with gastrointestinal diseases, such as colon cancer and cholesterol gallstones. “A small number of microbes inhabiting the (gastrointestinal) tract are the sole source of these molecules,” he explains.

His group and others have worked out how the bacterium Clostridium scindens  carries out the primary to secondary bile acid transformation. But it turns out C. scindens also can make androgens from glucocorticoids. Why is this important?

Hylemon explains that, in the gut, androgens can be further modified by other members of the gut microbiota to make testosterone-type derivatives. “It is possible that these steroid metabolites interact with host nuclear receptors or other gut organisms. In males, for instance, the prostate gland is against the rectum wall. Therefore, androgens produced by gut bacteria are capable of passively diffusing into this organ, perhaps altering the physiology of cells in the prostate,” he says.

C. scindens is the only bacterium in the human GI tract known to convert glucocorticoids into androgens, but how does it do it?

Hylemon and colleagues decided to use high-throughput nucleic acid sequencing to identify the genes encoding the enzymes involved in this biotransformation. They knew the genes were turned on by cortisol, a stress-induced steroid hormone. By comparing levels of mRNA from C. scindens cultivated in broth with and without cortisol, the investigators reasoned that they would be able to identify candidate genes.

They identified a cluster of genes that encode a transketolase whose sequence is different from those involved in carbohydrate metabolism. A question now is if the C. scindens transketolase evolved to carry out the biotransformation of glucocorticoids into androgens specifically.

The implication of the work is that a bacterium like C. scindens could play an important role in the endocrine system. “It is generally agreed in the field that the gut microbiota constitute a virtual organ. We believe that, like other organs in the body, this organ has specialized cells that produce hormones that may be derived from host-synthesized bile acids and steroid hormones,” says Hylemon. Because the gut microbiome can produce hormones, Jason Ridlon, the first author on the paper, says, “we consider the gut microbiome to be an endocrine organ.”

The investigators now would like to see if androgen-like molecules produced by the gut microbiome have the same effects on physiology as do the ones generated by the host endocrine system. Hylemon says, “Our next step is to screen bacterial-generated bile acids and steroid hormone metabolites for their ability to bind to and activate host G-protein-coupled receptors and nuclear receptors.”

Hens shift lipid metabolism away from egg-making when stressed

April 30, 2013 § Leave a comment

A rooster (left) and a hen (right). Image from http://en.wikipedia.org/wiki/File:Female_pair.jpg

A rooster (left) and a hen (right). Image from http://en.wikipedia.org/wiki/File:Female_pair.jpg

It’s hard to make babies when you’re stressed, even if you are a chicken. In a recent paper in the Journal of Lipid Research, a group of Chinese investigators looked into how stress can disrupt lipid metabolism, a source of reproductive energy, in egg-laying hens.

“Stress is a common problem that disrupts breeding in either birds or mammals,” explains Hai Lin at Shandong Agricultural University in China, who led the team of investigators. “Glucocorticoids participate in the arousal of stress responses and trigger physiological adjustments that shift energy away from reproduction toward survival.”

Glucocorticoids work to control whole-body homeostasis and trigger stress responses. Lin says the group’s previous work on immature chickens showed that glucocorticoids enhanced hepatic lipogenesis and fat deposition in adipose tissues, indicating the redistribution of energy stores.

To see how energy sources got redistributed from reproduction to survival, Lin and colleagues tested the effects of corticosterone, a type of glucocorticoid, on egg-laying hens. They did two different experiments to see how corticosterone affected the development of ovarian follicles in hens. These follicles supply yolk precursors, which are very low-density lipoproteins, for eggs. In the first experiment, the investigators looked into how fasting and feeding affected ovarian follicular development and lipid production in the liver with or without corticosterone. In the second experiment, the investigators tested the effects of corticosterone on two groups of hens, each fed a diet with a different calorie count.

Lin says their results demonstrated that corticosterone “mimicked the endogenous glucocorticoids under stress to shift the energy expenditure away from reproduction to survival by suppressing ovarian follicular development, laying rate and egg production via multiple actions.” The investigators concluded that stress’ effects to suppress reproduction were energy-dependent.

The group will next look into the effects of stress on estrogen release. (Estrogen plays a role in triglyceride synthesis). Lin explains that the investigators are interested in this direction of research because in their current study “the circulating concentration of estrogen was decreased by corticosterone, suggesting that the suppressive effect of corticosterone on ovarian follicular development is associated with a reduced estrogen release.” They also would like to see if isoflavones, a class of plant-derived compounds with estrogenic activity, such as those found in soy, has any potential to regulate the effects on stress-induced perturbation in reproduction.

Was lipid peroxidation compromised in Neanderthals?

March 13, 2013 § Leave a comment

Mounted Neanderthal skeleton at the American Museum of Natural History. Image by Claire Houck http://en.wikipedia.org/wiki/File:Neanderthalensis.jpg

Mounted Neanderthal skeleton at the American Museum of Natural History. Image by Claire Houck http://en.wikipedia.org/wiki/File:Neanderthalensis.jpg

It very well may be possible that compromised leukotriene signaling is one of the reasons Neanderthals are not among us today. In a recent paper in the Journal of Lipid Research, investigators compared the genome sequences of Homo neanderthalensis and Homo sapiens to see if the two hominid subspecies shared genes for the biosynthesis of leukotrienes and other inflammatory mediators. The investigators, led by Hartmut Kuhn at the University Medicine Berlin-Charité, found that the Neanderthal genome contained six genes encoding for six different lipid-peroxidizing isoenzymes called lipoxygenases (LOXs). Previous work has shown that we too have six LOX genes. However, the cDNA for two of the enzymes contained premature stop codons in the Neanderthal sequence, suggesting that expression of these enzymes was compromized.

Neanderthals are our closest evolutionary relatives. The youngest Neanderthal fossils have been dated to some 30,000 years ago, but there is evidence that Neanderthals may have survived in southwestern Europe until about 25,000 years ago.

A draft sequence of the Neanderthal genome was recently published. Global comparison of the genomic sequences of H. sapiens and H. neanderthalensis hinted that a number of genomic regions were different between the two subspecies of hominids. “Among them was the gene encoding the cysteinyl leukotriene receptor 2, which was mutated in the Neanderthal genome,” says Kuhn. “Although no direct functional studies have been carried out, the sequence data suggest that Neanderthals might have suffered from compromised leukotriene signaling.”

Leukotriene signaling, in which cysteinyl leukotriene receptor 2 is involved during processes of inflammation, requires the biosynthesis of leukotrienes. These molecules are made by LOXs. LOXs are lipid peroxidizing enzymes that have been implicated in cell differentiation and in the pathogenesis of inflammatory, hyperproliferative and neurodegenerative diseases. “Except from a large number of genomic LOX sequences that have been deposited in the publically available databases, virtually nothing is known is know about the evolution of this enzyme family,” says Kuhn.

Kuhn and colleagues carried out a series of bioinformatic experiments and protein biochemical assays to compare and contrast the LOX genes of Neanderthals and modern humans. They established that the genomes of H. sapiens and H. neanderthalensis contained six LOX genes – nALOX15, nALOX12, nALOX5, nALOX15B, nALOX12B and nALOXE3 – and one functionless pseudogene. “Since this pseudogene is functional in mice, it appears to have been corrupted later on in mammal evolution,” says Kuhn.

The sequences of the LOX genes confirmed that the two subspecies were related closely in evolutionary terms. But nALOX12 and nALOXE3 had two premature stop codons, hinting that the expression of these two LOX isoforms in Neanderthals might have been compromised. But Kuhn cautions that this conclusion should be interpreted carefully because there may be sequencing artifacts and problems with sample collection.

Nonetheless, Kuhn and colleauges are pressing ahead with doing more sequence comparisons. The complete genomic sequence of another ancient human ancestor, the Denisovan, recently was released. The Denisovan hominids share a number of anatomical similarities with Neanderthals. “We are about to apply the combined research strategy of our Neanderthal study to these sequences to find out of whether or not the take-home messages we concluded from the Neanderthal genome may also be applicable for Denisovan individuals,” says Kuhn. He says the hope is the sequence comparison will help to confirm or reject that there are premature stop codons in nALOX12 and nALOXE3.

Tomatoes engineered with mimic of good-cholesterol peptide benefit mice

February 20, 2013 § 1 Comment

Mice fed 6F-engineered tomato powder in a high-cholesterol diet had less plaque buildup (right) than mice who weren't given the genetically engineered tomato powder. Image courtesy of Srinivasa Reddy.

Mice fed 6F-engineered tomato powder in a high-cholesterol diet had less plaque buildup (right) than mice who weren’t given the genetically engineered tomato powder. Image courtesy of Srinivasa Reddy.

Special tomatoes to stave off heart attacks and strokes? In a recent paper in the Journal of Lipid Research, a group of researchers describe a genetically engineered tomato that contains a protein that helps stave off atherosclerosis, the buildup of plaque in arteries that leads to heart attacks and strokes.

ApoA-I mimetic therapy is currently one way to treat atherosclerosis. Apolipoprotein (apo)A-I, which has 243 amino acids, is the main component in high-density lipoprotein, also known as good cholesterol. In animal models and humans, infusions of apoA-I have been associated with improvements in atherosclerosis. But given its length, it’s an expensive protein to produce and has to be given intravenously.

Mimics of apoA-I have been produced with only 18 to 26 amino acids. They don’t have sequence similarities with apoA-I but they bind lipids in the same way. Srinivasa Reddy and Alan Fogelman at the David Geffen School of Medicine at the University of California Los Angeles, along with their colleagues, have been studying an apoA-I mimetic peptide called 4F.

4F has been demonstrated in animal models to reduce inflammation, atherosclerosis and other disease processes associated with inflammation. The animal studies spawned two clinical trials. Data from the trials led the investigators to conclude that 4F was most effective when taken orally and processed in the small intestine.

But the problem was that the necessary oral dose was high. “The 4F peptide can only be made by chemical synthesis,” explains Reddy. “The cost of producing enough 4F peptide by chemical synthesis to achieve efficacy prevented this from being pursued as a therapy in humans.”

So the investigators began a search for a peptide that didn’t require extensive chemical synthesis and could be produced by genetic engineering. They came up with another peptide called 6F and decided to see if they could produce it in tomatoes. “We wanted to produce the peptide in a plant that could be eaten without cooking because we felt that cooking the peptide might denature it,” says Fogelman. “The tomato was a convenient and tasty choice.”

The investigators genetically engineered tomatoes to produce the 6F peptide, freeze-dried the fruit, ground them into a powder and added the powder to a high-fat, high-cholesterol Western diet for mice. “We found that, some hours after feeding the peptide, it was still intact in the small intestine,” says Reddy. “Markers of inflammation in the blood were significantly reduced, HDL-cholesterol and HDL function were significantly improved, and atherosclerosis of the aorta was significantly reduced.”

Put together, the investigators say, the work demonstrates that tomatoes engineered to produce an apoA-I mimic could potentially be used as-is to reduce inflammation and atherosclerosis without having to extract and purify the peptide from the plant.

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