Warren symposium follows legacy of geneticist giant

If we want to understand how the brain creates memories, and how genetic disorders distort the brain’s machinery, then the fragile X gene is an ideal place to start. That’s why the Stephen T. Warren Memorial Symposium, taking place November 28-29 at Emory, will be a significant event for those interested in neuroscience and genetics. Stephen T. Warren, 1953-2021 Warren, the founding chair of Emory’s Department of Human Genetics, led an international team that discovered Read more

Mutations in V-ATPase proton pump implicated in epilepsy syndrome

Why and how disrupting V-ATPase function leads to epilepsy, researchers are just starting to figure Read more

Tracing the start of COVID-19 in GA

At a time when COVID-19 appears to be receding in much of Georgia, it’s worth revisiting the start of the pandemic in early 2020. Emory virologist Anne Piantadosi and colleagues have a paper in Viral Evolution on the earliest SARS-CoV-2 genetic sequences detected in Georgia. Analyzing relationships between those virus sequences and samples from other states and countries can give us an idea about where the first COVID-19 infections in Georgia came from. We can draw Read more
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NAFLD

Bile acid uptake inhibitor prevents NASH/fatty liver in mice

Drugs that interfere with bile acid recycling can prevent several aspects of NASH (nonalcoholic steatohepatitis) in mice fed a high-fat diet, scientists from Emory University School of Medicine and Children’s Healthcare of Atlanta have shown.

The findings suggest that these drugs, known as ASBT inhibitors, could be a viable clinical strategy to address NASH, an increasingly common liver disease. The results were published in Science Translational Medicine on September 21, 2016.

“By targeting a process that takes place in the intestine, we can improve liver function and reduce insulin resistance in a mouse model of NASH,” says senior author Saul Karpen, MD, PhD. “We can even get fat levels in the liver down to what we see in mice fed a regular diet. These are promising results that need additional confirmation in human clinical trials.”

Karpen is Raymond F. Schinazi distinguished professor of pediatrics at Emory University School of Medicine and chief of the Division of Pediatric Gastroenterology, Hepatology and Nutrition at Children’s Healthcare of Atlanta. He and Paul Dawson, PhD, Emory professor of pediatrics, jointly run a lab that investigates the role of bile acids in liver disease.

Saul Karpen, MD, PhD

Saul Karpen, MD, PhD

Many people in developed countries have non-alcoholic fatty liver disease, an accumulation of fat in the liver that is linked to diet and obesity. Fatty liver disease confers an elevated risk of type II diabetes and heart disease. NASH is a more severe inflammation of the liver that can progress to cirrhosis, and is a rising indication for liver transplant. Besides diet and exercise, there are no medical treatments for NASH, which affects an estimated 2 to 5 percent of Americans. Read more

Posted on September 22, 2016 by Quinn Eastman in Uncategorized Leave a comment

Leaky gut plus diet together drive liver disease

 

Frank Anania, MD

Lots of people in the United States consume a diet that is high in sugar and fat, and many develop non-alcoholic fatty liver disease, a relatively innocuous condition. NASH (non-alcoholic steatohepatitis) is the more unruly version, linked to elevated risk of cardiovascular and metabolic diseases, and can progress to cirrhosis. NASH is expected to become the leading indication for liver transplant. But only a fraction of people with non-alcoholic fatty liver disease go on to develop NASH.

Thus, many researchers are trying to solve this equation:

High-sugar, high-fat diet plus X results in NASH.

Emory hepatologist Frank Anania and colleagues make the case in a recent Gastroenterology paper that a “leaky gut”, allowing intestinal microbes to promote liver inflammation, could be a missing X factor.

Anania’s lab started off with mice fed a diet high in saturated fat, fructose and cholesterol (in the figure, PrintHFCD). This combination gives the mice moderate fatty liver disease and metabolic syndrome (see this 2015 paper, and we can expect to hear more about this model soon from Saul Karpen). Leaky gut, brought about by removing a junction protein from intestinal cells, sped up and intensified the development of NASH.

The authors say that this model could be useful for the study of NASH, which has been difficult to reproduce in mice.

The researchers could attenuate liver disease in the mice by treatment with antibiotics or sevelamer, a phosphate binding polymer that soaks up inflammatory toxins from bacteria. Sevelamer is now used to treat excess phosphate in patients with chronic kidney disease, and is being studied clinically in connection with insulin resistance.
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Posted on August 29, 2016 by Quinn Eastman in Uncategorized Leave a comment

Low-level cadmium toxicity and fatty liver disease

A recent study concluded that it’s more difficult for adults today to maintain the same weight as those a few decades ago, even with the same levels of food intake and exercise. On one level, this news is comforting to anyone in middle age, who may have been athletic as a teenager in the 1980s but isn’t anymore. It’s just harder nowadays!

However, the study authors also suggested, in an interview with The Atlantic’s Olga Khazan, an array of factors that might be contributing to the rise in obesity: exposure to chemicals such as pesticides and flame retardants, prescription drugs such as antidepressants, and altered microbiomes linked with antibiotic use in livestock.

The heavy metal cadmium may belong on that list of chemicals, not primarily as a booster of obesity, but instead in connection with the increase in prevalence in NAFLD (non-alcoholic fatty liver disease) over the last few decades.

Researchers led by Young-Mi Go and Dean Jones exposed mice to low levels of cadmium, so that the amounts of cadmium in their livers were comparable to those present in average middle age Americans, without tobacco or occupational exposure. They observed that cadmium-treated mice had more fat accumulation in the liver and elevated liver enzymes in their blood, compared with control mice with 10 times less cadmium.

Cadmium accumulates in the body over time. Tobacco smoke and the industrial workplace can be routes for cadmium exposure, but food is the major source for most non-smokers. Until the 1990s, most batteries were made with cadmium, and much cadmium production still goes into batteries. It is also found in paint and in corrosion-resistant steel. Read more

Posted on October 26, 2015 by Quinn Eastman in Uncategorized Leave a comment

The unsweetened option

Pediatric hepatologist Miriam Vos is starting a new study testing the effects of a low-sugar diet in children with NAFLD (non-alcoholic fatty liver disease). The study is supported by the Nutrition Science Initiative and conducted in a partnership with UCSD/Rady Children’s Hospital, San Diego. See below for more on NUSI.

While there are no medications approved for NAFLD – a healthy diet and exercise are the standard of care – plenty of drugs are under development, as a recent article from Mitch Leslie in Science illustrates. As a reality check and benchmark, the NUSI study will address whether the low-tech intervention of altering diet can be effective.

Lab Land has delved into NAFLD and its increasing prevalence in previous posts. Plenty of correlational data shows that sugar intake is linked to NAFLD (a recent paper from the Framingham Heart Study), but Vos points out that there are no studies showing that reducing sugar is sufficient to drive improvement in the disease.

Diet is a challenge to examine in humans rigorously. In observational studies, investigators are always bumping up against the limits of memory and accurate reporting. In an interventional study with adults, it’s possible to provide them a completely defined menu for a short time in a closed environment, but that’s less practical for longer periods or with children.

The press release announcing the NUSI study says: half of the families will eat and drink what they normally do while the rest will be put on sugar-free meals and snacks, all of which will be provided for the participants and their families for eight weeks.

Miriam Vos, MD

I was curious about how this would work, especially for boys aged 11 to 16 (the participants in her study), so I asked Vos more about it for Lab Land.

“We try to provide them a diet that is otherwise similar to what the family is used to,” she says. “For example, if they’re accustomed to home-cooked meals, our team of nutritionists will work with them to find different recipes.” Read more

Posted on September 2, 2015 by Quinn Eastman in Uncategorized Leave a comment

Spotlight on liver fibrosis

For a May explainer, we’d like to spotlight liver fibrosis. Two recent papers from Emory research teams in the journal Hepatology focus on this process.

Liver fibrosis is an accumulation of scar tissue and proteins outside cells that occurs as a result of chronic damage to the liver. It involves inflammation and immune cells, as well as activation of a type of cell in the liver (hepatic stellate cells), which usually stores fat and vitamin A. Fibrosis and cirrhosis are not the same. Think of it this way: cirrhosis is the late stage of the disease, but fibrosis is how someone can get there.

The liver has a remarkable, even mythical, ability to regenerate, but there is a long list of ways that someone can injure this most vital organ. Quickly – take too much acetaminophen (the most common cause of acute liver failure in the United States). More slowly – develop a hepatitis C infection. Drink large quantities of alcohol. Or something with more subtle effects: consume a diet high in sugar, which can lead to fatty liver. The relationship between fatty liver and more serious liver disease is currently under investigation.

One of the Hepatology papers comes at liver fibrosis from a malaria angle. Patrice Mimche, Tracey Lamb and colleagues show the involvement of EphB2 tyrosine kinase, a signaling molecule not previously known to be involved in liver fibrosis.

Malaria parasites have a complex life cycle, growing in the liver and then in the blood. Lamb says an important part of her paper was the finding that in mouse malaria infection, EphB2 is activated during the blood stage on immune cells infiltrating into the liver. EphB2 (an active drug discovery target) may be acting as a tissue-specific adhesion molecule, she says.

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Posted on May 14, 2015 by Quinn Eastman in Immunology Leave a comment