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
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
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, HFCD). 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.
For a May explainer, weâ€™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.Â 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 diseaseÂ is currently underÂ 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 stageÂ on immune cells infiltrating intoÂ the liver. EphB2 (an active drug discovery target)Â may be acting as a tissue-specific adhesion molecule, she says.