While visiting former college classmates in China, Zhanxiang Zhou, PhD, learned that several of them suffered from alcohol-induced fatty liver disease (FLD).
Zhou, who is co-director of the UNCG Center for Translational Biomedical Research at the North Carolina Research Campus (NCRC), is an expert on the disease. During his visit, Zhou counseled his friends on dietary changes that might help them. One day, he plans to offer them a therapeutic treatment developed from his research.
Currently, the US Food and Drug Administration (FDA) has not approved a treatment for alcohol-induced FLD. The use of natural products and vitamins, Zhou said, is at best speculative. Zhou’s research addresses the gaps in scientific and medical knowledge. He’s uncovered organ-organ mechanisms and dietary deficiencies underlying the development of alcohol-induced FLD. He’s also discovered dietary interventions, such as zinc supplementation, that in animal models prevent and even reverse some of the liver damage caused by FLD.
What is Fatty Liver Disease?
FLD is an accumulation of fat in the cells of the liver. The majority of cases are caused by either alcohol abuse or obesity. Although FLD can lead to an enlarged liver and accompanying discomfort, it is a disease with few other symptoms. What FLD does is to disturb liver function so that the organ is more susceptible to inflammatory mediators, toxic agents and viruses, which contribute to the development of hepatitis, cirrhosis and liver cancer.
According to the American Liver Foundation, liver disease is one of the top 10 causes of death in the United States. The World Health Organization (WHO) lists cirrhosis of the liver as one of the top 20 causes of death in the world. WHO statistics show that globally hepatitis C kills 350,000 people each year, infects another three to four million people and places another 150 million people with chronic infections at risk for developing cirrhosis or liver cancer.
Zhou’s paper Chronic alcohol exposure stimulates adipose tissue lipolysis in mice: Role of reverse triglyceride transport in the pathogenesis of alcoholic steatosis, published in March 2012 in the American Journal of Pathology, was one of the first to report that an adipose tissue storage dysfunction is an underlying cause of alcohol-induced FLD. In a healthy person, adipose tissue or body fat stores excess energy in the form of triglycerides. In people with alcohol-induced FLD, triglycerides from adipose tissue are released and deposited in the liver.
Zhou first noticed in mouse models that the animals regularly exposed to alcohol had less body fat. Those findings motivated him to find out why this was happening. With an RO1 grant from the National Institutes of Health, he was able to study the link between alcohol abuse and triglyceride breakdown, a process called lipolysis. By labeling triglycerides with deuterium, a stable isotope of hydrogen, Zhou was able to monitor the uptake of triglycerides in the liver in a mouse model.
“We found out (after) two to four weeks of alcohol exposure, the amount of deuterium-labeled triglycerides in adipose tissue was greatly reduced, but the amount of deuterium-labeled triglycerides in the liver greatly increased,” he said. “That means the alcohol caused a reverse transport of triglycerides from the adipose tissue to the liver. That means adipose tissue dysfunction in lipid storage is a direct cause of the development of fatty liver.”
Previous to these findings, most research looked at lipid metabolism in the liver. Zhou was one of the first to look at alcohol-induced FLD in terms of adipose tissue-liver interactions. Following these finding, he began looking at dietary factors affecting the adipose tissue dysfunction.
Zinc is the Answer
Zinc is the second most abundant trace element in the human body. It is an essential mineral of exceptional biologic and public health importance. Nearly 10 percent of the proteins encoded in the human genome require zinc for their proper structure and function, including over 300 enzymes. Zinc is essential to healthy cell division, fertility, the immune system, skin, hair and nail health and brain function related to vision, taste, smell and appetite. Zinc deficiency has been well documented in alcoholic liver disease. Building on that knowledge, Zhou designed studies using zinc supplementation. He found that with zinc supplementation hepatic triglyceride levels were reduced.
“Basically,” he said, “dietary zinc supplementation can move the triglyceride from the liver to the adipose tissue.”
The mechanism Zhou discovered that explains how zinc removes triglycerides from the liver to adipose tissue involves two zinc transcription factors, peroxisome proliferator-activated receptor-alpha (PPAR-alpha) and Hepatocyte nuclear factor 4- aplha (HNF4-alpha). Both are zinc binding proteins that play crucial roles in regulating the lipid metabolism of the liver.
“Alcohol abuse actually reduces the expression of these transcription factors,” Zhou said, “but zinc can restore the function of these transcription factors. Zinc supplements not only reduced the lipid accumulation in the liver but also ameliorated the liver damage.”
To take these findings a step further, Zhou is partnering with physicians at the University of Louisville Hospital in Kentucky to submit a grant to begin human clinical trials for the treatment of alcohol-induced FLD with a zinc supplement. The trials, Zhou hopes, will lead to proof that zinc supplementation is an effective treatment and one that can undergo the testing needed to gain FDA approval.
From Zinc to Polyphenols
“Now we are also working on polyphenols,” Zhou said. “We are using cell culture study to screen probably 25 polyphenolic compounds to see which one works best. Then we will use this to select the perfect compound for animal studies. Hopefully, we can identify some effective compounds for treating alcohol- induced FLD.”
Zhou is also interested in polyphenolic compounds that may accelerate alcohol detoxification. “The basic disorder of the alcohol-induced liver damage is the production of toxic metabolites,” he said. “Alcohol, per say, does not have toxicity. Once the alcohol is metabolized to acetaldehyde in the liver, this can cause cytotoxicity.”
Zhou hopes his research will lead to therapies that are approved and marketed in time to help his former college friends. Whether or not his friends benefit, his research still provides hope to thousands of others suffering from alcohol-induced FLD and many others globally who may yet develop it.
For more information, contact the UNCG Center for Translational Biomedical Research.