Fatty-liver disease discovery promises new treatments for diabetes, other problems

May 1, 2012
By: Ann Brody Guy, CNR

Two types of naturally produced substances—one of them a bear bile acid—reduce the uptake of fat by the liver, opening the door to the development of new treatments for fatty liver disease and type 2 diabetes, according to a new study by researchers at the University of California, Berkeley, published online last week (April 24) in the journal Hepatology.

“Fatty liver disease goes hand in hand with the obesity epidemic and it exacerbates insulin resistance in people with type 2 diabetes,” said Andreas Stahl, professor in the Department of Nutritional Sciences and Toxicology and the senior author on the study. “The discovery that these compounds are effective in slowing or blocking the disease creates new potential prevention and treatment approaches for these obesity-related conditions.”

One in three adults and a growing number of children in developed countries are estimated to suffer from fatty liver disease, according to the widely cited Dallas Heart Study, and it is frequently underdiagnosed. But beyond the potential medical significance of the finding, Stahl said, the study had some fascinating surprises for the research team. The most common bear bile acid, ursodeoxycholic acid (UDCA), was one of only two substances out of more than 30 tested that researchers found to be effective.

“Naturally, as good Cal citizens we let loose a few ‘Go Bears!’ shouts when we saw the results,” he said. In addition, UDCA is also the main ingredient in a traditional Chinese medicine used to treat liver disorders. “With traditional remedies, it’s usually difficult for scientists to verify if they work, and if they do work, how they work,” Stahl said. “Our findings shed new light on how a centuries-old remedy might be effective in treating liver disease.”

The second effective compound, deoxycholic acid (DCA), a common human bile acid, opens up another significant new avenue for treatment options. “Our bodies already make DCA, and this findings indicates that manipulating our levels of it, through diet or drugs, can lower the amount of fat the liver absorbs,” said the study’s lead author Biao Nie, who was a postdoctoral researcher in Stahl’s lab at the time of the study and is now at the University of Michigan-Ann Arbor.

One fatty liver, many causes

Fat accumulation in the liver, an organ central to the body’s metabolism, can have detrimental effects throughout the body, including increased cardiovascular disease risk and the development of insulin resistance, the hallmark of pre-diabetes and type 2 diabetes. A fatty liver can lead to life-threatening conditions such as liver failure or cancer if combined with a second hit—alcohol abuse, infections, or certain drugs, for example.

Non-alcoholic fatty liver disease can result from the excessive uptake and storage of dietary fat by the liver, or from the liver converting carbohydrates into fat. Thus, blocking the liver from absorbing fat—with UDCA, for example—would mainly help people on a high-fat rather than high-carb diet. In fact, UDCA previously had been tested as a treatment for fatty liver disease, with mixed results. But these studies may have not seen the effectiveness of UDCA, Stahl said, because it will only be effective on the specific subgroup of people whose condition is caused mainly by a high-fat diet—which in the United States is frequently the case.

“I hope that our result will prompt a re-evaluation of UDCA for clinical use in treating fatty liver disease and potentially type 2 diabetes,” Stahl said. UDCA, produced synthetically, is already used in Western medicine to treat gallstone and related diseases and is known to be safe, even at high doses.

A focus on bile acids

Bile acids, produced by all mammals, are the product of the breakdown of cholesterol and in humans are stored in the gallbladder. They eliminate extra cholesterol, and, thanks to their soap-like properties, aid in the absorption of dietary fats.

The study tested the ability of various bile acids to impede transporter proteins that carry fat, in the form of fatty acid, into the liver. It followed up on previous research, also in Stahl’s lab, that first identified these liver-specific transporters as good targets for inhibiting fat uptake to the liver, and then found a bile acid to be the one compound, out of more than 1,000 various molecules tested, to inhibit the fatty liver–specific transporters. Building on that research, this new study tested more than 30 bile acids in an attempt to discover which ones were most effective in blocking the liver-specific transporters.

After identifying UDCA and DCA as the two most effective inhibitor compounds, researchers showed that mice that ate a high-fat diet and were treated with either bile acid had much lower fat accumulation in their livers than the ones on the same high-fat diet but treated with a control bile acid.

DCA also has significant implications for new treatments, researchers said. It is a secondary bile acid—one impacted by interaction with bacteria during the digestive cycle—that is the most common of its kind in humans, and naturally varies in quantity in our bodies based on the interplay of diet and genetics with intestinal microbes. Scientists already know that secondary bile acids like DCA play an important role in disease, Stahl said, “but we still don’t know how. This is a new connection between gut microbes and our health—making different amounts of DCA can influence how much dietary fat ends up in the liver. It opens up a whole new area of investigation.”

Stahl cautions that neither UDCA nor DCA is a silver bullet in the fight against obesity-related diseases; DCA, in particular, can become toxic in high doses. His lab will continue to look for other liver-specific transporter inhibitors, and also plans to test whether UDCA and DCA can protect animals against type 2 diabetes.

Researchers from the UC San Francisco Department of Medicine, the UCSF Liver Center and the City of Hope Diabetes Center contributed to the study. The research was supported by grants from the National Institute of Health and the National Institute of Diabetes and Digestive and Kidney Diseases.