People who eat high fat diets may be adversely altering the immune system makeup in their livers and contributing to fatty liver disease. The findings were confirmed in recent research using mice,1 and while animal studies aren't always reproducible in humans, they may serve as a warning for people, the investigators stated.
"This is the first study that has shown dietary effects on the liver innate immune system and hepatic inflammation," explained the study's lead researcher, Zhiping Li, MD, an assistant professor of Gastroenterology and Hepatology at Johns Hopkins University, in an interview.
While earlier research has confirmed the potentially adverse effects of diet on the liver, these studies only examined diet's role in alcoholic liver disease, Li explained.
Diet Altered NKT Cell Levels
In the study, a group of mice fed diets high in fat and sugar developed immune system abnormalities in their livers, including a reduced number of natural killer T (NKT) cells. These are a type of white blood cell primed to kill from the moment they are formed. They target foreign organisms, like viruses, cancer cells, and other disease-causing substances in the body.2
NKT cells are often the body's first line of defense against viral infections and are regulatory in nature, overseeing some of the functions of other immune system cells.2 NKT cells are formed in the thymus, an organ included in the lymphoid system in the body, but build up in the liver where they oversee the production of cytokines, a type of immune cell protein.
Diet's Link to Fatty Liver Disease
Mice consuming the high-fat diets in the study also were more prone to develop fatty liver disease, similar to a disease in humans known as non-alcoholic fatty liver disease (NAFLD). While these and other researchers have published findings that obese mice with lower levels of a fat-producing protein known as leptin, which plays a role in controlling appetite, had depleted levels of NKT cells in their livers,3 people considered obese have high leptin levels in their bodies. So, the researchers in the latest study weren't sure if their findings in mice were relevant to human fatty liver disease.
In hopes of answering this question, this latest research included a type of fatty liver disease in mice caused by a high-fat diet, similar to what occurs in people.
In the study, Li and his associates fed a group of mice diets with varying nutritional values—some of them were high-fat diets and some were more nutritious—for up to 12 weeks. At the end of this period, the researchers then obtained liver and blood samples for the rodents. They studied the health of specific liver cells in these samples, and measured levels of a liver enzyme known as alanine aminotransferase (ALT), which is released into the bloodstream when the liver is injured.
Fatty Liver and NKT Cell Relationship
The mice fed high-fat diets gained significantly more weight than mice on non-fat diets. The mice in the high-fat diet group also developed fatty livers. After studying the health of the mice's liver cells, Li and his team learned that rodents fed high-fat diets had significantly lower levels of immune cells, including NKT cells. Other tests showed that these cells contained higher levels of interleukin-12 (IL-12), a protein that helps lower NKT cell activity and boosts NKT cell death.
"Preliminary studies suggest that NKT cell numbers remain constant [in the liver] before high fat-fed mice develop significant steatosis [fatty liver] after consuming the high fat diet for one week," Li's group wrote. "However, more studies are needed to better understand the relationship between development of steatosis and NKT cell depletion."
Tipping the Inflammation Balance
The study also found that high-fat diets increased the production of immune cell proteins known as proinflammatory cytokines. These cytokines act as messengers in the immune system, directing white blood cells and other immune cells to areas in the body where infection exists. Other cytokines slow down immune activity, helping end an immune response. (Naturally-made interferons, on which is based the interferon medication you may take for hepatitis, is a type of cytokine).2
Proinflammatory cytokines increase inflammation in the liver, which contributes to liver damage. Inflammation is a side effect of the immune response.
Beyond the increases in inflammatory cytokines, when the research team induced liver injury in the mice on various diets, they found that the mice that had eaten diets high in fat experienced more liver inflammation and liver cell death (necrosis) than those eating the "normal" diets.
According to Li and his colleagues, high fat diets cause an inflammatory state in the liver, which helps boost the likelihood of chronic liver disease. This is because, they theorize, high-fat diets lower levels of NKT cells in the liver that would otherwise balance the production of pro and anti-inflammatory cytokines in the organ.
More research is needed to understand this relationship, they wrote. "Nevertheless, our findings are important because they clearly demonstrate significant dietary effects on 'classic' NKT cells and cytokine production by other liver cells," Li and his team concluded.
Same Thing in People?
"It is possible" that this effect that diet has on the liver could be similar in people because "the human liver has similar NKT cells," Li explained. "The difficulty is to get enough human liver tissue (normal and NAFLD) to study them."
The opposite may also be true, he added. Reducing fat/sucrose intake may restore the balance of pro- and anti-inflammatory cytokines in the liver. "Our studies in progress have shown those effects," said Li. "These have not been published."
In the meantime, he hopes this study and others like it might, one day, lead to an effective therapy for NAFLD.
1. Li Z, Soloski MJ, Diehl AM. Dietary factors alter hepatic innate immune system in mice with nonalcoholic fatty liver disease. Hepatology 2005 Oct;42(4):880-5.
2. The Merck Manual. Immune Disorders. Biology of the Immune System. Nonspecific Immunity. Available at: http://www.merck.com/mmhe/sec16/ch183/ch183b.html?qt=natural%20killer%20t%20cells&alt=sh. Accessed October 27, 2005.
3. Li Z, Oben JA, Yang S et al. Norepinephrine regulates hepatic innate immune system in leptin-deficient mice with nonalcoholic steatohepatitis. Hepatology 2004 Aug;40(2):434-41.
John Martin is a long-time health journalist and an editor for Priority Healthcare. His credits include overseeing health news coverage for the website of Fox Television's The Health Network, and articles for the New York Post and other consumer and trade publications.
