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Environmental Factor

Environmental Factor

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June 2018

Distinguished Lecture highlights mechanisms of liver cancer

Liver cancer expert Michael Karin, Ph.D., explained the molecular events that lead to the disease during his NIEHS Distinguished Lecture.

Michael Karin Karin is a Distinguished Professor of Pharmacology and Pathology at the University of California, San Diego (UCSD) School of Medicine. (Photo courtesy of Steve McCaw)

NIEHS Distinguished Lecturer Michael Karin, Ph.D., began his presentation by saying the war on cancer has been successful — except when it comes to liver cancer. According to estimates from the U.S. Centers for Disease Control and Prevention, the U.S. has seen a significant reduction in mortality from organ-specific cancers in the past 30 years. Nonetheless, the nation’s incidence of liver cancer tripled during the same time, with a three percent increase each year. Karin wants to know why liver cancer is the outlier. Could what Americans eat be responsible?

In his May 15 seminar, "Metabolic and Immune Control of Liver Tumorigensis," Karin discussed the sequence of pathological changes in the liver that eventually lead to liver cancer, also known as hepatocellular carcinoma. Bill Suk, Ph.D., director of the NIEHS Superfund Research Program (SRP), hosted the talk.

Bill Suk Suk explained that Karin has been focused on studying the relationship among inflammation, cancer, and metabolic disease at UCSD since 1986. (Photo courtesy of Steve McCaw)

Karin mentioned several causes of liver cancer, such as viruses, environmental chemicals, and alcohol, but the route he studies involves hepatitis or liver inflammation associated with energy-rich foods. People who eat a high-fat diet increase their chances of undergoing a series of health challenges that compromise their liver. It starts out with increased lipids in the liver, and progresses to steatosis or fatty liver. Continuing a junk food existence brings the next stage, which is fatty liver with inflammation and scarring, called cirrhosis. At that point, it is a short jump to liver cancer.

NASH

The Karin group is interested in nonalcoholic steatohepatitis (NASH), an illness on one end of the spectrum of metabolic disorders known as nonalcoholic fatty liver disease (NAFLD). NAFLD, which affects one-third of U.S. adults, starts as simple fatty liver, but 10-15 percent of patients will develop NASH due to secondary factors.

"The factors that control the switch from simple fatty liver to NASH are not clear," Karin said, "but some speculate that it is associated with stress in a part of the cell called the endoplasmic reticulum [ER]."

The ER is a network of tubules in plant and animal cells that produce lipid and proteins. Karin and his colleagues decided to test the hypothesis by using mice that are more likely to develop ER stress in the liver.

Using mice to understand NASH

MUP-uPA transgenic mice, developed by Eric Sandgren, V.M.D., Ph.D., at the University of Wisconsin-Madison School of Veterinary Medicine, express high amounts of secreted protein. Karin said early in their life, the mice experience liver cell death, but because the liver regenerates itself, the damage is not permanent, and the mice appear normal as they age. However, after the mice eat a high-fat diet for several months, they develop clinical signs identical to human NASH (see text box).

After 32 weeks on a high-fat diet, the mice develop liver tumors. Two months later, 90 percent of them display liver cancer. The studies Karin and his colleagues conducted revealed what happens to these mice at the molecular level. The experiments determined that a high-fat diet increases ER stress, which leads to the activation of sterol regulatory element-binding proteins (SREBPs), major transcription factors that control lipid metabolism in the liver. Chronic SREBP activation, generated by an enzyme that cuts proteins called caspase-2, along with inflammatory signaling molecules, speed up the production of cholesterol and fatty acids. The process gives rise to cell death and inflammation, and ultimately, the transition from simple fatty liver to NASH.

"Not only does the MUP-uPA mouse strain provide a new model for understanding the development of NASH, it may also uncover what happens in the steps from NASH to liver cancer," Suk said.


NASH or fatty liver?

Karin pointed out three major signs of NASH, in mice and humans, which distinguish it from fatty liver:

  • An increase in the degeneration of liver cells. They expand, eventually exploding and releasing their cellular contents into the microenvironment of the liver.
  • Invokes the spread of inflammation. As a result, liver cells develop large lipid droplets, larger than those in fatty liver.
  • Develop liver fibrosis. This scarring process initiates a thickening of tissue, similar to wound healing.
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