Biomarker Linked to Cause of Liver Fibrosis

Cases of liver fibrosis, and in particular a type called non-alcoholic steatohepatitis, also known as fatty liver, are on the rise, in part because of increasing rates of obesity. Non-alcoholic steatohepatitis is second-leading cause for liver transplantation in the U.S. and the leading cause for liver transplantation for female patients at Cedars-Sinai. Fibrosis may also progress to cirrhosis, or end-stage liver damage, the 12th-leading cause of death in the U.S., according to the study team.

"There is a pressing need for better understanding and treatment of liver fibrosis, particularly fibrosis caused by non-alcoholic steatohepatitis," said Ekihiro Seki, MD, PhD, associate professor of Medicine and senior author of the study. Mazen Noureddin, MD, director of the Cedars-Sinai Fatty Liver Program, and Yoon Mee Yang, PhD, a former postdoctoral scientist at Cedars-Sinai, were co-first authors.

The study, published June 12 in the journal Science Translational Medicine, shed light on the role of the molecule hyaluronan in liver fibrosis. It was already known that a buildup of hyaluronan was associated with this disease, but its significance was not clear.

Hyaluronan helps lubricate, hydrate and strengthen the extracellular matrix, the gel-like material in which all cells are suspended. A healthy liver system regularly flushes out excess hyaluronan, keeping levels in check. But a sick liver cannot regulate hyaluronan, leading to a buildup of the substance.

For their study, researchers analyzed samples of liver tissue from patients with chronic liver disease at multiple institutions. They found increased levels of a substance called HAS2, an enzyme that initiates production of hyaluronan. They determined that hyaluronan was being overproduced in patients with liver fibrosis—a new explanation for the buildup.

The team then deleted HAS2 enzymes in specially bred mice with liver fibrosis. This action lowered both hyaluronan levels and fibrosis in the liver.

Seki said the finding suggests that targeting production of hyaluronan could provide a potential treatment of liver fibrosis, which might prevent the need for liver transplantation.

Researchers also developed a new way to measure hyaluronan that distinguishes between lower and higher molecular weights. Lower weight hyaluronan induces fibrosis, whereas higher weight hyaluronan seems to protect against fibrosis. This finding, Seki explained, could lead to a more sensitive marker test than currently exists to detect liver fibrosis.

The international study, based at Cedars-Sinai, was conducted in collaboration with Putuo Hospital, Shanghai University of Traditional Chinese Medicine; University of Queensland and Princess Alexandra Hospital in Australia; Chungbuk National University College of Pharmacy in South Korea; California Liver Research Institute in Pasadena; and Columbia University in New York. For a complete list of authors, see the Science Translational Medicine article.

Funding: Research reported in this publication was supported by the National Institutes of Health under award numbers R01DK085252, R21AA025841, R01AA027036, R01DK107288, R01HL122068, R01AI052201, 1T32HL134637-01 and P01HL108793; the American Liver Foundation Postdoctoral Fellowship, AASLD The Leonard B. Seeff Young Investigator Award, the Winnick Research award from Cedars-Sinai, Basic Science Research Program of the Ministry of Education, the National Natural Science Foundation of China, Peak Discipline of Colleges in Shanghai, the IMB Centre for Inflammation and Disease Research at the University of Queensland and the National Health and Medical Research Council of Australia and the National Research Foundation of Korea.

The IACUC numbers for animal subjects in research reported in this article are 8412 and 5857.

The IRB number for human subjects in research reported in this article is 00042709.