Lipid metabolism in liver cells confers protection from viral infection

Hepatitis C virus persists in the human body for decades and damages the liver by inducing chronic inflammation, ultimately leading to cirrhosis and liver cancer. A new study led by researchers at the Tokyo Metropolitan Institute of Medical Science (TMIMS) and Ochanomizu University reveals that lipid metabolism in liver cells provides protection against hepatitis C virus infection. Results published in Cell Chemical Biology show that high levels of polyunsaturated fatty acids (PUFAs) in liver cells are associated with resistance to hepatitis C virus infection. PUFA synthesis is regulated predominantly by the enzyme fatty acid desaturase 2 (FADS2), hence increased FADS2 expression leads to elevated PUFA levels. PUFAs react with reactive oxygen species produced by iron to undergo oxidative degradation (lipid peroxidation). Lipid peroxidation occurs on PUFA-enriched membranes where viral replication machinery (RNA replicase) is anchored. Upon exposure to lipid peroxidation, the viral replicase alters its conformation and shuts off its ability to replicate the viral genome.

“The process that promotes lipid peroxidation and restricts viral replication is quite similar to what occurs during ferroptosis, an iron-dependent form of programmed cell death characterized by increased lipid peroxidation,” said Daisuke Yamane, D.V.M., Ph.D., the study’s co-author and a chief researcher at the Viral Infection Control Project, Tokyo Metropolitan Institute of Medical Science. “By enhancing the oxidation of PUFAs using drugs called ‘ferroptosis inducers’, liver cells can limit hepatitis C virus replication, even at low doses of drugs that do not trigger ferroptosis.”

The regulatory mechanisms controlling lipid peroxidation have been studied extensively, particularly in the field of cancer biology since the recognition that certain types of cancer cells are sensitive to ferroptosis. Several ferroptosis-inducing drugs with improved stability and efficacy have been developed as a strategy to treat chemotherapy-resistant cancers. However, these drugs have not been shown to have antiviral effects.

“Our findings suggest that ferroptosis inducers may increase the efficacy of antiviral drugs targeting the viral replicase component. More animal experiments are needed to test this idea, and different ferroptosis-inducing drugs can be examined for efficacy, safety, dosage, and timing,” said Dr. Yamane.

The study also revealed an unusual fatty acid metabolism in cultured liver cells widely used in laboratories. Mead acid is usually absent in the human body but is found in individuals with low dietary intake of essential PUFAs, including linoleic acid and a-linolenic acid; however, the study found an abundance of Mead acid in cultured cells. “Cells cultured in laboratories are fed animal serum as a source of PUFAs but our results suggest that this may not be sufficient for some cell types,” said Ikuyo Ichi, Ph.D., the study’s co-author and an associate professor in the Faculty of Core Research Natural Science Division of Ochanomizu University. “Our findings highlight the need for improved cell culture models that recapitulate fatty acid metabolism in the human body. Nonetheless, our data indicate that cellular PUFA synthesis regulates lipid peroxidation, sensitivity to iron-regulated cell death, and hepatitis C virus replication.”

About the Tokyo Metropolitan Institute of Medical Science

The Tokyo Metropolitan Institute of Medical Science (TMIMS) is dedicated to advancing basic and medical research in order to improve human health and quality of life. Founded in 2011 through the consolidation of three medical institutes, TMIMS is funded by the Tokyo metropolitan government and supports basic research in molecular and cellular biology in areas including genome replication, protein degradation, and infectious and neurodegenerative diseases. TMIMS also supports the development of new technologies in areas such as genome editing, control of neural prostheses, and vaccine development, and clinical research in fields such as optimization of nursing care and development of new treatments for psychiatric, neurodegenerative and other diseases. By integrating top-down applied research with bottom-up basic research, a goal of TMIMS is to more efficiently translate basic research results into treatments beneficial for humankind. For more information about TMIMS, see www.igakuken.or.jp/english.