Targeting cholesterol metabolism in macrophages to eliminate viral infection

December 27, 2019

Recent evidence suggests a link between cholesterol metabolism and innate immunity. Upon viral infection, macrophages show reduced cholesterol synthesis accompanied by enhanced expression of antiviral genes, including type I interferon (IFN-I).

IFN-I can induce 25-hydroxycholesterol (25-HC) accumulation, which blocks viral entry. However, it has been unclear whether other cholesterol-associated metabolic products or enzymes regulate innate immunity.

A new study published in Immunity now provides important new information. WANG Hongyan's team from the Center for Excellence in Molecular and Cellular Science, Institute of Biochemistry and Cell Biology of the Chinese Academy of Sciences (CAS), in collaboration with Prof. WEI Bin at Shanghai University (the former PI of the Wuhan Institute of Virology of CAS), screened expression levels of multiple enzymes that regulate cholesterol metabolism to better understand how cholesterol metabolites combats infection.

In order to find the enzymes or corresponding natural cholesterol metabolites involved in antiviral infection, the researchers screened differentially expressed genes in liver tissue from patients infected with hepatitis B virus and from mice infected with vesicular stomatitis virus (VSV).

DHCR7 (7-dehydrocholesterol reductase) is an enzyme that converts 7-dehydrocholesterol (7-DHC) into cholesterol. Patients carrying Dhcr7 mutations have mental retardation. However, the role of DHCR7 in innate immunity has been unclear. This study shows that DHCR7 knock-out (KO) or DHCR7 inhibitor treatment can promote IRF3 activation and type I interferon (IFNβ) production to clear multiple viruses in vitro or in vivo.

Interestingly, Tamoxifen, a chemotherapy drug used to treat breast cancer, was approved by the U.S. Food and Drug Administration to inhibit DHCR7's enzyme activity.

This study also reveals that Tamoxifen treatment inhibits infection by VSV and the Zika virus at the cellular level, suggesting a possible application for Tamoxifen as an anti-infective. Mice treated with the DHCR7 inhibitor AY9944 showed a significant increase in serum 7-DHC concentration, which promotes IRF3 phosphorylation and enhances IFNβ production in macrophages, thus protecting mice against lethal doses of VSV or the H1N1 influenza virus.

In addition, the research shows that viral infection enhanced AKT3 expression and 7-DHC treatment further activated AKT3. AKT3 directly bound and phosphorylated IRF3 at Ser385, together with TBK1-induced phosphorylation of IRF3 Ser386, to achieve IRF3 dimerization and full activation.

In conclusion, this study reveals that both the intermediate cholesterol metabolite 7-DHC and DHCR7 inhibitors promote IFN-I production and an antiviral response by activating AKT3 and IRF3. These findings may aid in the development of new drugs to treat viral infections. The research also provides new insights on how cholesterol metabolism regulates innate immunity.

Chinese Academy of Sciences Headquarters

Related Cholesterol Articles from Brightsurf:

Cholesterol's effects on cellular membranes
The findings have far-reaching implications in the general understanding of disease, the design of drug delivery methods, and many other biological applications that require specific assumptions about the role of cholesterol in cell membranes.

Autism-cholesterol link
Study identifies genetic link between cholesterol alterations and autism.

Microbes might manage your cholesterol
Researchers discover a link between human blood cholesterol levels and a gene in the microbiome that could one day help people manage their cholesterol through diet, probiotics, or entirely new types of treatment.

Experimental cholesterol-lowering drug effective at lowering bad cholesterol, study shows
Twice-yearly injections of an experimental cholesterol-lowering drug, inclisiran, were effective at reducing low-density lipoprotein (LDL) cholesterol, often called bad cholesterol, in patients already taking the maximum dose of statin drugs, according to data of the ORION-10 trial presented Saturday, Nov.

Rethinking how cholesterol is integrated into cells
Cholesterol is best known in connection with cardiovascular disease, but cholesterol is also vital for many fundamental processes in the body.

Seed oils are best for LDL cholesterol
Using a statistical technique called network meta-analysis, researchers have combined the results of dozens of studies of dietary oils to identify those with the best effect on patients' LDL cholesterol and other blood lipids.

Cholesterol leash: Key tethering protein found to transport cellular cholesterol
Cholesterol is an essential component of living organisms, but the mechanisms that transport cholesterol inside the cell are poorly understood.

New way to treat cholesterol may be on the horizon
A breakthrough discovery by scientists at Houston Methodist Research Institute could change the way we treat cholesterol.

How low should LDL cholesterol go?
New analysis shows that in a high-risk population, achieving ultra-low LDL cholesterol levels, down to <10 mg/dL, safely results in additional lowering of risk of cardiovascular events.

Does boosting 'good' cholesterol really improve your health?
A new review addresses the mysteries behind 'good' HDL cholesterol and why boosting its levels does not necessarily provide protection from cardiovascular risk for patients.

Read More: Cholesterol News and Cholesterol Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to