New insights into mechanism of therapy to reduce liver fat and prevent fibrosis

Date:
August 26, 2020
Source:
Massachusetts General Hospital
Summary:
Researchers have taken an important step forward in the goal of
developing a potential treatment for non-alcoholic fatty liver
disease.



FULL STORY ==========================================================================
A team led by researchers at Massachusetts General Hospital (MGH) has
taken an important step forward in the goal of developing a potential
treatment for non- alcoholic fatty liver disease (NAFLD), the most common
form of chronic liver disease. There are currently no approved medications
for NAFLD, but in a study published in the journal JCI Insight on August
20, 2020, investigators conducted a genetic analysis that has identified
how one promising therapy may work to improve the adverse effects of
this increasingly prevalent health threat.


========================================================================== NAFLD is an umbrella term for a spectrum of conditions that begin with
a build- up of liver fat, which can set the stage for inflammation that
may promote scarring known as fibrosis. Over time, fibrosis can progress
to potentially fatal cirrhosis and even a form of liver cancer called hepatocellular carcinoma (HCC). Between 30 and 40 percent of adults in
the United States have NAFLD, and the incidence appears to be rising.

Last year, a team led by endocrinologist Steven Grinspoon, MD, chief
of the MGH Metabolism Unit, published a randomized controlled study in
Lancet HIV showing that the drug tesamorelin (Egrifta) reduced liver
fat and fibrosis progression in patients with HIV, who have an increased
risk for NAFLD.

Tesamorelin is approved by the Food and Drug Administration (FDA) for
treating excess abdominal fat in HIV-infected people, but how the drug
might improve critical features of NAFLD was unknown. In collaboration
with colleagues at the Harvard T.H. Chan School of Public Health and the
Broad Institute, as well as with collaborators at the National Institutes
of Health (NIH), Grinspoon and his team decided to find out.

Using a technique called gene set enrichment analysis (GSEA), Grinspoon
and his colleagues studied liver biopsy specimens from participants
in the Lancet HIV study, half of whom received tesamorelin, while the
others got inactive placebos. GSEA revealed that the drug appeared to
increase expression of a set of genes that are associated with burning
of fat in the mitochondria -- the "furnaces" in cells that play a
key role in energy metabolism. In turn, increased expression of key
oxidative phosphorylation genes was associated with reduced expression
of fibrosis genes. "Increasing oxidative phosphyloration may be a key
process by which tesamorelin reduces fat in the liver and ultimately
prevents progression of fibrosis," says Grinspoon.

What's more, the study revealed that genes associated with inflammation
were relatively silenced, or downregulated, in patients treated with tesamorelin compared with placebo. Likewise, genes associated with
cell repair and cell division were also downregulated. "That's likely beneficial," explains Grinspoon, noting that the body may over-respond
to inflammation with collagen deposits that promote fibrosis. Moreover,
a high rate of cell division could increase the risk for HCC. While it's unknown whether tesamorelin prevents liver cancer, genes associated with
a favorable prognosis of HCC were upregulated in patients given the drug.

The MGH group is conducting additional studies with tesamorelin in
both HIV and non-HIV patients. "This treatment strategy has effects on
critical NAFLD pathways that could alter the milieu of the liver in a
positive way in non-HIV patients, as well," says Grinspoon.


========================================================================== Story Source: Materials provided by Massachusetts_General_Hospital. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Lindsay T. Fourman, James M. Billingsley, George Agyapong, Shannan
J. Ho
Sui, Meghan N. Feldpausch, Julia Purdy, Isabel Zheng, Chelsea
S. Pan, Kathleen E. Corey, Martin Torriani, David E. Kleiner,
Colleen M. Hadigan, Takara L. Stanley, Raymond T. Chung, Steven
K. Grinspoon. Effects of tesamorelin on hepatic transcriptomic
signatures in HIV-associated NAFLD.

JCI Insight, 2020; 5 (16) DOI: 10.1172/jci.insight.140134 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200826140902.htm

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