Nonalcoholic fatty liver disease is caused by the organ’s inability to process excessive lipid. It can be attributed to a lowering of fat storage capacity in the body’s adipose tissue. But what’s happening on the cellular and molecular levels in livers?
Researchers led by the Karolinska Institutet in Sweden found that immune cells known as liver macrophages contribute to the organ’s response to lipid accumulation. Silencing an RNA molecule called miR-144 could restore the normal function of the immune cells in mice, they showed in a new study published in Science Translational Medicine.
Because miR-144 is also upregulated in the liver of obese insulin-resistant individuals who are at high risk of developing fatty liver disease, the team suggests the findings could lead to new strategies for treating the condition in humans.
When obesity causes changes in the body’s adipose tissue—which is the normal venue for lipid storage—fatty acids are instead delivered to the liver. As a protective response, liver macrophages try to break down this unwanted lipid accumulation, and, in the process, they produce excessive oxidants that can damage the liver, the team demonstrated in obese mice fed a high-fat diet. The same thing happens in humans.
Oxidative stress is known to trigger an antioxidant response regulated by the expression of transcription factor Nrf2. But in both obese mice and humans, scientists have observed significantly reduced levels of the Nrf2 protein in the liver macrophages.
“This lack of Nrf2 protein tells us that obese individuals do not have the ability to properly respond to oxidative stress induced by fat accumulation in the liver,” the study’s first author, Valerio Azzimato, said in a statement.
Nrf2 is an important transcription factor that controls many detoxifying or anti-inflammatory defense mechanisms. Reata Pharmaceuticals is developing several Nrf2 activators. Its lead project, omaveloxolone, recently succeeded in a pivotal clinical trial in Friedreich’s ataxia, an inherited degenerative neuromuscular disorder. AbbVie holds royalty rights to that drug, even though it exited an agreement with Reata on Nrf2 development last year.
Under normal conditions, Nrf2 levels stay low because of a repressor called Keap1. University College London scientists previously reported that targeting Keap1 to increase Nrf2 activity could hold promise as a therapeutic strategy against Alzheimer’s disease, demonstrating that such a strategy could protect mouse neurons from amyloid-beta plaques.
However, in obesity-associated liver samples, Azzimato and colleagues found that Keap1-induced degradation may not be related to a decrease in Nrf2 in liver macrophages, because Keap1 expression is unchanged during obesity. So they went on to investigate whether microRNAs, which are small non-coding RNA molecules, affect Nrf2 after transcription.
They found that miR-144 expression spikes in the livers of obese mice and obese insulin-resistant people. Both the immune cells and hepatocytes—the liver’s most abundant cells—produce more miR-144. They observed the increase only in the liver, as its expression remained unchanged in other organs.
To further investigate the role of miR-144, the researchers silenced it specifically in liver macrophages. They observed a significant increase of Nrf2 in the livers of obese mice, which led to reduced oxidative stress and restored metabolic functioning of the liver.
The researchers argue that targeting liver macrophages—or miR-144 specifically—to lower the burden of oxidative stress during obesity could offer a new strategy for tackling chronic liver diseases.
“Given that using exogenous antioxidants has been associated with long-term side effects in several tissues, we believe that targeting miR-144 to increase the endogenous antioxidant response represents a promising therapeutic strategy for the treatment of liver diseases in obese patients including non-alcoholic steatohepatitis which is becoming a major cause of liver cancer worldwide and currently has no pharmacological treatment,” Myriam Aouadi, the study’s senior author, said in the statement.