Liver antioxidant response impaired in obesity-associated insulin resistance

Last Updated: 2020-03-09

By Will Boggs MD

NEW YORK (Reuters Health) - Liver macrophages inhibit the antioxidant response in obesity-associated insulin resistance, researchers report.

"Despite a dramatic increase in oxidative stress due to excessive lipid accumulation in liver of obese mice and humans, the endogenous antioxidant response was completely shut down," Dr. Myriam Aouadi of Karolinska Institutet, in Huddinge, Sweden, told Reuters Health by email.

Excessive lipid accumulation in obesity-associated insulin resistance leads to fatty liver with aberrant lipid peroxidation and excessive production of reactive oxygen and nitrogen species, Dr. Aouadi and her colleagues note in Science Translational Medicine. The direct role of liver macrophages in the regulation of this oxidative stress remains unclear.

The team investigated the link between obesity and nonalcoholic fatty liver disease (NAFLD), hypothesizing that liver macrophages might regulate oxidative stress independently of their inflammatory status in obesity-induced insulin resistance.

In livers of obese insulin-resistant mice and humans, oxidative stress failed to induce the antioxidant response normally mediated by nuclear factor erythroid 2-related factor 2 (NRF2), however.

The microRNA miR-144 was significantly upregulated in obese mice, and this upregulation was associated with decreases in NRF2.

miR-144 expression appeared to be driven by the transcription factor GATA4, which was activated by the extracellular signal-regulated kinase (PRK) pathway in insulin-resistant mice and humans.

Silencing of miR-144 in liver macrophages reduced the release of reactive oxygen species, which led to decreased expression of miR-144 in hepatocytes, thereby reducing oxidative stress and improving hepatic metabolism in insulin-resistant mice.

"Although our study clearly shows that the antioxidant response is impaired in obese insulin-resistant patients and animals through overexpression of miR-144 targeting NRF2, further work will be required to validate the role of miR-144 at different points of liver diseases," the authors note.

"While antioxidants have been considered as a promising therapeutic strategy, they have been associated with long-term side effects in several tissues," Dr. Aouadi said. "We believe that targeting miR-144 to increase the endogenous antioxidant response represents a better therapeutic strategy for the treatment of nonalcoholic steatohepatitis (NASH), which is becoming a major cause of liver cancer worldwide and has currently no pharmacological treatment."

"Here we propose to restore the antioxidant response, rather than providing antioxidants that eventually would only have the opposite effect of shutting down the endogenous antioxidant response," she said.

The study was supported in part by a grant from AstraZeneca. Dr. Aouadi and one of her colleagues report being inventors on a pending patent application.

SOURCE: https://bit.ly/2x6Jo3X Science Translational Medicine, online February 26, 2020.