4:23 PM
Apr 13, 2018
 |  BC Extra  |  Preclinical News

Autophagy enhancers as metabolic syndrome therapy

In a study published in Nature Communications, a team of South Korean researchers identified small molecule autophagy enhancers that could help treat metabolic syndromes.

Autophagy -- a lysomome-mediated degradation pathway -- is an increasingly popular target for drug developers looking to treat multiple diseases due to its role as a regulator of cellular homeostasis. While autophagy inhibition has shown promise in treating cancer, boosting autophagy could be a general strategy for combating neurodegenerative diseases involving aggregated proteins (see BioCentury Innovations, May 4, 2017).

Previous studies have linked impairments in autophagy to metabolic diseases such as diabetes.

In this study, a team led by researchers at Severance Biomedical Science Institute screened a library of 7250 compounds for small molecules that increased autophagy in human hepatocellular carcinoma cells and reduced serum glucose levels in a mouse model of obesity. The researchers selected one of the hits, dubbed MSL, for further testing.

In a cell culture model of lipid-induced metabolic stress, MSL and an optimized derivative, MSL-7, decreased cellular lipid levels compared with vehicle. The two compounds also reduced inflammasome activation, pro-inflammatory cytokine expression and mitochondrial dysfunction in peritoneal macrophages.

The researchers then showed the compounds improved metabolic and glucose profiles and decreased inflammation in mouse models of obesity.

In a genetic mouse model of obesity, MSL and MSL-7 decreased inflammatory cytokine levels, inflammasome activation and morphological markers of metabolic inflammation in adipose tissue. MSL also reduced steatosis, liver triglycerides and biomarkers of liver damage in the mice.

In the genetically obese mice, MSL and MSL-7 reduced fasting and non-fasting blood glucose levels and improved glucose tolerance and insulin sensitivity without causing significant serum toxicity. The small molecules also decreased blood glucose in a mouse model of diet-induced obesity.

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