Metabolism

These “outlier” enzymes, called AIG1 and ADTRP, appear to break down a class of lipids Saghatelian uncovered in 2014 called fatty acid esters of hydroxy fatty acids (FAHFAs). Saghatelian had found that boosting the levels of one FAHFA lipid normalizes glucose levels in diabetic mice. In principle, inhibitors of AIG1 and ADTRP could be developed into FAHFA-boosting therapies that reduce inflammation as well as improve glucose levels and insulin sensitivity.

The labs are collaborating on further studies of the new enzymes and potential benefits of inhibiting them in mouse models of diabetes, inflammation and autoimmune disease.

To detail this pathway, first author Run Shen and colleagues studied a genetic switch in the brain called Crtc. They found that the guts of fruit flies without Crtc expressed molecules indicating that the immune system was keyed up, suggesting that without Crtc, bacteria leak from the gut into the fly’s circulation.

The normal role of Crtc is to fortify the barriers of the gut to prevent bacteria from entering the bloodstream and awakening the immune system. Without Crtc, the connections between cells that line the gut tube became disrupted, causing bacteria to leak out, activating the immune response and depleting energy reserves. The team also discovered that without the protein sNPF (found in the fly brain and with a human equivalent), the flies showed signs of gut inflammation similar to those flies missing Crtc. What’s more, the normally tight seals along the GI tract were broken down, letting bacteria out. Conversely, flies expressing more than the normal amounts of Crtc or sNPF in their neurons were able to survive longer without food and showed less disruption to the tight junctions that maintain their GI barriers. The team is conducting more experiments to understand how the neuropeptides activate the gut receptors that help protect it from bacterial invasion.

According to Shaw, the connection between AMPK and lysosomes reveals more about cellular growth and metabolism.

Currently, lysosome inhibitors are in dozens of clinical trials for certain cancers, even though the exact link between lysosomes and tumors is not understood. “We are decoding underlying connections that might indicate when and how cancer drugs might be useful,” says Shaw. “This work may help us make better, more specific ways of targeting lysosomes in cancer.”

The study’s first author Xuan Zhao, Evans and colleagues analyzed levels and molecular characteristics of REV-ERB in the livers of mice. After the protein’s levels peaked during the day, two other proteins, CDK1 and FBXW7, reduced REV-ERB to a low point by the middle of the night. When the team targeted these proteins to block the degradation of REV-ERB, normal daily fluctuations in gene expression were suppressed, but the timing of the cycles wasn’t affected. Altering the strength of the gene expression oscillations profoundly affected metabolism, disrupting the levels of fats and sugars in the blood. What’s more, mice that lacked REV-ERB developed fatty liver disease, stressing the importance of regulating the intensity of the cycle.