{"id":26156,"date":"2020-05-01T08:13:08","date_gmt":"2020-05-01T15:13:08","guid":{"rendered":"https:\/\/vermont.salk.edu\/?post_type=disclosure&p=26156"},"modified":"2023-02-08T21:04:40","modified_gmt":"2023-02-09T05:04:40","slug":"experimental-drug-boosts-levels-of-good-fats","status":"publish","type":"disclosure","link":"https:\/\/www.salk.edu\/zh\/news-release\/experimental-drug-boosts-levels-of-good-fats\/","title":{"rendered":"Experimental drug boosts levels of \u201cgood\u201d fats"},"content":{"rendered":"

LA JOLLA\u2014Salk and Scripps Research Institute scientists, along with collaborators at the pharmaceutical company Lundbeck, identified two genes that can regulate levels of healthy fats, called FAHFAs, in mice. The team found that the loss of the two genes led to higher-than-normal levels of the beneficial FAHFAs, while blocking the genes\u2019 activity with an experimental drug also increased FAHFA levels.<\/p>\n

Because FAHFAs decrease inflammation and increase insulin sensitivity, a better understanding of the activity of their regulatory genes may eventually lead to therapies for people with diabetes and inflammation.<\/p>\n

\"In
In mice, blocking the proteins Aig1 and ADTRP, either with a drug or by deleting their corresponding genes, boosts levels of the healthy FAHFA fat called 9-PAHSA.<\/p>\n

Click here<\/a> for a high-resolution image.<\/p>\n

Credit: Salk Institute<\/figcaption><\/figure>\n

\u201cThis study is a really great starting point to answer important questions about FAHFAs,\u201d says Alan Saghatelian<\/a>, a professor in Salk\u2019s Clayton Foundation Laboratories for Peptide Biology and corresponding author of the new paper, which appeared in the Journal of Biological Chemistry<\/em><\/a> on May 1, 2020. \u201cTargeting them in this way might have important implications for treating metabolic and inflammatory diseases.\u201d<\/p>\n

In 2014, Saghatelian and collaborators discovered FAHFAs<\/a> (short for fatty acid esters of hydroxy fatty acids) when studying a strain of obese mice that were unexpectedly resistant to diabetes. The mice, they found, had sixteen times more FAHFAs than usual. The researchers went on to show that people with pre-diabetes have lower-than-average levels of FAHFAs in their fat and blood. Together, the results suggested that higher levels of FAHFAs may be beneficial to health. Further studies also found a connection between FAHFAs and reduced inflammation in the body.<\/p>\n

While many types of fat are ingested through food, FAHFAs are naturally produced by the body, so altering their levels is more difficult. But in 2016, Saghatelian\u2019s group, with Benjamin Cravatt of The Scripps Research Institute, reported that two proteins, AIG1 and ADTRP, seemed to alter levels of FAHFAs<\/a> in isolated cells.<\/p>\n

In the new work, Saghatelian and Cravatt\u2019s labs, along with the Saez lab at Scripps and industrial partners at Lundbeck, collaborated to further study how AIG1 and ADTRP regulate FAHFAs in living animals. The researchers found that when mice lacked both AIG1 and ADTRP, levels of FAHFAs in their fat tissues were up to nine times higher than levels seen in normal mice. Experiments confirmed that FAHFAs were increasing because AIG1 and ADTRP weren\u2019t there to break down the beneficial fats, as they usually would. No other types of fat were affected, however.<\/p>\n

\"From
From left: Justin Wang, Alan Saghatelian and Meric Erikci Ertunc.<\/p>\n

Click here<\/a> for a high-resolution image.<\/p>\n

Credit: Salk Institute<\/figcaption><\/figure>\n

\u201cWhat this tells us is that these proteins are very, very specific for this biochemical activity,\u201d says Salk postdoctoral fellow Meri\u00e7 Erikci Ertunc, the first author of the new paper.<\/p>\n

The researchers then worked with Lundbeck researchers to test a library of compounds for molecules that could block the activity of both AIG1 and ADTRP. They found one, called ABD-110207, and tested its effect on mice.<\/p>\n

\u201cUntil this point, we\u2019d only ever studied the therapeutic potential of FAHFAs by feeding FAHFAs to mice,\u201d says Erikci Ertunc. \u201cThat\u2019s not a very natural situation, but we didn\u2019t have any other way to alter levels until we generated mice lacking FAHFA degrading enzymes and found ABD-110207.\u201d<\/p>\n

The drug-like small molecule successfully increased FAHFA levels, mimicking the results seen in the mice lacking both proteins. In mice lacking the proteins, metabolic benefits were not observed compared to what has been seen in mice that directly consumed FAHFAs. This isn\u2019t surprising, the researchers say, given that fats ingested are processed differently than those made naturally by the body.<\/p>\n

The team next hopes to study more about the role of FAHFAs in the body and how their levels are normally regulated.<\/p>\n

\u201cThis could have implications in studying and treating not only diabetes and inflammation but things like cardiovascular disease or even neurodegenerative diseases in which FAHFAs may play a role,\u201d says Saghatelian, who holds the Dr. Frederik Paulsen Chair.<\/p>\n

Other authors on the study are Justin Wang, Dan Tan, Cynthia Donaldson, Antonio Pinto and Joan Vaughan of the Salk Institute; Bernard Kok, Enrique Saez and Benjamin Cravatt of The Scripps Research Institute; William Parsons of Oberlin College; and Nhi Ngo, Kenneth Lum, Cassandra Henry, Aundrea Coppola and Micah Niphakis of Lundbeck La Jolla Research Center.<\/p>\n

The work was supported by grants from the National Institutes of Health, The Leona M. and Harry B. Helmsley Charitable Trust, the National Cancer Institute, Dr. Frederick Paulsen Chair\/Ferring Pharmaceuticals, and the Hewitt Foundation for Medical Research.<\/p>","protected":false},"featured_media":0,"template":"","faculty":[111],"disease-research":[333,123],"class_list":["post-26156","disclosure","type-disclosure","status-publish","hentry","faculty-alan-saghatelian","disease-research-genetics","disease-research-metabolism-and-diabetes"],"acf":[],"yoast_head":"\nExperimental drug boosts levels of \u201cgood\u201d fats - Salk Institute for Biological Studies<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/www.salk.edu\/zh\/news-release\/experimental-drug-boosts-levels-of-good-fats\/\" \/>\n<meta property=\"og:locale\" content=\"zh_CN\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Experimental drug boosts levels of \u201cgood\u201d fats - Salk Institute for Biological Studies\" \/>\n<meta property=\"og:description\" content=\"LA JOLLA\u2014Salk and Scripps Research Institute scientists, along with collaborators at the pharmaceutical company Lundbeck, identified two genes that can regulate levels of healthy fats, called FAHFAs, in mice. 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