Flavin-containing monooxygenase 3 as a potential player in diabetes-associated atherosclerosis

• Published in: Nature communications Vol. 6; no. 1; p. 6498
• Main Authors: Miao, Ji, Ling, Alisha V., Manthena, Praveen V., Gearing, Mary E., Graham, Mark J., Crooke, Rosanne M., Croce, Kevin J., Esquejo, Ryan M., Clish, Clary B., Vicent, David, Biddinger, Sudha B.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.04.2015; Nature Publishing Group; Nature Pub. Group
• Subjects: 13/1; 13/106; 13/109; 13/89; 38/39; 38/61; 631/443/319/1642/137; 631/443/592/75/593/2100; 64/60; 692/308; 692/700/565; 82/80; Animals; Atherosclerosis - genetics; Atherosclerosis - metabolism; Blotting, Western; Cardiovascular diseases; Cholesterol, HDL - metabolism; Cholesterol, LDL - metabolism; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Forkhead Box Protein O1; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Gene Expression Profiling; Gene Knockdown Techniques; Hepatocytes - drug effects; Hepatocytes - metabolism; Humanities and Social Sciences; Humans; Hyperglycemia - genetics; Hyperglycemia - metabolism; Hyperlipidemias - genetics; Hyperlipidemias - metabolism; Hypoglycemic Agents - pharmacology; In Vitro Techniques; Insulin - metabolism; Insulin - pharmacology; Insulin Resistance; Liver - drug effects; Liver - metabolism; Male; Mice; multidisciplinary; Obesity - genetics; Obesity - metabolism; Oxygenases - drug effects; Oxygenases - genetics; Oxygenases - metabolism; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; RNA, Messenger - metabolism; Science; Science (multidisciplinary); Triglycerides - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms7498

Despite the well-documented association between insulin resistance and cardiovascular disease, the key targets of insulin relevant to the development of cardiovascular disease are not known. Here, using non-biased profiling methods, we identify the enzyme flavin-containing monooxygenase 3 ( Fmo3 ) to be a target of insulin. FMO3 produces trimethylamine N-oxide (TMAO), which has recently been suggested to promote atherosclerosis in mice and humans. We show that FMO3 is suppressed by insulin in vitro , increased in obese/insulin resistant male mice and increased in obese/insulin-resistant humans. Knockdown of FMO3 in insulin-resistant mice suppresses FoxO1, a central node for metabolic control, and entirely prevents the development of hyperglycaemia, hyperlipidemia and atherosclerosis. Taken together, these data indicate that FMO3 is required for FoxO1 expression and the development of metabolic dysfunction. The hepatic enzyme FMO3 has been linked to atherosclerosis. Here the authors show that FMO3 is upregulated in various models of diabetes and link FMO3 with key transcriptional regulators of hepatic glucose and cholesterol synthesis, thus proposing a mechanistic connection between diabetes and atherosclerosis.