Flavin containing monooxygenase 3 exerts broad effects on glucose and lipid metabolism and atherosclerosis.
We performed silencing and overexpression studies of flavin containing monooxygenase (FMO) 3 in hyperlipidemic mouse models to examine its effects on trimethylamine N-oxide (TMAO) levels and atherosclerosis. Knockdown of hepatic FMO3 in LDL receptor knockout mice using an antisense oligonucleotide resulted in decreased circulating TMAO levels and atherosclerosis. Surprisingly, we also observed significant decreases in hepatic lipids and in levels of plasma lipids, ketone bodies, glucose, and insulin. FMO3 overexpression in transgenic mice, on the other hand, increased hepatic and plasma lipids. Global gene expression analyses suggested that these effects of FMO3 on lipogenesis and gluconeogenesis may be mediated through the PPARα and Kruppel-like factor 15 pathways. In vivo and in vitro results were consistent with the concept that the effects were mediated directly by FMO3 rather than trimethylamine/TMAO; in particular, overexpression of FMO3 in the human hepatoma cell line, Hep3B, resulted in significantly increased glucose secretion and lipogenesis. Our results indicate a major role for FMO3 in modulating glucose and lipid homeostasis in vivo, and they suggest that pharmacologic inhibition of FMO3 to reduce TMAO levels would be confounded by metabolic interactions.
Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA.
Diana M
DM
Shih
Department of Cellular and Molecular Medicine (NC10), Cleveland Clinic Lerner Research Institute, Cleveland, OH.
Zeneng
Z
Wang
Isis Pharmaceuticals, Carlsbad, CA.
Richard
R
Lee
Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA.
Yonghong
Y
Meng
Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA.
Nam
N
Che
Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA.
Sarada
S
Charugundla
Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA.
Hannah
H
Qi
Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA.
Judy
J
Wu
Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA.
Calvin
C
Pan
Department of Cellular and Molecular Medicine (NC10), Cleveland Clinic Lerner Research Institute, Cleveland, OH.
J Mark
JM
Brown
Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA.
Thomas
T
Vallim
Department of Genetics, University of North Carolina, Chapel Hill, NC.
Brian J
BJ
Bennett
Isis Pharmaceuticals, Carlsbad, CA.
Mark
M
Graham
Department of Cellular and Molecular Medicine (NC10), Cleveland Clinic Lerner Research Institute, Cleveland, OH.
Stanley L
SL
Hazen
Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA Departments of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA.
Aldons J
AJ
Lusis
D000818:Animals; D050197:Atherosclerosis / Q000201:enzymology*; D001647:Bile Acids and Salts / Q000378:metabolism; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism; D066273:Diet, Western; D005243:Feces / Q000737:chemistry; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D055785:Gene Knockdown Techniques; D055786:Gene Knockout Techniques; D005947:Glucose / Q000096:biosynthesis / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000097:blood; D007413:Intestinal Mucosa / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors; D050356:Lipid Metabolism; D050155:Lipogenesis; D008074:Lipoproteins / Q000097:blood; D008099:Liver / Q000378:metabolism; D008744:Methylamines / Q000378:metabolism; D051379:Mice; D010105:Oxygenases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D047493:PPAR alpha / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism
D001647:Bile Acids and Salts; D004268:DNA-Binding Proteins; D007328:Insulin; C467418:Klf15 protein, mouse; D051741:Kruppel-Like Transcription Factors; D008074:Lipoproteins; D008744:Methylamines; D047493:PPAR alpha; D011973:Receptors, LDL; D014157:Transcription Factors; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); C005855:trimethyloxamine; D005947:Glucose; C023336:trimethylamine
trimethylamine-N-oxide • peroxisome proliferator-activated receptor alpha • insulin