Foxa2 regulates lipid metabolism and ketogenesis in the liver during fasting and in diabetes.
The regulation of fat and glucose metabolism in the liver is controlled primarily by insulin and glucagon. Changes in the circulating concentrations of these hormones signal fed or starvation states and elicit counter-regulatory responses that maintain normoglycaemia. Here we show that in normal mice, plasma insulin inhibits the forkhead transcription factor Foxa2 by nuclear exclusion and that in the fasted (low insulin) state Foxa2 activates transcriptional programmes of lipid metabolism and ketogenesis. In insulin-resistant or hyperinsulinaemic mice, Foxa2 is inactive and permanently located in the cytoplasm of hepatocytes. In these mice, adenoviral expression of Foxa2T156A, a nuclear, constitutively active Foxa2 that cannot be inhibited by insulin, decreases hepatic triglyceride content, increases hepatic insulin sensitivity, reduces glucose production, normalizes plasma glucose and significantly lowers plasma insulin. These changes are associated with increased expression of genes encoding enzymes of fatty acid oxidation, ketogenesis and glycolysis. Chronic hyperinsulinaemia in insulin-resistant syndromes results in the cytoplasmic localization and inactivation of Foxa2, thereby promoting lipid accumulation and insulin resistance in the liver. Pharmacological intervention to inhibit phosphorylation of Foxa2 may be an effective treatment for type 2 diabetes.
Wolfrum
Christian
C
Laboratory of Metabolic Diseases, Howard Hughes Medical Institute, The Rockefeller University, 1230 York Avenue, New York, New York 10021, USA.
Asilmaz
Esra
E
Luca
Edlira
E
Friedman
Jeffrey M
JM
Stoffel
Markus
M
D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D005215:Fasting / Q000378:metabolism*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D005947:Glucose / Q000378:metabolism; D051542:Hepatocyte Nuclear Factor 3-beta; D006801:Humans; D006946:Hyperinsulinism / Q000097:blood / Q000378:metabolism / Q000473:pathology; D007328:Insulin / Q000097:blood / Q000502:physiology; D007333:Insulin Resistance; D007657:Ketone Bodies / Q000096:biosynthesis / Q000378:metabolism*; D050356:Lipid Metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008928:Mitochondria / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D010766:Phosphorylation; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; C496502:FOXA2 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C496503:Foxa2 protein, mouse; C467200:Foxo1 protein, mouse; D007328:Insulin; D007657:Ketone Bodies; D009687:Nuclear Proteins; C497387:SREBF1 protein, human; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D051542:Hepatocyte Nuclear Factor 3-beta; D005947:Glucose