title: Diet1 is a regulator of fibroblast growth factor 15/19-dependent bile acid synthesis.
abstract: BACKGROUND
  A fascinating aspect of bile acid homeostasis is the coordination between bile acid uptake in intestine and hepatic bile acid synthesis. In response to bile acid uptake in enterocytes, farnesoid X receptor is activated and induces transcription of fibroblast growth factor (FGF)15 in mice, or FGF19 in humans. FGF15/19 is secreted into the enterohepatic circulation, and through activation of hepatic receptors, leads to repression of Cyp7a1, a rate-limiting enzyme for bile acid synthesis. Using a genetic approach, we identified a novel protein, Diet1, as a control point for FGF15/19 production.
  
  
  CONCLUSIONS
  Mice with a Diet1-null mutation have reduced FGF15 secretion, causing impaired feedback repression of hepatic bile acid synthesis, and increased fecal bile acid excretion. As a result, Diet1-deficient mice constitutively convert cholesterol to bile acids and are resistant to diet-induced hypercholesterolemia and atherosclerosis. Diet1 affects FGF15/19 production at the posttranscriptional level, and the proteins appear to have overlapping subcellular localization in enterocytes. Diet1 appears to be a control point for the production of FGF15/19 in enterocytes, and thus a regulator of bile acid and lipid homeostasis. Studies to evaluate the role of common and rare DIET1 genetic variants in human health and disease are warranted.
  
  
  CONCLUSIONS
  Further elucidation of the Diet1-FGF15/19 interaction will provide new insights into the intricate regulatory mechanisms underlying bile acid metabolism.
authors.affiliation: Department of Human Genetics, University of California, Los Angeles, Calif., USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Reue
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Lee
authors.forename: Laurent
authors.initials: L
authors.lastname: Vergnes
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000037:antagonists & inhibitors; D020895:Enterocytes / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D019073:HT29 Cells; D006706:Homeostasis; D006801:Humans; D051379:Mice; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*
chemical_list: D001647:Bile Acids and Salts; D002352:Carrier Proteins; C585655:Diet1 protein, mouse; C117476:FGF19 protein, human; C539830:MALRD1 protein, human; D012333:RNA, Messenger; D011973:Receptors, LDL; C108526:fibroblast growth factor 15, mouse; D005346:Fibroblast Growth Factors; C553219:CYP7A1 protein, human; D002790:Cholesterol 7-alpha-Hydroxylase; C502772:Cyp7a1 protein, mouse; D005947:Glucose