title: Liver BCATm transgenic mouse model reveals the important role of the liver in maintaining BCAA homeostasis.
abstract: Unlike other amino acids, the branched-chain amino acids (BCAAs) largely bypass first-pass liver degradation due to a lack of hepatocyte expression of the mitochondrial branched-chain aminotransferase (BCATm). This sets up interorgan shuttling of BCAAs and liver-skeletal muscle cooperation in BCAA catabolism. To explore whether complete liver catabolism of BCAAs may impact BCAA shuttling in peripheral tissues, the BCATm gene was stably introduced into mouse liver. Two transgenic mouse lines with low and high hepatocyte expression of the BCATm transgene (LivTg-LE and LivTg-HE) were created and used to measure liver and plasma amino acid concentrations and determine whether the first two BCAA enzymatic steps in liver, skeletal muscle, heart and kidney were impacted. Expression of the hepatic BCATm transgene lowered the concentrations of hepatic BCAAs while enhancing the concentrations of some nonessential amino acids. Extrahepatic BCAA metabolic enzymes and plasma amino acids were largely unaffected, and no growth rate or body composition differences were observed in the transgenic animals as compared to wild-type mice. Feeding the transgenic animals a high-fat diet did not reverse the effect of the BCATm transgene on the hepatic BCAA catabolism, nor did the high-fat diet cause elevation in plasma BCAAs. However, the high-fat-diet-fed BCATm transgenic animals experienced attenuation in the mammalian target of rapamycin (mTOR) pathway in the liver and had impaired blood glucose tolerance. These results suggest that complete liver BCAA metabolism influences the regulation of glucose utilization during diet-induced obesity.
authors.affiliation: Department of Human Nutrition, Foods, and Exercise, Virginia Tech, Integrated Life Sciences Building 0913, 1981 Kraft Drive Blacksburg, VA, 24060, USA. Electronic address: elitsa.ananieva-stoyanova@dmu.edu.
authors.forename: Elitsa A
authors.initials: EA
authors.lastname: Ananieva
authors.affiliation: Department of Biochemistry and Molecular Biology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, 27157, USA. Electronic address: cvanhorn@wakehealth.edu.
authors.forename: Cynthia G
authors.initials: CG
authors.lastname: Van Horn
authors.affiliation: Department of Human Nutrition, Foods, and Exercise, Virginia Tech, Integrated Life Sciences Building 0913, 1981 Kraft Drive Blacksburg, VA, 24060, USA. Electronic address: meghanrjones@gmail.com.
authors.forename: Meghan R
authors.initials: MR
authors.lastname: Jones
authors.affiliation: Department of Human Nutrition, Foods, and Exercise, Virginia Tech, Integrated Life Sciences Building 0913, 1981 Kraft Drive Blacksburg, VA, 24060, USA. Electronic address: susanh5@vt.edu.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Hutson
mesh_terms: D000597:Amino Acids, Branched-Chain / Q000097:blood / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001823:Body Composition / Q000235:genetics; D059305:Diet, High-Fat; D005260:Female; D005786:Gene Expression Regulation; D006706:Homeostasis; D008099:Liver / Q000378:metabolism*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000637:Transaminases / Q000235:genetics* / Q000378:metabolism
chemical_list: D000597:Amino Acids, Branched-Chain; D001786:Blood Glucose; C094227:Bcat1 protein, mouse; D000637:Transaminases; D000076222:Mechanistic Target of Rapamycin Complex 1
keywords: Amino acids; BCAA metabolism; BCATm; High-fat diet; Liver transgenic mouse