Regulation of gluconeogenesis by Krüppel-like factor 15.
In the postabsorptive state, certain tissues, including the brain, require glucose as the sole source of energy. After an overnight fast, hepatic glycogen stores are depleted, and gluconeogenesis becomes essential for preventing life-threatening hypoglycemia. Mice with a targeted deletion of KLF15, a member of the Krüppel-like family of transcription factors, display severe hypoglycemia after an overnight (18 hr) fast. We provide evidence that defective amino acid catabolism promotes the development of fasting hypoglycemia in KLF15-/- mice by limiting gluconeogenic substrate availability. KLF15-/- liver and skeletal muscle show markedly reduced mRNA expression of amino acid-degrading enzymes. Furthermore, the enzymatic activity of alanine aminotransferase (ALT), which converts the critical gluconeogenic amino acid alanine into pyruvate, is decreased (approximately 50%) in KLF15-/- hepatocytes. Consistent with this observation, intraperitoneal injection of pyruvate, but not alanine, rescues fasting hypoglycemia in KLF15-/- mice. We conclude that KLF15 plays an important role in the regulation of gluconeogenesis.
Gray
Susan
S
Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. sgray@rics.bwh.harvard.edu
Wang
Baiqiu
B
Orihuela
Yvette
Y
Hong
Eun-Gyoung
EG
Fisch
Sudeshna
S
Haldar
Saptarsi
S
Cline
Gary W
GW
Kim
Jason K
JK
Peroni
Odile D
OD
Kahn
Barbara B
BB
Jain
Mukesh K
MK
D000410:Alanine Transaminase / Q000378:metabolism; D000596:Amino Acids / Q000097:blood / Q000378:metabolism; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation; D005943:Gluconeogenesis / Q000235:genetics*; D005947:Glucose / Q000378:metabolism; D005990:Glycerol / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors; D019344:Lactic Acid / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000201:enzymology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D000596:Amino Acids; D004268:DNA-Binding Proteins; C467418:Klf15 protein, mouse; D051741:Kruppel-Like Transcription Factors; D014157:Transcription Factors; D019344:Lactic Acid; D000410:Alanine Transaminase; D005947:Glucose; D005990:Glycerol