Regulation of Gluconeogenesis by Krüppel-like Factor 15

Abstract

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.

Time course of gene expression during mouse skeletal muscle hypertrophy

“…The inactivation of Klf15 resulted in a modest but significant increase in lean mass that was associated with a reduced expression of multiple genes encoding amino acid-degrading enzymes, including Bcat2 (8). However, a more recent study from this same group reported no change in skeletal muscle mass (9), while Klf15 null mice developed a severe cardiac hypertrophy in response to pressure overload (6).…”

Kruppel-like Factors (KLFs) in muscle biology

“…Recent studies from our group and others implicate KLF15 as an important regulator of cardiac hypertrophy [27], glucose homeostasis [33] and adipocyte differentiation [33,40]. With respect to SMCs, KLF15 is expression is robust at baseline but strongly attenuated following vascular injury or in response to pro-proliferative stimuli [93].…”

“…Our group has demonstrated that KLF15 is robustly expressed in skeletal muscle where it regulates expression of the glucose transporter GLUT4. Recently, we have reported that KLF15(−/−) mice have severe fasting hypoglycemia which is caused by a defect in the ability of critical amino acids to enter the gluconeogenetic pathway in the liver [33] though the significance of this metabolic block in the heart or skeletal muscle has not been fully determined. KLF15 has also been shown to regulate the fasting-induced transcriptional activation of mitochondrial acetyl-CoA sythetase-2 in skeletal muscle [96].…”

Kruppel-like Factor 15 Is a Critical Regulator of Cardiac Lipid Metabolism

“…Therefore, it is likely that balance between such catabolic and anabolic upstream signals, with additional synchronization via the circadian clock, regulates cardiac KLF15 function. In addition to its newly defined role in cardiac lipid metabolism, KLF15 also regulates the catabolism of skeletal muscle branched chain amino acids, the body's major store of glucogenic precursors (24,25). Because cardiac and skeletal muscle share similar substrate flux machinery, it is possible that KLF15 might also regulate myocardial amino acid homeostasis in a manner that influences metabolism of other substrates and cardiac function.…”