ReviewKrüppel-like factor 15: Regulator of BCAA metabolism and circadian protein rhythmicity
Graphical abstract
Introduction
Regulation of nutrient intake, utilization, and storage exhibits a circadian rhythmicity that allows organisms to anticipate and adequately respond to changes in the environment across day/night cycles. Tight control of these homeostatic processes is crucial to the health and continuance of the organism; disturbances in these processes lead to a broad spectrum of disease, ranging from metabolic syndrome to heart failure. The branched-chain amino acids (BCAAs) leucine, isoleucine, and valine are important modulators of metabolic health. These three BCAAs are among the nine essential amino acids for humans and play extensive roles in both physiologic and pathologic contexts. For example, in states of fasting, BCAA catabolism is required to provide carbon substrates for gluconeogenesis in the liver to maintain euglycemia [1]. Additionally, administration of BCAAs has been shown to have antiobesity effects and improve insulin sensitivity, although paradoxically, individuals with obesity and type 2 diabetes tend to have higher levels of circulating BCAAs (Reviewed in Lynch and Adams [2]).
Krüppel-like factor 15 has recently emerged as a critical regulator of BCAA metabolism, and the absence of this transcription factor results in severe pathologies such as Duchenne muscular dystrophy and heart failure [3,4]. This review highlights KLF15’s role as a central regulator of BCAA metabolism during periods of fasting, throughout day/night cycles, and in experimental models of muscle disease.
Section snippets
Metabolism and Krüppel-like factor 15
Krüppel-like factors (KLFs) are a family of Cys2/His2 zinc-finger transcription factors that regulate diverse biological functions including metabolism, homeostasis, cellular proliferation, differentiation, and development [5,6]. To exert their effects, members of the KLF family bind to DNA at GC-rich sequences, with a preference for the 5′-CACCC-3′ motif in the promoters and enhancers of target genes [5]. KLFs also alter transcription through the recruitment or sequestration of various
KLF15 control of BCAA metabolism in fasting
During periods of nutrient deprivation, skeletal muscle BCAA catabolism is requisite for euglycemia: the release of alanine and other amino acids into the circulation for uptake by the liver as substrates for gluconeogenesis maintains glucose homeostasis and preserves the function of obligate glucose users such as the brain. KLF15 plays an essential role in maintaining euglycemia, as demonstrated by the severe hypoglycemia that systemic KLF15-deficient mice experience following an overnight
KLF15-dependent diurnal rhythms in BCAA catabolism
In mammals, day and night cycles have driven the evolution of molecular clocks which synchronize physiologic and cellular processes to an approximately 24 h cycle. Circadian rhythmicity in mammals allows for the anticipation of regular changes in the environment such as day/night cycles, temperature change, and nutrient availability. Within the suprachiasmatic nucleus, a central clock is entrained by light to coordinate organ-specific “peripheral” clocks, which impose diurnal oscillations to
KLF15 regulation of BCAA metabolism in muscle pathology
KLF15 deficiency contributes to severe pathology in striated muscle through impaired BCAA metabolism. Prior studies have shown that KLF15 levels are reduced in both murine and human heart failure. In mice, loss of KLF15 plays an important role in the development of cardiac pathology ranging from cardiac hypertrophy to fibrosis by controlling protein synthesis and breakdown [[30], [31], [32]]. Recently, Sun et al. reported that suppression of the BCAA catabolic pathway is the most significant
Concluding remarks
Considerable investigative effort has been dedicated to the elucidation of the molecular regulators underpinning metabolic programs in hopes of identifying therapeutic targets and prolonging health. Work from the past 15 years has established KLF15 as an essential regulator of metabolism across all major nutrient classes and tissues. Nascent studies have shown KLF15 to be a critical mediator of BCAA catabolism and rhythmicity, influencing processes ranging from gluconeogenesis during fasting to
Conflict of interest
The authors declare no conflicts of interest.
Acknowledgements
This work was supported by the National Institute of Health (NIH) grants R01DK111468, R35HL135789, and R01HL086548 (to M.K.J.), T32GM007250 (to D.R.S., L.F., P.N.H.), F30AG054237 (to P.N.H.), T32HL134622 (to L.F.), and F30HL139014 (to D.R.S.).
References (35)
Regulation of gluconeogenesis by Krüppel-like factor 15
Cell Metab.
(2007)Krüppel-like factors: three fingers in many pies
J. Biol. Chem.
(2001)The Krüppel-like factor KLF15 regulates the insulin-sensitive glucose transporter GLUT4
J. Biol. Chem.
(2002)Overexpression of KLF15 transcription factor in adipocytes of mice results in down-regulation of SCD1 protein expression in adipocytes and consequent enhancement of glucose-induced insulin secretion
J. Biol. Chem.
(2011)Kruppel-like factor 15 is a critical regulator of cardiac lipid metabolism
J. Biol. Chem.
(2014)Role of Krüppel-like factor 15 (KLF15) in transcriptional regulation of adipogenesis
J. Biol. Chem.
(2005)c-Jun regulates adipocyte differentiation via the KLF15-mediated mode
Biochem. Biophys. Res. Commun.
(2016)Adipose KLF15 controls lipid handling to adapt to nutrient availability
Cell Rep.
(2017)KLF15 enables rapid switching between lipogenesis and gluconeogenesis during fasting
Cell Rep.
(2016)Role of Krüppel-like factor 15 in PEPCK gene expression in the liver
Biochem. Biophys. Res. Commun.
(2005)
Klf15 orchestrates circadian nitrogen homeostasis
Cell Metab.
KLF15 establishes the landscape of diurnal expression in the heart
Cell Rep.
Circadian orchestration of the hepatic proteome
Curr. Biol.
The Kruppel-like factor KLF15 inhibits connective tissue growth factor (CTGF) expression in cardiac fibroblasts
J. Mol. Cell. Cardiol.
Crosstalk between glucocorticoid receptor and nutritional sensor mTOR in skeletal muscle
Cell Metab.
Branched-chain amino acids in metabolic signalling and insulin resistance
Nat. Rev. Endocrinol.
Glucocorticoids enhance muscle endurance and ameliorate Duchenne muscular dystrophy through a defined metabolic program
Proc. Natl. Acad. Sci.
Cited by (46)
Branched-chain amino acid catabolic defect in vascular smooth muscle cells drives thoracic aortic dissection via mTOR hyperactivation
2024, Free Radical Biology and MedicineThe role of branched chain amino acids metabolic disorders in tumorigenesis and progression
2022, Biomedicine and PharmacotherapyCitation Excerpt :Liu et al. established that BCAAs may act as a signal molecule and negatively regulate the expression of KLF15, a probable tumor suppressor and key transcription factor in glycemic, lipid, and amino acids metabolism by activating PI3K/AKT pathway [98]. KLF15 regulates the mRNA level of many BCAAs metabolic enzymes, such as BCAT2, BCKDH and PPM1K [47,145,153]. It is found to be highly associated with cell growth and proliferation when de-regulated.
Transcription factors KLF15 and PPARδ cooperatively orchestrate genome-wide regulation of lipid metabolism in skeletal muscle
2022, Journal of Biological ChemistryFoxO-KLF15 pathway switches the flow of macronutrients under the control of insulin
2021, iScienceCitation Excerpt :Recently, we have revealed that Krüppel-like factor 15 (KLF15) interacts with LXR to repress Srebf1c gene transcription as the essential mechanism of the nutritional regulation in the liver (Takeuchi et al., 2016). Hepatic KLF15 is rapidly induced during fasting, and also known to contribute to the regulation of hepatic gluconeogenesis, amino acid catabolism, endobiotic metabolism, and xenobiotic metabolism (Fan et al., 2018; Gray et al., 2007; Han et al., 2019; Jeyaraj et al., 2012b; Takashima et al., 2010; Teshigawara et al., 2005). KLF15 is widely expressed in various tissues (Du et al., 2009; Gray et al., 2002; Haldar et al., 2012; Han et al., 2015; Jeyaraj et al., 2012a; Matoba et al., 2017; Uchida et al., 2000; Yamamoto et al., 2004), and in skeletal muscle and adipose tissue, the expression of KLF15 is regulated by glucocorticoid receptor (GR), a member of the nuclear receptor family (Asada et al., 2011; Morrison-Nozik et al., 2015; Shimizu et al., 2011).
High protein diet-induced metabolic changes are transcriptionally regulated via KLF15-dependent and independent pathways
2021, Biochemical and Biophysical Research CommunicationsCitation Excerpt :It has a wide tissue expression with the highest levels in liver and kidney [33], and it is already reported that KLF15 is at least in part responsible for the HPD-induced responses in the liver [27]. Considering KLF15's massive involvement in the control of protein metabolism and pursuant nitrogen detoxification [34], it is reasonable that impaired KLF15-mediated pathways play a significant role in the development of Duchene muscular dystrophy, heart failure, increased weight and diabetes [35–37]. On the other hand, it is obvious that other transcription factors than KLF15 are also involved in the HPD-induced responses because nitrogen homeostasis is not fully abolished but partially conserved in KLF15 knockout mice [27].