Krüppel-like factor 15: Regulator of BCAA metabolism and circadian protein rhythmicity

doi:10.1016/j.phrs.2017.12.018

Pharmacological Research

Volume 130, April 2018, Pages 123-126

https://doi.org/10.1016/j.phrs.2017.12.018 Get rights and content

Abstract

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. The branched-chain amino acids (BCAAs) leucine, isoleucine, and valine are important modulators of metabolism and metabolic health – for example, their catabolism yields carbon substrates for gluconeogenesis during periods of fasting. Krüppel-like factor 15 (KLF15) has recently emerged as a critical transcriptional regulator of BCAA metabolism, and the absence of this transcription factor contributes to severe pathologies such as Duchenne muscular dystrophy and heart failure. 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.

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.).

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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.
Branched-chain amino acids (BCAAs) are essential amino acids in human bodies. They have complex metabolic pathways and various metabolites. Both BCAAs and its metabolites are involved in various processes such as protein anabolism and catabolism, energy supply, signaling transduction and so on. Previous studies have observed the widely alternations of BCAAs and its related proteins in multiple tumor phenotypes, which suggests that BCAAs metabolic disorders may have emerged as a powerful factor for tumor metabolism reprogramming. BCAAs metabolism has a pivotal role in tumorigenesis and progression, including cell growth, proliferation, migration, invasion, and so on. In this review, we try to shed light on the crucial role of BCAAs metabolic disorders in different tumor types by focusing on the impacts of metabolic disorders of BCAAs and discussing the notable proteins involved in cancer metabolic reprogramming of BCAAs, such as BCAT1/2, BCKDH-BCKDK-PPM1K complex, transporters of BCAAs and its metabolites, transcription factors and so on, and present several possible diagnose approaches and therapies to BCAAs-related cancers.
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Skeletal muscle dynamically regulates systemic nutrient homeostasis through transcriptional adaptations to physiological cues. In response to changes in the metabolic environment (e.g., alterations in circulating glucose or lipid levels), networks of transcription factors and coregulators are recruited to specific genomic loci to fine-tune homeostatic gene regulation. Elucidating these mechanisms is of particular interest as these gene regulatory pathways can serve as potential targets to treat metabolic disease. The zinc-finger transcription factor Krüppel-like factor 15 (KLF15) is a critical regulator of metabolic homeostasis; however, its genome-wide distribution in skeletal muscle has not been previously identified. Here, we characterize the KLF15 cistrome in vivo in skeletal muscle and find that the majority of KLF15 binding is localized to distal intergenic regions and associated with genes related to circadian rhythmicity and lipid metabolism. We also identify critical interdependence between KLF15 and the nuclear receptor PPARδ in the regulation of lipid metabolic gene programs. We further demonstrate that KLF15 and PPARδ colocalize genome-wide, physically interact, and are dependent on one another to exert their transcriptional effects on target genes. These findings reveal that skeletal muscle KLF15 plays a critical role in metabolic adaptation through its direct actions on target genes and interactions with other nodal transcription factors such as PPARδ.
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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).
KLF15 is a transcription factor that plays an important role in the activation of gluconeogenesis from amino acids as well as the suppression of lipogenesis from glucose. Here we identified the transcription start site of liver-specific KLF15 transcript and showed that FoxO1/3 transcriptionally regulates Klf15 gene expression by directly binding to the liver-specific Klf15 promoter. To achieve this, we performed a precise in vivo promoter analysis combined with the genome-wide transcription-factor-screening method “TFEL scan”, using our original Transcription Factor Expression Library (TFEL), which covers nearly all the transcription factors in the mouse genome. Hepatic Klf15 expression is significantly increased via FoxOs by attenuating insulin signaling. Furthermore, FoxOs elevate the expression levels of amino acid catabolic enzymes and suppress SREBP-1c via KLF15, resulting in accelerated amino acid breakdown and suppressed lipogenesis during fasting. Thus, the FoxO-KLF15 pathway contributes to switching the macronutrient flow in the liver under the control of insulin.
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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].
High protein diet (HPD) is an affordable and positive approach in prevention and treatment of many diseases. It is believed that transcriptional regulation is responsible for adaptation after HPD feeding and Kruppel-like factor 15 (KLF15), a zinc finger transcription factor that has been proved to perform transcriptional regulation over amino acid, lipid and glucose metabolism, is known to be involved at least in part in this HPD response. To gain more insight into molecular mechanisms by which HPD controls expressions of genes involved in amino acid metabolism in the liver, we performed RNA-seq analysis of mice fed HPD for a short period (3 days). Compared to a low protein diet, HPD feeding significantly increased hepatic expressions of enzymes involved in the breakdown of all the 20 amino acids. Moreover, using KLF15 knockout mice and in vivo Ad-luc analytical system, we were able to identify Cth (cystathionine gamma-lyase) as a new target gene of KLF15 transcription as well as Ast (aspartate aminotransferase) as an example of KLF15-independent gene despite its remarkable responsiveness to HPD. These findings provide us with a clue to elucidate the entire transcriptional regulatory mechanisms of amino acid metabolic pathways.

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ReviewKrüppel-like factor 15: Regulator of BCAA metabolism and circadian protein rhythmicity

Abstract

Graphical abstract

Introduction

Section snippets

Metabolism and Krüppel-like factor 15

KLF15 control of BCAA metabolism in fasting

KLF15-dependent diurnal rhythms in BCAA catabolism

KLF15 regulation of BCAA metabolism in muscle pathology

Concluding remarks

Conflict of interest

Acknowledgements

Cell Metab.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Cell Rep.

Cell Rep.

Biochem. Biophys. Res. Commun.

Cell Metab.

Cell Rep.

Curr. Biol.

J. Mol. Cell. Cardiol.

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.

Review
Krüppel-like factor 15: Regulator of BCAA metabolism and circadian protein rhythmicity