Transcriptional Regulation of Metabolism

Abstract

Our understanding of metabolism is undergoing a dramatic shift. Indeed, the efforts made towards elucidating the mechanisms controlling the major regulatory pathways are now being rewarded. At the molecular level, the crucial role of transcription factors is particularly well-illustrated by the link between alterations of their functions and the occurrence of major metabolic diseases. In addition, the possibility of manipulating the ligand-dependent activity of some of these transcription factors makes them attractive as therapeutic targets. The aim of this review is to summarize recent knowledge on the transcriptional control of metabolic homeostasis. We first review data on the transcriptional regulation of the intermediary metabolism, i.e., glucose, amino acid, lipid, and cholesterol metabolism. Then, we analyze how transcription factors integrate signals from various pathways to ensure homeostasis. One example of this coordination is the daily adaptation to the circadian fasting and feeding rhythm. This section also discusses the dysregulations causing the metabolic syndrome, which reveals the intricate nature of glucose and lipid metabolism and the role of the transcription factor PPARγ in orchestrating this association. Finally, we discuss the molecular mechanisms underlying metabolic regulations, which provide new opportunities for treating complex metabolic disorders.

Genetic variations in regulatory pathways of fatty acid and glucose metabolism are associated with obesity phenotypes: a population-based cohort study

“…DNA was extracted using a salting out method as described by Hoebee et al 28 Selection of candidate genes and SNPs Candidate genes were selected by a pathway-driven approach based on literature, with emphasis on regulatory Candidate gene pathways and obesity SW van den Berg et al pathways that control fatty acid, glucose, cholesterol and bile salt homeostasis. 25 The selection procedure started from the master regulator genes encoding nuclear receptors (PPARs, LXR, FXR (NR1H4)) and transcription factors (SREBPs) and continued by selecting their co-activators, corepressors and target genes. In addition, hormonal receptors (insulin receptor) and their downstream signaling proteins were selected.…”

“…The nuclear receptors PPAR, LXR and FXR (encoded by NR1H4), the SREBP transcription factors and the insulin receptor have an important regulatory function in adipocyte differentiation, fatty acid synthesis, fatty acid oxidation, fat storage in adipose tissue and glucose homeostasis. 25 Therefore, genetic variation in these key regulators and their pathways may be involved in the onset of obesity.…”

Pharmacological modulators of the circadian clock as potential therapeutic drugs

“…Among the transcriptional targets of the CLOCK/BMAL1 complex are genes encoding CRYPTOCHROME (CRY1 and 2) and PERIOD (PER1 and 2) proteins, which function as potent suppressors of CLOCK/BMAL1-dependent transactivation [8], and two nuclear receptors, REV-ERBα and RORα, which respectively repress or activate transcription of the Bmal1 gene [9], forming an interlocked loop. In addition to the core components of the molecular oscillator, the CLOCK/BMAL1 complex drives rhythmic transcription of numerous clock-controlled genes either directly via the E-box regulatory element in their promoter region, or indirectly, via the rhythmic control of other transcription factors whose expression is under clock control [10]. The results of global temporal transcriptional profiling of various tissues using a microarray hybridization approach have estimated that as much as 10% of mammalian transcriptome oscillates in a circadian manner [11][12][13].…”

Subtle metabolic and liver gene transcriptional changes underlie diet-induced fatty liver susceptibility in insulin-resistant mice

“…Functional genomic tools, including transcriptomics and metabonomics, a technology designed to quantify metabolites in biological samples [6], generate high-density data sets underlying disease-related mechanisms at either end of the regulation of gene expression. Alterations in transcription regulation of hepatic carbohydrate and lipogenic pathways have a central role in mechanisms contributing to insulin resistance and NAFLD [7,8].…”