The transcription factors CREBH, PPARa, and FOXO1 as critical hepatic mediators of diet-induced metabolic dysregulation - PubMed (original) (raw)

Review

The transcription factors CREBH, PPARa, and FOXO1 as critical hepatic mediators of diet-induced metabolic dysregulation

Zhao Yang et al. J Nutr Biochem. 2021 Sep.

Abstract

The liver is a critical mediator of lipid and/or glucose homeostasis and is a primary organ involved in dynamic changes during feeding and fasting. Additionally, hepatic-centric pathways are prone to dysregulation during pathophysiological states including metabolic syndrome (MetS) and non-alcoholic fatty liver disease. Omics platforms and GWAS have elucidated genes related to increased risk of developing MetS and related disorders, but mutations in these metabolism-related genes are rare and cannot fully explain the increasing prevalence of MetS-related pathologies worldwide. Complex interactions between diet, lifestyle, environmental factors, and genetic predisposition jointly determine inter-individual variability of disease risk. Given the complexity of these interactions, researchers have focused on master regulators of metabolic responses incorporating and mediating the impact of multiple environmental cues. Transcription factors are DNA binding, terminal executors of signaling pathways that modulate the cellular responses to complex metabolic stimuli and are related to the control of hepatic lipid and glucose homeostasis. Among numerous hepatic transcription factors involved in regulating metabolism, three emerge as key players in transducing nutrient sensing, which are dysregulated in MetS-related perturbations in both clinical and preclinical studies: cAMP Responsive Element Binding Protein 3 Like 3 (CREB3L3), Peroxisome Proliferator Activated Receptor Alpha (PPAR), and Forkhead Box O1 (FOXO1). Additionally, these three transcription factors appear to be amenable to dietary and/or nutrient-based therapies, being potential targets of nutritional therapy. In this review we aim to describe the activation, regulation, and impact of these transcription factors in the context of metabolic homeostasis. We also summarize their perspectives in MetS and nutritional therapies.

Keywords: CREBH; FOXO1; Metabolic syndrome; NAFLD; PPAR; diet induced obesity.

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Conflict of interest statement

The authors declare that there are no competing financial interests.

Figures

Figure 1.

Overview of CREB3L3 regulation and activation. Transcription of Creb3l3 is upregulated by fasting through glucocorticoid receptor. Fasting or HFD treatment may also modulate activation of CREB3L3. Insulin induces phosphorylation of CREB3L3 precursor and prevents its cleavage by activating PI3K pathway. Responding to multiple metabolic signals, CREB3L3 initiates target genes involved in glucose and lipid metabolism.

Figure 2.

Overview of PPARα activation and regulation. PPARα activity is mediated by intra/extra-cellular metabolic signaling. Fasting induces elevation of fatty acids, the insulin signaling pathway, elevation of blood glucose, and glucagon which may stimulate expression and/or activity of PPARα under physiological metabolic conditions leading to increased lipid consumption.

Figure 3.

Overview of FOXO1 activation and regulation. Post translational modifications determine the activity and half-life of FOXO1. Phosphorylation of FOXO1 facilitates its binding with RAN-XPO1 complex, which mediates nuclear export and degradation of FOXO1. Acetylation increases affiliation of FOXO1 with the 14-3-3 proteins, leading to inhibition.

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The transcription factors CREBH, PPARa, and FOXO1 as critical hepatic mediators of diet-induced metabolic dysregulation - PubMed (original) (raw)