Ann Pediatr Endocrinol Metab.  2016 Dec;21(4):193-198. 10.6065/apem.2016.21.4.193.

Transcriptional coordination of hepatic autophagy by nutrient-sensing nuclear receptor PPARα and FXR

• Lee JM

• KMID: 2366809
• DOI: http://doi.org/10.6065/apem.2016.21.4.193

Abstract

Nuclear receptors are in general ligand-dependent transcription factors that control a variety of mammalian physiologies including development, differentiation, proliferation, and homeostasis. Recent studies have found that two nutrient-sensing nuclear receptors, peroxisome proliferator-activated receptor α and farnesoid x receptor, responding to fasting or feeding state, respectively are able to regulate autophagy, an evolutionarily conserved catabolic process involved in lysosomal degradation. In this review, we discuss the role of these nutrient-sensing nuclear receptors in an aspect of transcriptional regulation of autophagy, and how these nuclear receptor-driven transcriptional programs integrate lipophagy, a lipid autophagy with fatty acid oxidation to coordinate hepatic lipid metabolism in the fasted state of the liver.

Keyword

Nuclear receptor; Transcription; Autophagy; Nonalcoholic fatty liver disease; Nonalcoholic steatohepatitis

Figure

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  Fig. 1 Working mechanisms of transcriptional regulation of autophagy by nutrient-sensing NRs and CREB. In the fed state of wild-type mice, FXR activated by its endogenous agonist CDCA (shown in yellow colored circle) binds to DR1 RE as a heterodimeric complex with RXR in the distal regulatory regions of autophagy-related genes. Moreover, activated FXR can also form a piggyback interaction with a CRE-bound CREB in the proximal regulator regions of autophagy-related genes via the dissociation of a coactivator CRTC2. These 2 different mechanisms may account for the transcriptional repression of autophagy-related genes by FXR activation in the fed state of mouse liver. In contrast, fasting-activated PPARα by its endogenous ligands, FFAs or PC (16:0-18:1)(shown in light blue colored circle), binds to DR1 RE via the formation of a heterodimeric complex with RXR in the distal regions of autophagy-related genes. CREB also recruits its coactivator CRTC2 in the proximal regions of autophagy-related genes. These complimentary transcription complexes ensure that fasting leads to turning on the expression of many core autophagy-related genes in the fasted state of mouse livers. Overall, activated PPARα or FXR competes with each other for binding to shared DNA sequences in the distal regions of autophagy-related genes. Additionally, FXR competes with CRTC2 for binding to CREB in the proximal regions of autophagy-related genes. NRs, nuclear receptors; CDCA, chenodeoxycholic acid; FFAs, free fatty acids; PC, phosphatidylcholine; FXR, farnesoid x receptor; RXR, retinoid x receptor; DR1 RE, direct repeat 1 response element; CRE, cAMP response element; CREB, cAMP response element binding protein; PPARα, peroxisome proliferator-activated receptor α; CRTC2, CREB regulated transcription coactivator 2.

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