Transcriptional Regulation of Hepatic Autophagy by Nuclear Receptors - PubMed (original) (raw)
Review
Transcriptional Regulation of Hepatic Autophagy by Nuclear Receptors
Eun Young Kim et al. Cells. 2022.
Abstract
Autophagy is an adaptive self-eating process involved in degradation of various cellular components such as carbohydrates, lipids, proteins, and organelles. Its activity plays an essential role in tissue homeostasis and systemic metabolism in response to diverse challenges, including nutrient depletion, pathogen invasion, and accumulations of toxic materials. Therefore, autophagy dysfunctions are intimately associated with many human diseases such as cancer, neurodegeneration, obesity, diabetes, infection, and aging. Although its acute post-translational regulation is well described, recent studies have also shown that autophagy can be controlled at the transcriptional and post-transcriptional levels. Nuclear receptors (NRs) are in general ligand-dependent transcription factors consisting of 48 members in humans. These receptors extensively control transcription of a variety of genes involved in development, metabolism, and inflammation. In this review, we discuss the roles and mechanisms of NRs in an aspect of transcriptional regulation of hepatic autophagy, and how the NR-driven autophagy pathway can be harnessed to treat various liver diseases.
Keywords: autophagy; liver; macroautophagy; nuclear receptor.
Conflict of interest statement
The authors declare no conflict of interest.
Figures
Figure 1
Autophagy is a catabolic process degrading cytoplasmic molecules, aggregated proteins, and infectious pathogens. There are three major types of autophagy: macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). Macroautophagy is initiated from an isolation membrane (also termed phagophore) to gather soluble materials and organelles for autophagosome formation. Autophagosomes fuses with lysosomes to form autolysosomes where cytoplasmic cargo molecules are finally degraded by lysosomal acidic hydrolases. Rubicon is a Beclin1-interacting protein involved in autophagy initiation and autophagosome maturation. Rubicon could directly bind to Class III PI3K-Beclin1-UVRAG complex for inhibition of autolysosome formation. In microautophagy, inward invagination of the lysosomal membrane or late endosome membrane engulfs small cytosolic components for their degradation. Lastly, CMA is mediated by a direct translocation of cargo proteins but not by the membrane reconstruction shown in macroautophagy or microautophagy. The cytosolic chaperone protein heat shock cognate 70 (Hsc70) and cochaperones recognize the specific pentameric peptide sequence (a KFERQ-like motif). The cytosolic proteins containing the KFERQ-like pentapeptide captured by Hsc70-cochaperone are translocated into the lysosome through a lysosomal associated membrane protein 2A (LAMP-2A) receptor on lysosomal membrane. This schematic diagram was created in
BioRender.com
(accessed on 20 January 2022).
Figure 2
Human nuclear receptor superfamily. Human genome encodes 48 members of nuclear receptors (NRs). NRs are divided into two groups based on the source and type of their ligands. Classical endocrine receptors include steroid hormone receptors and RXR heterodimeric receptors. Adopted and orphan receptors include several receptors for dietary lipids, cholesterol derivatives, bile acids, phospholipids, and heme, and receptors with unknown ligands. The hormone response element (HRE) core sequence AGGTCA is represented by black arrows. N indicates any nucleotide between the half sites of HRE. Endocrine receptors usually bind as homodimers to palindromic DNA sequences (inverted repeats) separated by three nucleotides (IR3). Some NRs bind DNA as heterodimers with RXR to direct repeats separated by zero to six nucleotides (DR0-6) or to inverted repeats spaced by zero or one nucleotide (IR0-1). A few NRs interact with DNA as monomers to HRE containing a three-nucleotide 5’-extension. NRs shown in red colored letters are known to regulate hepatic autophagy, which is discussed in this review. This schematic diagram was created in
BioRender.com
(accessed on 20 January 2022).
Figure 3
Transcriptional control of hepatic autophagy by nuclear receptors. (a) Each step of macroautophagy is typically controlled by multiple NRs: vesicle induction (TRβ and PPARα), vesicle nucleation (TRβ, ERRα, HNF4α, and REV-ERBα), vesicle elongation (PPARα, FXR, and ERRα), vesicle completion (PPARα, PPARγ, FXR, and VDR), and docking and fusion (TRβ, FXR, LXRα and RORα). (b) GR and FXR regulate expression of genes encoding master transcription factors FoxO1 and TFEB. PPARα, ERRα, VDR, and FXR control genes involved in core autophagy-related genes. FXR typically downregulates these core autophagy genes via the disruption of CREB-CRTC2 complex or competition with PPARα. Lastly, LXRα increases expressions of miRNAs let7a2 and miR34a that in in turn downregulate transcripts of Atg4b and Rab8b genes. PPARα and TRβ increases expressions of genes associated with either upstream regulators (Sestrin2, AMPK, CaMKK2, DAPK2) or PINK1, a critical kinase for mitophagy. RORα induces Atp6v1g1 gene encoding a subunit of v-ATPase, which is critical for lysosomal acidification. This schematic diagram was created in
BioRender.com
(accessed on 5 February 2022).
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