Lysosome: regulator of lipid degradation pathways - PubMed (original) (raw)

Review

Lysosome: regulator of lipid degradation pathways

Carmine Settembre et al. Trends Cell Biol. 2014 Dec.

Abstract

Autophagy is a catabolic pathway that has a fundamental role in the adaptation to fasting and primarily relies on the activity of the endolysosomal system, to which the autophagosome targets substrates for degradation. Recent studies have revealed that the lysosomal-autophagic pathway plays an important part in the early steps of lipid degradation. In this review, we discuss the transcriptional mechanisms underlying co-regulation between lysosome, autophagy, and other steps of lipid catabolism, including the activity of nutrient-sensitive transcription factors (TFs) and of members of the nuclear receptor family. In addition, we discuss how the lysosome acts as a metabolic sensor and orchestrates the transcriptional response to fasting.

Keywords: Autophagy; FOXOs; TFEB; TP53; lipophagy; lysosome; mTORC1; nuclear receptors; transcription factors.

Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

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Figures

Figure 1

Figure 1

Autophagy mediates substrate catabolism during fasting. During nutrient deprivation proteins, glycogen and fat are sequestered by autophagosomes and targeted to lysosomes where they are degraded by resident hydrolases and transformed into amino acids, fatty acids, and glucose, which are then released into the cytoplasm to support cellular energetic demands. Abbreviations: AV, autophagosome; LYS, lysosome.

Figure 2

Figure 2

Proposed model of coordinated transcriptional regulation of lipid catabolism via forkhead box protein class O (FOXO), transcription factor EB (TFEB), p53, and nuclear receptors. The nuclear translocation of TFEB, p53, and FOXOs is induced under conditions of metabolic stress such as nutrient depletion and growth factor deprivation. These transcription factors (TFs) regulate directly the expression of autophagy genes and the nuclear receptor and co-receptor peroxisome proliferator-activated receptor (PPAR)α and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), respectively, which control lipid catabolism.

Figure 3

Figure 3

The lysosome as a regulator of lipid metabolism. In the fed state (upper panel), the presence of lysosomal amino acids (AA), glucose, and growth factors induces activation of mechanistic target of rapamycin complex 1 (mTORC1) on the lysosomal membrane. Active mTORC1 transcriptionally induces lipogenesis and adipogenesis by activating SREBPs and peroxisome proliferator-activated receptor (PPAR)γ transcription factors, respectively. Concomitantly, mTORC1 blocks autophagy and fatty acid oxidation via transcription factor EB (TFEB) and PPARα inhibition, respectively. In the fasted state (lower panel), lower levels of lysosomal AA, glucose, and growth factors induce mTORC1 detachment from the lysosomal membrane and its consequent inhibition. mTORC1 inhibition in turn activates TFEB and PPARα transcription factors, which leads to the transcriptional induction of lipophagy and β-oxidation, respectively. Concomitantly, SREBPs and PPARγ are no longer activated by mTORC1, therefore lipogenesis and adipogenesis are inhibited. Abbreviations: Rheb, Ras homolog enriched in brain; Rags, Ras-related small GTP-binding protein; SREBPs, sterol regulatory element-binding proteins.

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