Function of the endolysosomal network in cholesterol homeostasis and metabolic-associated fatty liver disease (MAFLD)

Vos, Dyonne; Sluis, Bart van de

doi:10.1016/j.molmet.2020.101146

Cited by 20 publications

(12 citation statements)

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“…Since the inactivation and clearance of LDLR depend on the lysosome‐dependent degradation, 22 we next investigated the co‐localization of LDLR with Rab11 or the lysosome marker Lamp1 in vitro. Quantitation of the overlap of LDLR with Rab11 showed a considerable level of co‐localization after Ang II stimulation, as assessed by Pearson's correlation coefficient and the overlap coefficient (Figure 4A ).…”

Section: Resultsmentioning

confidence: 99%

Alteration in Rab11‐mediated endocytic trafficking of LDL receptor contributes to angiotensin II‐induced cholesterol accumulation and injury in podocytes

Zhu

Chen

et al. 2022

Cell Proliferation

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Objectives: Exposure of podocytes to angiotensin II (Ang II) enhances the abundance of the cell surface glycoprotein, low-density lipoprotein receptor (LDLR) and promotes significant changes in the cellular cholesterol content. Recent investigation provides evidence that the small GTPase Rab11 is involved in the regulation of LDLR, but the exact mechanisms remain unknown. In this study, the role of Rab11 in posttranscriptional regulation of LDLR was evaluated to investigate potential mechanisms of podocyte cholesterol dysregulation in chronic kidney disease. Materials and Methods: Cholesterol content, LDLR and Rab11 expression were assessed in podocytes from Ang II-infused mice. In vitro, the intracellular localization of LDLR was detected under different conditions. Rab11 expression was modulated and we then explored the effect of anti-lipid cytotoxicity by detecting LDLR expression and trafficking, cholesterol content and apoptosis in podocytes. Results: Cholesterol accumulation, upregulated expression of LDLR and Rab11 were discovered in podocytes from Ang II-infused mice. Ang II enhanced the co-precipitation of LDLR with Rab11 and accelerated the endocytic recycling of LDLR to the plasma membrane. Additionally, silencing Rab11 promoted lysosomal degradation of LDLR and alleviated Ang II-induced cholesterol accumulation and apoptosis in podocytes. Conversely, overexpression of Rab11 or inhibition of lysosomal degradation up-regulated the abundance of LDLR and aggravated podocyte cholesterol deposition. Conclusions: Rab11 triggers the endocytic trafficking and recycling of LDLR; overactivation of this pathway contributes to Ang II-induced podocyte cholesterol accumulation and injury. | INTRODUCTIONThe precise architecture of podocytes takes part in maintaining the selective permeability of the glomerular filtration barrier. For several Jijia Hu and Zijing Zhu contributed equally to this work.

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Section: Resultsmentioning

confidence: 99%

Alteration in Rab11‐mediated endocytic trafficking of LDL receptor contributes to angiotensin II‐induced cholesterol accumulation and injury in podocytes

Zhu

Chen

et al. 2022

Cell Proliferation

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“…How precisely IDOL mediates degradation of the LDL receptor is not known, but it seems to be unaffected by proteasome blockers, suggesting that it takes place in endo-lysosomes ( Zelcer et al, 2009 ). Additional regulatory mechanisms for LDL-receptor recycling versus degradation have been discovered and are discussed in a recent dedicated review ( Vos and van de Sluis, 2021 ). Ubiquitination followed by proteasomal degradation is another important regulatory mechanism, which controls the abundance of SREBPs, LXRs, the LDL-receptor, and ATP-binding cassette (ABC) transporters, such as ABCA1 ( Sharpe et al, 2014 ).…”

Section: Cholesterol Homeostasis By Feedback-regulated De N...mentioning

confidence: 99%

Pathways and Mechanisms of Cellular Cholesterol Efflux—Insight From Imaging

Juhl

Wüstner

2022

Front. Cell Dev. Biol.

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Cholesterol is an essential molecule in cellular membranes, but too much cholesterol can be toxic. Therefore, mammalian cells have developed complex mechanisms to remove excess cholesterol. In this review article, we discuss what is known about such efflux pathways including a discussion of reverse cholesterol transport and formation of high-density lipoprotein, the function of ABC transporters and other sterol efflux proteins, and we highlight their role in human diseases. Attention is paid to the biophysical principles governing efflux of sterols from cells. We also discuss recent evidence for cholesterol efflux by the release of exosomes, microvesicles, and migrasomes. The role of the endo-lysosomal network, lipophagy, and selected lysosomal transporters, such as Niemann Pick type C proteins in cholesterol export from cells is elucidated. Since oxysterols are important regulators of cellular cholesterol efflux, their formation, trafficking, and secretion are described briefly. In addition to discussing results obtained with traditional biochemical methods, focus is on studies that use established and novel bioimaging approaches to obtain insight into cholesterol efflux pathways, including fluorescence and electron microscopy, atomic force microscopy, X-ray tomography as well as mass spectrometry imaging.

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“…Despite being understudied, research shows that lysosomal degradation plays a principal role in NAFLD pathogenesis. Key proteins of interest in lysosomal degradation are RABs (Ras-related protein Rab), Sortilin (VSP10), and SIMPLE (small integral membrane protein of lysosome/late endosome) (Strong et al, 2012;Zeigerer et al, 2012;Du et al, 2020;Song et al, 2021;Vos and van de Sluis, 2021). RABs are a large family of GTPase essential in early endosome, late endosomes, and lysosome formation.…”

Section: Lysosomal Degradation During Nafldmentioning

confidence: 99%

ER Disposal Pathways in Chronic Liver Disease: Protective, Pathogenic, and Potential Therapeutic Targets

Duwaerts

Maiers

2022

Front. Mol. Biosci.

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The endoplasmic reticulum is a central player in liver pathophysiology. Chronic injury to the ER through increased lipid content, alcohol metabolism, or accumulation of misfolded proteins causes ER stress, dysregulated hepatocyte function, inflammation, and worsened disease pathogenesis. A key adaptation of the ER to resolve stress is the removal of excess or misfolded proteins. Degradation of intra-luminal or ER membrane proteins occurs through distinct mechanisms that include ER-associated Degradation (ERAD) and ER-to-lysosome-associated degradation (ERLAD), which includes macro-ER-phagy, micro-ER-phagy, and Atg8/LC-3-dependent vesicular delivery. All three of these processes are critical for removing misfolded or unfolded protein aggregates, and re-establishing ER homeostasis following expansion/stress, which is critical for liver function and adaptation to injury. Despite playing a key role in resolving ER stress, the contribution of these degradative processes to liver physiology and pathophysiology is understudied. Analysis of publicly available datasets from diseased livers revealed that numerous genes involved in ER-related degradative pathways are dysregulated; however, their roles and regulation in disease progression are not well defined. Here we discuss the dynamic regulation of ER-related protein disposal pathways in chronic liver disease and cell-type specific roles, as well as potentially targetable mechanisms for treatment of chronic liver disease.

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Function of the endolysosomal network in cholesterol homeostasis and metabolic-associated fatty liver disease (MAFLD)

Cited by 20 publications

References 159 publications

Alteration in Rab11‐mediated endocytic trafficking of LDL receptor contributes to angiotensin II‐induced cholesterol accumulation and injury in podocytes

Alteration in Rab11‐mediated endocytic trafficking of LDL receptor contributes to angiotensin II‐induced cholesterol accumulation and injury in podocytes

Pathways and Mechanisms of Cellular Cholesterol Efflux—Insight From Imaging

ER Disposal Pathways in Chronic Liver Disease: Protective, Pathogenic, and Potential Therapeutic Targets

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