Presecretory oxidation, aggregation, and autophagic destruction of apoprotein-B: A pathway for late-stage quality control

Pan, Meihui; Maitin, Vatsala; Parathath, Saj; Andréo, Ursula; Lin, Sharron X.; Germain, Carly St.; Yao, Zemin; Maxfield, Frederick R.; Williams, Kevin Jon; Fisher, Edward A.

doi:10.1073/pnas.0707460104

Cited by 121 publications

(117 citation statements)

References 49 publications

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“…Two decades ago, Hoff and colleagues ( 8 ) showed that lysosomal processes such as those needed for recycling of the LDL receptor were inactivated when macrophages were overloaded with oxidized LDL. More recent data suggest that polyunsaturated fatty acid-derived ROS increases hepatic autophagy of nascent lipoproteins that are oxidized and aggregated ( 9 ). Thus, those data and those in the current study by Jaishy et al ( 6 ) prove that intracellular lipid metabolism is central to regulation of autophagy.…”

supporting

confidence: 69%

A new pathway regulating autophagy

Trent

Goldberg

2015

Journal of Lipid Research

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Autophagy is required to remove damaged organelles and proteins in all healthy tissues. Within the heart, the turnover of intracellular damaged organelles and proteins might be especially important to respond to a variety of pathological conditions including ischemia and pressure overload-induced hypertrophy. Defective autophagy has been created in tissues by deletion of the autophagic mediators, most commonly autophagy proteins (ATG) 5 and ATG7 ( 1 ). These defects are invariably deleterious.Another role of autophagy is to provide energy during starvation. Many tissues store energy in lipid droplets and utilize these substrates primarily via hydrolysis of the esterifi ed fatty acids by adipose triglyceride lipids and hormone sensitive lipase ( 2 ). In several tissues, including the liver ( 3 ) and heart ( 4 ), autophagy is an alternative pathway to acquire fatty acids.Autophagy is negatively regulated by mTOR signaling complex 1 (mTORC1) activation. When mTORC1 is inactivated in response to nutrient or growth factor deprivation, autophagy is induced by the formation of a multiprotein kinase complex primarily composed of ATGs leading to the nucleation of the autophagosome. Further processing results in the matured autophagosome, defi ned by the closed double membrane, which can then fuse with the lysosome membrane to form the autophagolysome. The autophagosome internal membrane and contents are digested by hydrolases within the lysosome. ATG regulation and autophagosome formation are not completely understood, so autophagic fl ux must be measured by a functional readout, i.e., examining autophagosome morphology and quantity as well as microtubule-associated protein 1A/1B-light chain 3 (LC3) lipidation ( 1 , 5 ). LC3 linked to phosphotidylethanolamine resides on the autophagosome outer membrane and is commonly used as a signal for autophagic fl ux.The paper by Jaishy et al. ( 6 ) in this issue of the Journal of Lipid Research reports a novel pathway for regulation of the autophagy. The authors propose that changes in lysosomal pH due to fatty acids prevent the elimination of autophagosomes. Mice eating a high-fat diet had impaired cardiac autophagy, specifi cally at the level of lysosomal digestion of contents. This decrease in autophagic fl ux associated with increased cellular lipids had also been observed in insulin-resistant livers ( 3 ). However, these impairments in autophagic fl ux were independent of changes in mTORC1 because activation of mTORC1 was insuffi cient to restore autophagic fl ux. The surprising result was that this regulation of autophagy was independent of changes in protein kinase B/AKT and S6-kinase, which are thought to be major regulators of autophagy. Therefore, the autophagy defects occurred without defective insulin signaling, which one would expect to fi nd with longer-term palmitate treatment. Furthermore, there was no cardiac dysfunction observed in this short-term high-fat diet feeding.The authors went on to defi ne the specifi c mechanism whereby increased cardiac lipids reduced ...

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supporting

confidence: 69%

A new pathway regulating autophagy

Trent

Goldberg

2015

Journal of Lipid Research

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“…29,84 Also, others have reported that DHA-derived ROS is involved in protein quality control by regulating aggregation and further autophagic degradation of misfolded apolipoprotein B in hepatocytes. 85 Interestingly, both the basal and DHA-induced level of MAP1LC3B-I were elevated in cells depleted for NFE2L2 and SQSTM1. This increase in MAP1LC3B-I could indicate a compensatory role of autophagy under conditions of increased ROS levels.…”

Section: Discussionmentioning

confidence: 99%

The marine n-3 PUFA DHA evokes cytoprotection against oxidative stress and protein misfolding by inducing autophagy and NFE2L2 in human retinal pigment epithelial cells

et al. 2015

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“…Interestingly, plasmin treatment has been shown to disaggregate vortex-aggregated and phospholipase C-aggregated LDL particles ( 36 ), a fi nding pointing to the possibility that apoB-100 may have a more general role in governing LDL aggregation. In fact, it has been suggested that the unique susceptibility of apoB-100 to aggregation may serve as a quality control mechanism that blocks the secretion of potentially toxic lipoproteins by the liver, but may unfortunately lead to extracellular aggregation and retention in the arterial wall ( 25 ).…”

Section: Discussionmentioning

confidence: 99%