Physiological and coordinate downregulation of the NPC1 and NPC2 genes are associated with the sequestration of LDL‐derived cholesterol within endocytic compartments

Jelínek, David; Patrick, Sarah Mount; Kitt, Khameeka N.; Chan, Teddy; Garver, William S.

doi:10.1002/jcb.22339

Cited by 12 publications

(11 citation statements)

References 51 publications

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“…However, this sensitivity was only partial in the case of 3MA, pointing either to LAL-independent effects of autophagy that contribute to GSIS, or LAL working through other mechanisms in addition to lipophagy. The latter would be consistent with the role of LAL in mobilising lipids bound to lipoprotein [17,18].…”

Section: Discussionsupporting

confidence: 81%

“…The generally excellent concordance between all these approaches suggests that lipophagy serves as a constitutive negative regulator of GSIS. It will be important in future studies to address how this role intersects with the better-known function of LAL in hydrolysing lipid from LDL [17,18]. Although the contribution of the amplification pathway to GSIS is now well established, the underlying mechanisms remain obscure.…”

Section: Discussionmentioning

confidence: 99%

“…Historically, the chief function of this enzyme, as established in other cell types, was considered to be the breakdown of cholesteryl ester (CE) delivered to the cell via the LDL pathway [17,18]. However, LAL has also been implicated in the turnover of endogenous lipid stores (lipid droplets) via the process of lipophagy, first established in hepatocytes in 2009 [19].…”

Section: Introductionmentioning

confidence: 99%

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Lysosomal acid lipase and lipophagy are constitutive negative regulators of glucose-stimulated insulin secretion from pancreatic beta cells

et al. 2013

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Aims/hypothesis Lipolytic breakdown of endogenous lipid pools in pancreatic beta cells contributes to glucosestimulated insulin secretion (GSIS) and is thought to be mediated by acute activation of neutral lipases in the amplification pathway. Recently it has been shown in other cell types that endogenous lipid can be metabolised by autophagy, and this lipophagy is catalysed by lysosomal acid lipase (LAL). This study aimed to elucidate a role for LAL and lipophagy in pancreatic beta cells. Methods We employed pharmacological and/or genetic inhibition of autophagy and LAL in MIN6 cells and primary islets. Insulin secretion following inhibition was measured using RIA. Lipid accumulation was assessed by MS and confocal microscopy (to visualise lipid droplets) and autophagic flux was analysed by western blot. Results Insulin secretion was increased following chronic (≥8 h) inhibition of LAL. This was more pronounced with glucose than with non-nutrient stimuli and was accompanied by augmentation of neutral lipid species. Similarly, following inhibition of autophagy in MIN6 cells, the number of lipid droplets was increased and GSIS was potentiated. Inhibition of LAL or autophagy in primary islets also increased insulin secretion. This augmentation of GSIS following LAL or autophagy inhibition was dependent on the acute activation of neutral lipases. Conclusions/interpretation Our data suggest that lysosomal lipid degradation, using LAL and potentially lipophagy, contributes to neutral lipid turnover in beta cells. It also serves as a constitutive negative regulator of GSIS by depletion of substrate for the non-lysosomal neutral lipases that are activated acutely by glucose.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Lysosomal acid lipase and lipophagy are constitutive negative regulators of glucose-stimulated insulin secretion from pancreatic beta cells

et al. 2013

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“…Previous studies in fibroblasts have suggested that retention of cholesterol within lysosomal compartments may serve to protect cells from endoplasmic reticulum (ER) stress caused by an excess of FC in the ER membrane. Garver et al ( 2008 ) and Jelinek et al ( 2009 ) found that loading normal human fibroblasts with LDL results in reduced SREBP-dependent expression of NPC1 and NPC2. Jelinek et al ( 2012 ) reported that in a mouse model of diet induced obesity, dietary fatty acids but not cholesterol induced down regulation of NPC1 in both hepatic cells and peritoneal fibroblasts via feedback inhibition of the SREBP pathway.…”

Section: Indications Of a Lysosomal Cholesterol Trafficking Defectmentioning

confidence: 99%

Lysosomal acid lipase: at the crossroads of normal and atherogenic cholesterol metabolism

Dubland

Francis

2015

Front. Cell Dev. Biol.

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109

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Unregulated cellular uptake of apolipoprotein B-containing lipoproteins in the arterial intima leads to the formation of foam cells in atherosclerosis. Lysosomal acid lipase (LAL) plays a crucial role in both lipoprotein lipid catabolism and excess lipid accumulation as it is the primary enzyme that hydrolyzes cholesteryl esters derived from both low density lipoprotein (LDL) and modified forms of LDL. Evidence suggests that as atherosclerosis progresses, accumulation of excess free cholesterol in lysosomes leads to impairment of LAL activity, resulting in accumulation of cholesteryl esters in the lysosome as well as the cytosol in foam cells. Impaired metabolism and release of cholesterol from lysosomes can lead to downstream defects in ATP-binding cassette transporter A1 regulation, needed to offload excess cholesterol from plaque foam cells. This review focuses on the role LAL plays in normal cholesterol metabolism and how the associated changes in its enzymatic activity may ultimately contribute to atherosclerosis progression.

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“…The cholesterol needed for lipid raft formation and maintenance can be derived from exogenous sources such as lipoproteins, especially LDL, or from cellular synthesis via the mevalonate pathway in the ER followed by transport to the plasma membrane. 41, 97 Another source of cholesterol are intracellular lipid droplets. Movement of cholesterol out of lipid droplet relies upon extrinsic signals promoting the hydrolysis of CE by cholesterol ester hydrolases.…”

Section: Microdomain Cholesterol Regulation: the Role Of Effluxmentioning

confidence: 99%

Microdomains, Inflammation, and Atherosclerosis

Sorci‐Thomas

Thomas

2016

Circulation Research

144

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Elevated levels of cholesteryl ester (CE) enriched apoB containing plasma lipoproteins lead to increased foam cell formation, the first step in the development of atherosclerosis. Unregulated uptake of LDL cholesterol by circulating monocytes and other peripheral blood cells takes place through scavenger receptors and over time causes disruption in cellular cholesterol homeostasis. As lipoproteins are taken up, their CE core is hydrolyzed by liposomal lipases to generate free cholesterol (FC). FC can either be re-esterified and stored as CE droplets or shuttled to the plasma membrane for ATP binding cassette transporter A1 (ABCA1) mediated efflux. Since cholesterol is an essential component of all cellular membranes some FC may be incorporated into microdomains or lipid rafts. These platforms are essential for receptor signaling and transduction, requiring rapid assembly and disassembly. ABCA1 plays a major role in regulating microdomain cholesterol and is most efficient when lipid-poor HDL apolipoprotein A-I (apoA-I) packages raft cholesterol into soluble particles that are eventually catabolized by the liver. If FC is not effluxed from the cell, it becomes esterified and CE droplets accumulate. It follows that as the cell accumulates CE, microdomain cholesterol content becomes poorly regulated. This dysregulation leads to prolonged activation of immune cell signaling pathways, resulting in receptor over-sensitization. The availability of HDL apoA-I or other amphipathic α-helix rich apoproteins relieves the burden of excess microdomain cholesterol in immune cells allowing a reduction in immune cell proliferation and infiltration, thereby, stimulating regression of foam cells in the artery. Therefore, cellular balance between FC and CE is essential for proper immune cell function and prevents chronic immune cell overstimulation and proliferation.

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Physiological and coordinate downregulation of the NPC1 and NPC2 genes are associated with the sequestration of LDL‐derived cholesterol within endocytic compartments

Cited by 12 publications

References 51 publications

Lysosomal acid lipase and lipophagy are constitutive negative regulators of glucose-stimulated insulin secretion from pancreatic beta cells

Lysosomal acid lipase and lipophagy are constitutive negative regulators of glucose-stimulated insulin secretion from pancreatic beta cells

Lysosomal acid lipase: at the crossroads of normal and atherogenic cholesterol metabolism

Microdomains, Inflammation, and Atherosclerosis

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