Thiadiazole Carbamates: Potent Inhibitors of Lysosomal Acid Lipase and Potential Niemann−Pick Type C Disease Therapeutics

Rosenbaum, Anton I.; Cosner, Casey C.; Mariani, Christopher J.; Maxfield, Frederick R.; Wiest, Olaf; Helquist, Paul

doi:10.1021/jm100499s

Cited by 77 publications

(63 citation statements)

References 33 publications

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“…Inhibition of LAL increases insulin secretion To characterise the role of LAL in beta cell function more comprehensively, and to avoid confounding effects of incomplete gene knockdown, we employed Lalistat, an inhibitor that is highly specific for LAL over neutral lipases [23,31,32]. Lalistat pretreatment for 24 h dose dependently increased insulin secretion from MIN6 cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

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: Resultsmentioning

confidence: 99%

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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“…CE would have to be hydrolyzed by lipases in the lysosomes to produce cholesterol. However, we found that lalistat 1, a lysosomal lipase inhibitor (20), had a limited impact on nutrientdependent changes in ER cholesterol (Fig. S5A).…”

Section: Mtorc1 Activates Srebp-2 By Inhibiting Cholesterol Traffickimentioning

confidence: 94%

mTORC1 activates SREBP-2 by suppressing cholesterol trafficking to lysosomes in mammalian cells

Eid

Dauner

Courtney

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

107

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mTORC1 is known to activate sterol regulatory element-binding proteins (SREBPs) including SREBP-2, a master regulator of cholesterol synthesis. Through incompletely understood mechanisms, activated mTORC1 triggers translocation of SREBP-2, an endoplasmic reticulum (ER) resident protein, to the Golgi where SREBP-2 is cleaved to translocate to the nucleus and activate gene expression for cholesterol synthesis. Low ER cholesterol is a well-established trigger for SREBP-2 activation. We thus investigated whether mTORC1 activates SREBP-2 by reducing cholesterol delivery to the ER. We report here that mTORC1 activation is accompanied by low ER cholesterol and an increase of SREBP-2 activation. Conversely, a decrease in mTORC1 activity coincides with a rise in ER cholesterol and a decrease in SERBP-2 activity. This rise in ER cholesterol is of lysosomal origin: blocking the exit of cholesterol from lysosomes by U18666A or NPC1 siRNA prevents ER cholesterol from increasing and, consequently, SREBP-2 is activated without mTORC1 activation. Furthermore, when mTORC1 activity is low, cholesterol is delivered to lysosomes through two membrane trafficking pathways: autophagy and rerouting of endosomes to lysosomes. Indeed, with dual blockade of both pathways by Atg5and dominant-negative rab5, ER cholesterol fails to increase when mTORC1 activity is low, and SREBP-2 is activated. Conversely, overexpressing constitutively active Atg7, which forces autophagy and raises ER cholesterol even when mTORC1 activity is high, suppresses SREBP-2 activation. We conclude that mTORC1 actively suppresses autophagy and maintains endosomal recycling, thereby preventing endosomes and autophagosomes from reaching lysosomes. This results in a reduction of cholesterol in the ER and activation of SREBP-2. mTORC1 | SREBP-2 | cholesterol | autophagy | endosomal recycling

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“…Lalistat (lalistat-2; 3,4-disubstituted thiadiazole carbamate, compound 12 from Rosenbaum et al (21), was a gift from Paul Helquist (University of Notre Dame). The pyrazole-methanone compounds E4, F2, and H4 were described in VanderVen et al (23).…”

Section: Reagentsmentioning

confidence: 99%

Lysosome-mediated degradation of a distinct pool of lipid droplets during hepatic stellate cell activation

Tuohetahuntila

Molenaar

Spee

et al. 2017

Journal of Biological Chemistry

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Thiadiazole Carbamates: Potent Inhibitors of Lysosomal Acid Lipase and Potential Niemann−Pick Type C Disease Therapeutics

Cited by 77 publications

References 33 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

mTORC1 activates SREBP-2 by suppressing cholesterol trafficking to lysosomes in mammalian cells

Lysosome-mediated degradation of a distinct pool of lipid droplets during hepatic stellate cell activation

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