Potential role of autophagy in modulation of lipid metabolism

Kovsan, Julia; Bashan, Nava; Greenberg, Andrew S.; Rudich, Assaf

doi:10.1152/ajpendo.00562.2009

Cited by 49 publications

(39 citation statements)

References 57 publications

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“…It appears to function as a means of mobilising lipid stores in times of nutrient demand [37], or as a means of helping to regulate cellular cholesterol homeostasis [23]. LAL has recently been implicated as the important metabolising enzyme in this process [23,38].…”

Section: Discussionmentioning

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: Discussionmentioning

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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“…Degradation and lysosomal efflux By virtue of lysosomal degradation, autophagy contributes to regulating the metabolism of carbohydrates, lipids and proteins [90][91][92]. Like acidification defects in the endo/lysosomal compartment, defects in the transport or expression of lysosomal enzymes induce a blockade of autophagy, which is characterized by an accumulation of autophagic vacuoles [93,94].…”

Section: Acidification and Degradationmentioning

confidence: 99%

Overview of macroautophagy regulation in mammalian cells

et al. 2010

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Macroautophagy is a multistep, vacuolar, degradation pathway terminating in the lysosomal compartment, and it is of fundamental importance in tissue homeostasis. In this review, we consider macroautophagy in the light of recent advances in our understanding of the formation of autophagosomes, which are double-membrane-bound vacuoles that sequester cytoplasmic cargos and deliver them to lysosomes. In most cases, this final step is preceded by a maturation step during which autophagosomes interact with the endocytic pathway. The discovery of AuTophaGyrelated genes has greatly increased our knowledge about the mechanism responsible for autophagosome formation, and there has also been progress in the understanding of molecular aspects of autophagosome maturation. Finally, the regulation of autophagy is now better understood because of the discovery that the activity of Atg complexes is targeted by protein kinases, and owing to the importance of nuclear regulation via transcription factors in regulating the expression of autophagy genes.

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“…44 Recent studies also report that lipids can regulate the autophagic process, which in turn can regulate lipid metabolism and adipocyte differentiation. [45][46][47][48][49][50][51][52] Thus, SREBP1 may be important for lipid homeostasis not only by regulating lipid synthesis and signaling but also by regulating lipid degradation via the autophagy-lysosomal pathway. Maintenance of intracellular lipid metabolism and homeostasis is important in diseases such as diabetes, atherosclerosis, lipid storage disorders and neurodegeneration.…”

confidence: 99%