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

Dubland, Joshua A.; Francis, Gordon A.

doi:10.3389/fcell.2015.00003

Cited by 109 publications

(91 citation statements)

References 133 publications

(152 reference statements)

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“…Classically, physiological regulation of cytosolic lipolysis is modulated by catecholamines, hormones, and growth factors which commonly act on cyclic adenosine monophosphate (cAMP)–protein kinase A (PKA) signaling to control lipase activity [2,3]. Lysosomal lipolysis occurs at acidic pH in the lysosome and primarily involves lysosomal acid lipase- mediated degradation of endocytically derived lipids [4]. A major discovery in the field of lipolysis was the realization that autophagy, an intracellular catabolic pathway, is also utilized to deliver lipid droplets as cargo to the lysosome [5].…”

Section: Introduction To Intracellular Lipolysismentioning

confidence: 99%

Classical and alternative roles for autophagy in lipid metabolism

Zhang

Evans

Jeong

et al. 2018

Current Opinion in Lipidology

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Purpose of review Intracellular lipid metabolism is a complex interplay of exogenous lipid handling, trafficking, storage, lipolysis, and export. Recent work has implicated the cellular degradative process called autophagy in several aspects of lipid metabolism. We will discuss both the classical and novel roles of autophagy and the autophagic machinery in this setting. Recent findings The delivery of lipid droplets to lysosomes for hydrolysis, named lipophagy, was the first described functional role for autophagy in lipid metabolism. The molecular machinery and regulation of this selective form of macroautophagy is beginning to be discovered and has the potential to shed enormous light on intracellular lipolysis. Yet, the autophagic machinery appears to also be coopted for alternative roles that include interaction with cytosolic lipolysis pathways, supply and expansion of lipid droplets, and lipoprotein trafficking. Additionally, lesser studied forms of autophagy called microautophagy and chaperone-mediated autophagy have distinct roles in lipid handling that also intersect with classical macroautophagy. The integration of current knowledge in these areas into a holistic understanding of intracellular lipid metabolism will be a goal of this review. Summary As the field of autophagy has evolved and expanded to include functional roles in various aspects of cellular degradation, so has its role in intracellular lipid metabolism. Understanding the mechanisms underlying these classical and alternative roles of autophagy will not only enhance our knowledge in lipid biology but also provide new avenues of translation to human lipid disorders.

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Section: Introduction To Intracellular Lipolysismentioning

confidence: 99%

Classical and alternative roles for autophagy in lipid metabolism

Zhang

Evans

Jeong

et al. 2018

Current Opinion in Lipidology

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“…The lysosomal acid lipase (LAL) has a key role in lipid metabolism through the hydrolysis of cholesteryl esters and triglycerides in lysosomes (33). We reasoned that the LAL might be important for degradation of the eHEV membrane within the lysosome.…”

Section: Hev Released From Infected Cells Is Predominantly Quasi-envementioning

confidence: 99%

Distinct Entry Mechanisms for Nonenveloped and Quasi-Enveloped Hepatitis E Viruses

Yin

Ambardekar

et al. 2016

J Virol

214

264

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The hepatitis E virus (HEV) sheds into feces as nonenveloped virions but circulates in the blood in a membrane-associated, quasi-enveloped form (eHEV). Since the eHEV virions lack viral proteins on the surface, we investigated the entry mechanism for eHEV. We found that compared to nonenveloped HEV virions, eHEV attachment to the cell was much less efficient, requiring a longer inoculation time to reach its maximal infectivity. A survey of cellular internalization pathways identified clathrin-mediated endocytosis as the main route for eHEV entry. Unlike nonenveloped HEV virions, eHEV entry requires Rab5 and Rab7, small GTPases involved in endosomal trafficking, and blocking endosomal acidification abrogated eHEV infectivity. However, low pH alone was not sufficient for eHEV uncoating, suggesting that additional steps are required for entry. Supporting this concept, eHEV infectivity was substantially reduced in cells depleted of Niemann-Pick disease type C1, a lysosomal protein required for cholesterol extraction from lipid, or in cells treated with an inhibitor of lysosomal acid lipase. These data support a model in which the quasi-envelope is degraded within the lysosome prior to virus uncoating, a potentially novel mechanism for virus entry. IMPORTANCEThe recent discovery of quasi-enveloped viruses has shifted the paradigm of virus-host interactions. The impact of quasi-envelopment in the virus life cycle and pathogenesis is largely unknown. HEV is a highly relevant model to study these questions. HEV circulates as quasi-enveloped virions in the blood that are hidden from neutralizing antibodies. eHEV particles most likely are responsible for the cell-to-cell spread of the virus. Given the increasing concerns about persistent HEV infection and its potential for transmission via the blood supply, understanding how eHEV infects cells is important for understanding its pathogenesis and developing therapies. Our data provide evidence that eHEV uses a potentially novel mechanism for cellular entry. Several steps critical to eHEV entry were identified and may provide a basis for developing treatments for hepatitis E. Because quasienveloped viruses resemble exosomes, these data also may provide insights into the exosome-mediated intercellular communications.

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“…A high LDL-C gene score, based on the number of single nucleotide polymorphisms (SNP) known to be associated with hypercholesterolaemia, suggests a polygenic rather than a monogenic cause [30,34]. Xanthomata also occur in sitosterolaemia [35], which has a similar clinical presentation [36] and lysosomal acid lipase deficiency [37,38], although this has distinguishing features.…”

Section: Diagnosis Of Hofhmentioning

confidence: 97%

HEART UK statement on the management of homozygous familial hypercholesterolaemia in the United Kingdom

et al. 2016

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This consensus statement addresses the current three main modalities of treatment of homozygous familial hypercholesterolaemia (HoFH): pharmacotherapy, lipoprotein (Lp) apheresis and liver transplantation. HoFH may cause very premature atheromatous arterial disease and death, despite treatment with Lp apheresis combined with statin, ezetimibe and bile acid sequestrants. Two new classes of drug, effective in lowering cholesterol in HoFH, are now licensed in the United Kingdom. Lomitapide is restricted to use in HoFH but, may cause fatty liver and is very expensive. PCSK9 inhibitors are quite effective in receptor defective HoFH, are safe and are less expensive. Lower treatment targets for lipid lowering in HoFH, in line with those for the general FH population, have been proposed to improve cardiovascular outcomes. HEART UK presents a strategy combining Lp apheresis with pharmacological treatment to achieve these targets in the United Kingdom (UK). Improved provision of Lp apheresis by use of existing infrastructure for extracorporeal treatments such as renal dialysis is promoted. The clinical management of adults and children with HoFH including advice on pregnancy and contraception are addressed. A premise of the HEART UK strategy is that the risk of early use of drug treatments beyond their licensed age restriction may be balanced against risks of liver transplantation or ineffective treatment in severely affected patients. This may be of interest beyond the UK.

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

Cited by 109 publications

References 133 publications

Classical and alternative roles for autophagy in lipid metabolism

Classical and alternative roles for autophagy in lipid metabolism

Distinct Entry Mechanisms for Nonenveloped and Quasi-Enveloped Hepatitis E Viruses

HEART UK statement on the management of homozygous familial hypercholesterolaemia in the United Kingdom

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