The regulation, function, and role of lipophagy, a form of selective autophagy, in metabolic disorders

Zhang, Sheng; Peng, Xueqiang; Yang, Shuo; Li, Xinyu; Huang, Mingyao; Wei, Shibo; Liu, Jiaxing; He, Guangpeng; Zheng, Hongyu; Yang, Liang; Li, Hangyu; Fan, Qing

doi:10.1038/s41419-022-04593-3

Cited by 97 publications

(98 citation statements)

References 148 publications

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“…This supports the hypothesis that the TREM2 receptor is required for lipid droplets biogenesis and to buffer cholesterol-mediated toxicity in mouse and human microglia. Another possible interpretation of our findings, is that lysosomal dysfunction in NHD iMGLs would lead to an altered degradation of these lipidic structures [96].…”

Section: Discussionmentioning

confidence: 99%

Defects in lysosomal function and lipid metabolism in human microglia harboring a TREM2 loss of function mutation

Filipello

You

Mahali

et al. 2022

Preprint

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TREM2 is an innate immune receptor expressed by microglia in the adult brain. Homozygous TREM2 mutations cause a rare leukodystrophy, Nasu-Hakola disease (NHD). Despite extensive investigation, the role of TREM2 in NHD pathogenesis remains poorly understood. Here, we investigate the mechanisms by which a homozygous stop-gain TREM2 mutation (p.Q33X) contributes to NHD. Induced pluripotent stem cell (iPSC)-derived microglia (iMGLs) were generated from two siblings homozygous for the TREM2 p.Q33X mutation (termed NHD), one related non-carrier, and one unrelated non-carrier. Transcriptomic and biochemical analyses reveal defective activation, HLA antigen presentation, and NF-kB signaling in NHD iMGLs. Additionally, NHD iMGLs exhibited lysosomal dysfunction, downregulation of cholesterol metabolism genes, and reduced lipid droplets. These defects were validated in brain tissue from NHD patients. Thus, stem cell models reveal novel dysfunctional lysosomal pathways in NHD microglia and capture pathological processes that also occur in human brains from NHD patients.

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Section: Discussionmentioning

confidence: 99%

Defects in lysosomal function and lipid metabolism in human microglia harboring a TREM2 loss of function mutation

Filipello

You

Mahali

et al. 2022

Preprint

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“…Similarly, other damaged organelles are degraded by endoplasmic reticulum (ER)-phagy [154,155] or ribophagy [156]. Lipophagy is a type of selective autophagy where denatured lipids are stored in lipid droplets and serve as substrate for β-oxidation, contributing to the energy homeostasis [157]. Aggregated proteins, as can be observed in neurodegenerative diseases, are cleared by aggrephagy via ubiquitination and autophagosomal translocation [158].…”

Section: A Cellular Mechanism To Cope With Adverse Conditionsmentioning

confidence: 99%

Reinventing the Penumbra — the Emerging Clockwork of a Multi-modal Mechanistic Paradigm

Walther

Kirsch

Hellwig

et al. 2022

Transl. Stroke Res.

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The concept of the ischemic penumbra was originally defined as the area around a necrotic stroke core and seen as the tissue at imminent risk of further damage. Today, the penumbra is generally considered as time-sensitive hypoperfused brain tissue with decreased oxygen and glucose availability, salvageable tissue as treated by intervention, and the potential target for neuroprotection in focal stroke. The original concept entailed electrical failure and potassium release but one short of neuronal cell death and was based on experimental stroke models, later confirmed in clinical imaging studies. However, even though the basic mechanisms have translated well, conferring brain protection, and improving neurological outcome after stroke based on the pathophysiological mechanisms in the penumbra has yet to be achieved. Recent findings shape the modern understanding of the penumbra revealing a plethora of molecular and cellular pathophysiological mechanisms. We now propose a new model of the penumbra, one which we hope will lay the foundation for future translational success. We focus on the availability of glucose, the brain’s central source of energy, and bioenergetic failure as core pathophysiological concepts. We discuss the relation of mitochondrial function in different cell types to bioenergetics and apoptotic cell death mechanisms, autophagy, and neuroinflammation, to glucose metabolism in what is a dynamic ischemic penumbra.

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“…Autophagy can selectively and precisely target multiple cell compartments almost simultaneously, including mitochondria, endoplasmic reticulum, peroxisomes, nucleus, lysosomes, and even other cellular organelles such as fat droplets and accumulates, to maintain cell stability under both normal and abnormal conditions [ 13 , 14 ]. Many studies have individually examined macroautophagy, targeted autophagy, and autophagy regulators to broaden our knowledge of how autophagy functions in PC [ 15 , 16 ]. This review focuses on the role of autophagy in PC tumor formation, aggressiveness, and medicinal weaknesses.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Aspects and Molecular Targets of Autophagy to Control Pancreatic Cancer Management

et al. 2022

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Pancreatic cancer (PC) begins within the organ of the pancreas, which produces digestive enzymes, and is one of the formidable cancers for which appropriate treatment strategies are urgently needed. Autophagy occurs in the many chambers of PC tissue, including cancer cells, cancer-related fibroblasts, and immune cells, and can be fine-tuned by various promotive and suppressive signals. Consequently, the impacts of autophagy on pancreatic carcinogenesis and progression depend greatly on its stage and conditions. Autophagy inhibits the progress of preneoplastic damage during the initial phase. However, autophagy encourages tumor formation during the development phase. Several studies have reported that both a tumor-promoting and a tumor-suppressing function of autophagy in cancer that is likely cell-type dependent. However, autophagy is dispensable for pancreatic ductal adenocarcinoma (PDAC) growth, and clinical trials with autophagy inhibitors, either alone or in combination with other therapies, have had limited success. Autophagy’s dual mode of action makes it therapeutically challenging despite autophagy inhibitors providing increased longevity in medical studies, highlighting the need for a more rigorous review of current findings and more precise targeting strategies. Indeed, the role of autophagy in PC is complicated, and numerous factors must be considered when transitioning from bench to bedside. In this review, we summarize the evidence for the tumorigenic and protective role of autophagy in PC tumorigenesis and describe recent advances in the understanding of how autophagy may be regulated and controlled in PDAC.

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The regulation, function, and role of lipophagy, a form of selective autophagy, in metabolic disorders

Cited by 97 publications

References 148 publications

Defects in lysosomal function and lipid metabolism in human microglia harboring a TREM2 loss of function mutation

Defects in lysosomal function and lipid metabolism in human microglia harboring a TREM2 loss of function mutation

Reinventing the Penumbra — the Emerging Clockwork of a Multi-modal Mechanistic Paradigm

Therapeutic Aspects and Molecular Targets of Autophagy to Control Pancreatic Cancer Management

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