Intracellular and Plasma Membrane Events in Cholesterol Transport and Homeostasis

Litvinov, Dmitry; Savushkin, Eugeny V.; Dergunov, Alexander D.

doi:10.1155/2018/3965054

Cited by 75 publications

(62 citation statements)

References 189 publications

(193 reference statements)

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“…The resultant CEs are stored in lipid droplets in the cytosol before being secreted (Das et al, 2014). Thus, to preserve cholesterol homeostasis, the cell maintains crosstalk between the PM, where the bulk of the cell's cholesterol resides, and the ER, where the enzymatic activities that regulate cholesterol levels reside (Litvinov et al, 2018). This crosstalk is believed to be controlled by an as-yet-unknown sensor in the ER that triggers communication between the PM and the intracellular ER regulatory pool of cholesterol where ACAT1 is located (Lange et al, 1999;Infante & Radhakrishnan, 2017).…”

Section: Introductionmentioning

confidence: 99%

“…As mentioned above, when in excess, "accessible" cholesterol in the PM cholesterol pool will be proportionally transported to the ER cholesterol pool, where it will trigger feedback responses to maintain homeostasis (Das et al, 2014;Infante & Radhakrishnan, 2017;Litvinov et al, 2018). It has been suggested that this trafficking is regulated by cholesterol-sensing proteins and/or a specific cholesterol-sensing membrane domain in the ER associated with ACAT1 (Lange et al, 1999).…”

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confidence: 99%

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The Alzheimer's disease‐associated C99 fragment of APP regulates cellular cholesterol trafficking

et al. 2020

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The link between cholesterol homeostasis and cleavage of the amyloid precursor protein (APP), and how this relationship relates to Alzheimer's disease (AD) pathogenesis, is still unknown. Cellular cholesterol levels are regulated through crosstalk between the plasma membrane (PM), where most cellular cholesterol resides, and the endoplasmic reticulum (ER), where the protein machinery that regulates cholesterol levels resides. The intracellular transport of cholesterol from the PM to the ER is believed to be activated by a lipid-sensing peptide(s) in the ER that can cluster PM-derived cholesterol into transient detergent-resistant membrane domains (DRMs) within the ER, also called the ER regulatory pool of cholesterol. When formed, these cholesterol-rich domains in the ER maintain cellular homeostasis by inducing cholesterol esterification as a mechanism of detoxification while attenuating its de novo synthesis. In this manuscript, we propose that the 99-aa C-terminal fragment of APP (C99), when delivered to the ER for cleavage by c-secretase, acts as a lipid-sensing peptide that forms regulatory DRMs in the ER, called mitochondria-associated ER membranes (MAM). Our data in cellular AD models indicates that increased levels of uncleaved C99 in the ER, an early phenotype of the disease, upregulates the formation of these transient DRMs by inducing the internalization of extracellular cholesterol and its trafficking from the PM to the ER. These results suggest a novel role for C99 as a mediator of cholesterol disturbances in AD, potentially explaining early hallmarks of the disease.

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Section: Introductionmentioning

confidence: 99%

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The Alzheimer's disease‐associated C99 fragment of APP regulates cellular cholesterol trafficking

et al. 2020

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“…We uncovered a clear separation of the samples by their location using hierarchical clustering dendrogram (Fig 3D). In BM-Ad, proteins involved in cholesterol transport (apoliproproteins APO-A2, -C1 and -C4) and hydrolysis, such NCEH1 (Neutral Cholesterol Ester Hydrolysis) and LIPA (Lipase A) (Litvinov et al, 2018), were enriched. This cholesterol-oriented metabolism in BM-Ad is strengthening by the enrichment of several proteins involved in cholesterol biosynthesis and statin pathways (Fig EV3C).…”

Section: Resultsmentioning

confidence: 99%

Yellow adipocytes comprise a new adipocyte sub-type present in human bone marrow

Attané

Estève

Chaoui

et al. 2019

Preprint

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25During energy demanding conditions, white adipocytes store triglycerides and release fatty acids through lipolysis. 26In contrast, bone marrow adipocytes (BM-Ad) increase in size during caloric restriction, suggesting this fat depot 27 exhibits precise metabolic specificity. We found subcutaneous adipocytes (SC-Ad) and BM-Ad share 28 morphological features, but possess distinct lipid metabolism. BM-Ad show enrichment in cholesterol-oriented 29 metabolism that correlates with increased free cholesterol content, while proteins involved in lipolysis were 30 downregulated. A strong down-regulation in expression of monoacylglycerol (MG) lipase was observed leading 31 to an accumulation of major MG species and accordingly the basal and induced lipolytic responses were absent in 32 BM-Ad. These features are not recapitulated in vitro using differentiated bone marrow mesenchymal stem cells. 33Since our data demonstrate that BM-Ad comprise a distinct class of adipocytes, we propose renaming them yellow 34 adipocytes. 35 36 Keywords 37Bone Marrow adipocytes / cholesterol/lipolysis / monoacylglycerol lipase / proteomic 2 and well-studied fat deposits occur in subcutaneous regions (SC-AT) and in the abdominal cavity surrounding key 3 internal organs like the pancreas and intestines (Zwick et al, 2018). Other adipose-specific deposits also form 4 around the heart, kidney, prostate in men and mammary glands in women (Zwick et al, 2018). In addition to WAT, 5 mammals also possess brown adipose tissue (BAT) located in the interscapular and supraclavicular regions, 6 representing less than 5% of the total fat mass (Leitner et al, 2017; Nedergaard et al, 2007; Saito et al, 2009; 7 Zingaretti et al, 2009). Brown adipocytes participate in non-shivering thermogenesis and possess a specific 8 morphology that includes several small lipid droplets and high mitochondria content (Bartelt & Heeren, 2014; 9 Cinti, 2001). In contrast, white adipocytes store energy as triglycerides (TG) in their unique large lipid droplet 10 (LD) after energy intake and release free fatty acids (FFA) through lipolysis in energy demanding conditions 11 (Zechner, 2015). Lipolysis occurs through a biochemical pathway that uses consecutive actions of adipose 12 triglyceride lipase (ATGL), which catalyzes the conversion of TG to diacylglycerols (DG) and hormone-sensitive 13 lipase (HSL) and hydrolyzes DAG to monoacylglycerols (MG), monoacylglycerol lipase (MAGL) and the newly 14 identified α/β hydrolase domain-containing protein 6 (ABHD6), which hydrolyzes MG to FA (Zhao et al, 2016) 15 and glycerol (Zechner, 2015). White adipocytes also have an important endocrine function as they can release 16 multiple soluble factors called adipokines, such as leptin and adiponectin (Fasshauer & Blüher, 2015). 17One intriguing adipose tissue (AT) localizes to the bone marrow called bone marrow adipose tissue (BM-AT) that 18 constitutes over 10% of the total fat mass in lean and healthy humans (Cawthorn et al, 2014). Technological 19 advances in quantitative imaging...

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“…As mentioned above, when in excess, a pool of "active" cholesterol in the PM will be proportionally transported to the ER cholesterol pool, where it will trigger feedback responses to maintain homeostasis (7)(8)(9). It has been suggested that this trafficking is regulated by cholesterolsensing proteins and/or a specific cholesterol-sensing membrane domain in the ER associated with ACAT1 (10).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, to preserve cholesterol homeostasis, the cell maintains a crosstalk between the PM, where the bulk of cholesterol resides, and the ER, where the enzymatic activities that ensure cholesterol levels reside (9). This crosstalk is believed to be controlled by an as-yet-unknown sensor in the ER that triggers the communication between the PM and the intracellular ER regulatory pool of cholesterol where ACAT1 resides, or MAM (8,10).…”

mentioning

confidence: 99%

The C99 Fragment Of App Regulates Cholesterol Trafficking

Pera

Larrea

Montesinos

et al. 2019

Preprint

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The link between cholesterol homeostasis and the cleavage of the amyloid precursor protein (APP), and their relationship to the pathogenesis of Alzheimer's disease (AD) is still unknown. Cellular cholesterol levels are regulated by a crosstalk between the plasma membrane (PM), where most of the cholesterol resides, and the endoplasmic reticulum (ER), where the protein machinery that regulates cholesterol resides. This crosstalk between PM and ER is believed to be regulated by lipid-sensing peptide(s) that can modulate the internalization of extracellular cholesterol and/or its de novo synthesis in the ER. Our data here indicates that the 99-aa C-terminal fragment of APP (C99), a cholesterolbinding peptide, regulates cholesterol trafficking between the PM and the ER. In AD models, increases in C99 provoke the upregulation of cholesterol internalization and its delivery to the ER, which in turn result into the loss of lipid homeostasis and the appearance of AD signatures, such as higher production of longer forms of amyloid b. Our data suggest a novel role of C99 as mediator of cholesterol disturbances in AD, and as a potential early hallmark of the disease.The lipid composition of cellular membranes is adjusted constantly to regulate processes such as signal transduction and trans-membrane ionic gradients (1). To support these events, a network of enzymes interconnects the metabolism of all lipids, and controls the remodeling of the membrane into functional regions (2). Often, these functional regions have the characteristics of lipid-rafts or detergent-resistant domains (2). Lipid rafts are transient membrane subregions formed by local increases in cholesterol, which interacts with sphingomyelin (SM) and saturated phospholipids to shield cholesterol from the aqueous phase (2). These local elevations in cholesterol create highly ordered membrane microdomains that passively segregate lipid-binding proteins, thereby facilitating protein-protein interaction(s) and the regulation of specific signaling pathways (2). The formation of these domains is enabled by "lipid-sensing" proteins with the capacity to bind and cluster cholesterol (3). If the lipid-sensing proteins are eliminated from that domain, the lipid rafts are abrogated by hydrolysis of the "shielding" SM via activation of sphingomyelinases (SMases) that convert SM to ceramide (4). As opposed to SM, ceramide creates an unfavorable environment for cholesterol (5), which can then become accessible for removal via esterification (4). Hence, the turnover of lipid-raft domains and their capacity to regulate signaling pathways is tightly linked to the regulation of cholesterol homeostasis. Thus, alterations in the latter would affect the regulation of lipid raft formation, and vice versa.In the cell, cholesterol is either synthesized de novo in the endoplasmic reticulum (ER) or taken up as cholesterol esters (CEs) from lipoproteins (4). The de novo synthesis of cholesterol

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Intracellular and Plasma Membrane Events in Cholesterol Transport and Homeostasis

Cited by 75 publications

References 189 publications

The Alzheimer's disease‐associated C99 fragment of APP regulates cellular cholesterol trafficking

The Alzheimer's disease‐associated C99 fragment of APP regulates cellular cholesterol trafficking

Yellow adipocytes comprise a new adipocyte sub-type present in human bone marrow

The C99 Fragment Of App Regulates Cholesterol Trafficking

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