Duo in a Mystical Realm—Nuclear Lipid Droplets and the Inner Nuclear Membrane

Sołtysik, Kamil; Ohsaki, Yuki; Fujimoto, Toyoshi

doi:10.1177/2515256419896965

Cited by 12 publications

(14 citation statements)

References 99 publications

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“…Lipid droplets consist of neutral lipids, like triacylglycerols and cholesterol esters, coated by a phospholipid monolayer and proteins. They act as lipid reservoirs for energy production and membrane biogenesis, and are now seen as dynamic organelles that can interact with other organelles in a regulated manner [ 18 , 21 ]. Lipid droplets are found in the cytoplasm of many cells, but recent studies have also identified lipid droplets in the nucleus in several cell types, like hepatocytes and hepatocyte-derived cell lines [ 19 , 22 ].…”

Section: Nuclear Envelope and Lipid Metabolismmentioning

confidence: 99%

“…Recently, several studies have also implicated the nuclear envelope in playing active roles in lipid metabolism. These roles can be played directly through lipid metabolism enzymes situated at the nuclear envelope, by nuclear envelope proteins indirectly affecting transcription of lipidomic genes, or by a combination of these processes [16][17][18][19]. The ER is the main site of lipid synthesis in the cell, with most lipid synthesis enzymes being transmembrane proteins [17].…”

Section: Nuclear Envelope and Lipid Metabolismmentioning

confidence: 99%

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The Nuclear Envelope in Lipid Metabolism and Pathogenesis of NAFLD

Östlund

Hernandez‐Ono

Shin

2020

Biology

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Nonalcoholic fatty liver disease (NAFLD) is a burgeoning public health problem worldwide. Despite its tremendous significance for public health, we lack a comprehensive understanding of the pathogenic mechanisms of NAFLD and its more advanced stage, nonalcoholic steatohepatitis (NASH). Identification of novel pathways or cellular mechanisms that regulate liver lipid metabolism has profound implications for the understanding of the pathology of NAFLD and NASH. The nuclear envelope is topologically connected to the ER, where protein synthesis and lipid synthesis occurs. Emerging evidence points toward that the nuclear lamins and nuclear membrane-associated proteins are involved in lipid metabolism and homeostasis. We review published reports that link these nuclear envelope proteins to lipid metabolism. In particular, we focus on the recent work demonstrating the essential roles for the nuclear envelope-localized torsinA/lamina-associated polypeptide (LAP1) complex in hepatic steatosis, lipid secretion, and NASH development. We also discuss plausible pathogenic mechanisms by which the loss of either protein in hepatocytes leads to hepatic dyslipidemia and NASH development.

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Section: Nuclear Envelope and Lipid Metabolismmentioning

confidence: 99%

Section: Nuclear Envelope and Lipid Metabolismmentioning

confidence: 99%

The Nuclear Envelope in Lipid Metabolism and Pathogenesis of NAFLD

Östlund

Hernandez‐Ono

Shin

2020

Biology

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“…Consequently, our understanding of LD biology has evolved from that of lipid storage depots to one of dynamic organelles that functionally intersect with many cellular metabolic and signalling activities. This has been further challenged by the discovery and characterization of nuclear lipid droplets (nLD) that share features with their cytosolic counterparts but are unique in terms of biogenesis, their associated proteins and lipids, and ultimately their cellular activities (Sołtysik et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Running ‘LAPS’ Around nLD: Nuclear Lipid Droplet Form and Function

McPhee

Salsman

Foster

et al. 2022

Front. Cell Dev. Biol.

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The nucleus harbours numerous protein subdomains and condensates that regulate chromatin organization, gene expression and genomic stress. A novel nuclear subdomain that is formed following exposure of cells to excess fatty acids is the nuclear lipid droplet (nLD), which is composed of a neutral lipid core surrounded by a phospholipid monolayer and associated regulatory and lipid biosynthetic enzymes. While structurally resembling cytoplasmic LDs, nLDs are formed by distinct but poorly understood mechanisms that involve the emergence of lipid droplets from the lumen of the nucleoplasmic reticulum and de novo lipid synthesis. Luminal lipid droplets that emerge into the nucleoplasm do so at regions of the inner nuclear membrane that become enriched in promyelocytic leukemia (PML) protein. The resulting nLDs that retain PML on their surface are termed lipid-associated PML structures (LAPS), and are distinct from canonical PML nuclear bodies (NB) as they lack key proteins and modifications associated with these NBs. PML is a key regulator of nuclear signaling events and PML NBs are sites of gene regulation and post-translational modification of transcription factors. Therefore, the subfraction of nLDs that form LAPS could regulate lipid stress responses through their recruitment and retention of the PML protein. Both nLDs and LAPS have lipid biosynthetic enzymes on their surface suggesting they are active sites for nuclear phospholipid and triacylglycerol synthesis as well as global lipid regulation. In this review we have summarized the current understanding of nLD and LAPS biogenesis in different cell types, their structure and composition relative to other PML-associated cellular structures, and their role in coordinating a nuclear response to cellular overload of fatty acids.

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“…LDs are often found in the cytoplasm adjacent to the outer nuclear membrane, which is continuous with ER membranes [ 21 ]. However, several recent studies have shown that LDs also occur inside nuclei [ 22 ]. The function(s) of nuclear lipid droplets (nLDs) are not known, but possibilities include providing lipid for the growth of nuclear membranes, storage sites for normal proteins or for unfolded, hydrophobic proteins, and as sites for the detoxification of hydrophobic substances [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

“…The function(s) of nuclear lipid droplets (nLDs) are not known, but possibilities include providing lipid for the growth of nuclear membranes, storage sites for normal proteins or for unfolded, hydrophobic proteins, and as sites for the detoxification of hydrophobic substances [ 23 ]. Few or no nLDs have been observed in some types of cells that contain abundant cLDs, such as adipocytes, or stimulated fibroblasts, but nLDs have been found in multiple types of liver-derived cell lines [ 24 ] and in human patients with fatty-liver disease, or hepatic steatosis [ 22 ]. Obesity-related hepatic steatosis is estimated to affect 20–30% of the population of North America, including very high percentages of patients with morbid obesity or type 2 diabetes (reviewed in [ 20 ]).…”

Section: Introductionmentioning

confidence: 99%

Nuclear lipid droplets and nuclear damage in Caenorhabditis elegans

2021

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Fat stored in the form of lipid droplets has long been considered a defining characteristic of cytoplasm. However, recent studies have shown that nuclear lipid droplets occur in multiple cells and tissues, including in human patients with fatty liver disease. The function(s) of stored fat in the nucleus has not been determined, and it is possible that nuclear fat is beneficial in some situations. Conversely, nuclear lipid droplets might instead be deleterious by disrupting nuclear organization or triggering aggregation of hydrophobic proteins. We show here that nuclear lipid droplets occur normally in C. elegans intestinal cells and germ cells, but appear to be associated with damage only in the intestine. Lipid droplets in intestinal nuclei can be associated with novel bundles of microfilaments (nuclear actin) and membrane tubules that might have roles in damage repair. To increase the normal, low frequency of nuclear lipid droplets in wild-type animals, we used a forward genetic screen to isolate mutants with abnormally large or abundant nuclear lipid droplets. Genetic analysis and cloning of three such mutants showed that the genes encode the lipid regulator SEIP-1/seipin, the inner nuclear membrane protein NEMP-1/Nemp1/TMEM194A, and a component of COPI vesicles called COPA-1/α-COP. We present several lines of evidence that the nuclear lipid droplet phenotype of copa-1 mutants results from a defect in retrieving mislocalized membrane proteins that normally reside in the endoplasmic reticulum. The seip-1 mutant causes most germ cells to have nuclear lipid droplets, the largest of which occupy more than a third of the nuclear volume. Nevertheless, the nuclear lipid droplets do not trigger apoptosis, and the germ cells differentiate into gametes that produce viable, healthy progeny. Thus, our results suggest that nuclear lipid droplets are detrimental to intestinal nuclei, but have no obvious deleterious effect on germ nuclei.

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Duo in a Mystical Realm—Nuclear Lipid Droplets and the Inner Nuclear Membrane

Cited by 12 publications

References 99 publications

The Nuclear Envelope in Lipid Metabolism and Pathogenesis of NAFLD

The Nuclear Envelope in Lipid Metabolism and Pathogenesis of NAFLD

Running ‘LAPS’ Around nLD: Nuclear Lipid Droplet Form and Function

Nuclear lipid droplets and nuclear damage in Caenorhabditis elegans

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