Lipid droplets (LDs) in steroidogenic tissues have a cholesteryl ester (CE) core surrounded by a phospholipid monolayer that is coated with associated proteins. Compared with other tissues, they tend ...to be smaller in size and more numerous in numbers. These LDs are enriched with PLIN1c, PLIN2 and PLIN3. Both CIDE A and B are found in mouse ovary. Free cholesterol (FC) released upon hormone stimulation from LDs is the preferred source of cholesterol substrate for steroidogenesis, and HSL is the major neutral cholesterol esterase mediating the conversion of CEs to FC. Through the interaction of HSL with vimentin and StAR, FC is translocated to mitochondria for steroid hormone production. Proteomic analyses of LDs isolated from loaded primary ovarian granulosa cells, mouse MLTC-1 Leydig tumor cells and mouse testes revealed LD associated proteins that are actively involved in modulating lipid homeostasis along with a number of steroidogenic enzymes. Microscopy analysis confirmed the localization of many of these proteins to LDs. These studies broaden the role of LDs to include being a platform for functional steroidogenic enzyme activity or as a port for transferring steroidogenic enzymes and/or steroid intermediates, in addition to being a storage depot for CEs.
•In steroidogenic tissue: LDs are CE enriched and coated with many proteins.•HSL acts on CEs to release FC, which traffics to mitochondria for steroid production.•LDs interact with mitochondria and ER.
Obesity is the major contributing factor for the increased prevalence of type 2 diabetes (T2D) in recent years. Sustained positive influx of lipids is considered to be a precipitating factor for beta ...cell dysfunction and serves as a connection between obesity and T2D. Importantly, fatty acids (FA), a key building block of lipids, are a double‐edged sword for beta cells. FA acutely increase glucose‐stimulated insulin secretion through cell‐surface receptor and intracellular pathways. However, chronic exposure to FA, combined with elevated glucose, impair the viability and function of beta cells in vitro and in animal models of obesity (glucolipotoxicity), providing an experimental basis for the propensity of beta cell demise under obesity in humans. To better understand the two‐sided relationship between lipids and beta cells, we present a current view of acute and chronic handling of lipids by beta cells and implications for beta cell function and health. We also discuss an emerging role for lipid droplets (LD) in the dynamic regulation of lipid metabolism in beta cells and insulin secretion, along with a potential role for LD under nutritional stress in beta cells, and incorporate recent advancement in the field of lipid droplet biology.
Obesity is the major contributing factor for the increased prevalence of type 2 diabetes (T2D) in recent years. Sustained positive influx of lipids is considered to be a precipitating factor for beta cell dysfunction and serves as a connection between obesity and T2D. Importantly, fatty acids (FA), a key building block of lipids, are a double‐edged sword for beta cells. FA acutely increase glucose‐stimulated insulin secretion through cell‐surface receptor and intracellular pathways. However, chronic exposure to FA, combined with elevated glucose, impair the viability and function of beta cells in vitro and in animal models of obesity (glucolipotoxicity), providing an experimental basis for the propensity of beta cell demise under obesity in humans.
Adipose triglyceride lipase (ATGL) is the key-enzyme for the release of fatty acids (FAs) from triacylglycerol (TG) stores during intracellular lipolysis producing FAs used for energy production. ...There is growing evidence that the products and intermediates from lipolytic breakdown during the FA mobilization process also have fundamental regulatory functions affecting cell signaling, gene expression, metabolism, cell growth, cell death, and lipotoxicity. Regulation of ATGL is therefore vital for maintaining a defined balance between lipid storage and mobilization. This review addresses the regulation of ATGL activity at the post-translational level with special emphasis on protein-mediated interaction at the site of hydrolytic action, namely to the lipid droplet.
Purpose
Smaller lipid droplet morphology and GLUT 4 protein expression have been associated with greater muscle oxidative capacity and glucose uptake, respectively. The main purpose of this study was ...to determine the effect of an acute long-duration exercise bout on skeletal muscle lipid droplet morphology, GLUT4, perilipin 3, and perilipin 5 expressions.
Methods
Twenty healthy men (age 24.0 ± 1.0 years, BMI 23.6 ± 0.4 kg/m
2
) were recruited for the study. The participants were subjected to an acute bout of exercise on a cycle ergometer at 50%
V
O
2
max until they reached a total energy expenditure of 650 kcal. The study was conducted after an overnight fast.
Vastus lateralis
muscle biopsies were obtained before and immediately after exercise for immunohistochemical analysis to determine lipid, perilipin 3, perilipin 5, and GLUT4 protein contents while GLUT 4 mRNA was quantified using RT-qPCR.
Results
Lipid droplet size decreased whereas total intramyocellular lipid content tended to reduce (
p
= 0.07) after an acute bout of endurance exercise. The density of smaller lipid droplets in the peripheral sarcoplasmic region significantly increased (0.584 ± 0.04 to 0.638 ± 0.08 AU;
p
= 0.01) while larger lipid droplets significantly decreased (
p
< 0.05). GLUT4 mRNA tended to increase (
p
= 0.05). There were no significant changes in GLUT 4, perilipin 3, and perilipin 5 protein levels.
Conclusion
The study demonstrates that exercise may impact metabolism by enhancing the quantity of smaller lipid droplets over larger lipid droplets.
BACKGROUNDThe Perilipin (PLIN) family of genes were previously shown to be involved in the formation and degradation of Lipid Droplets (LDs). In addition, they may play important roles in the ...development and progression of breast cancer. However, the prognostic value of PLIN family members in breast cancer patients remains unclear. METHODSMutations and copy number alterations of PLIN family genes in breast cancer were examined using the cBioportal for Cancer Genomics. In addition, the expression patterns of PLIN family genes were explored using the UCSC Xena online tool. Finally, the Kaplan-Meier Plotter was used to investigate the prognostic value of PLIN family genes in breast cancer. RESULTSThe findings revealed a low frequency of genetic alterations and amplification was the most frequent change in the PLIN family genes. Additionally, there was an increase in the expression of Perilipin 3 (PLIN3) in breast cancer tissues compared to normal breast tissues. However, expression of the other genes in the PLIN family was significantly lower in breast cancer tissues compared to normal breast tissues. Moreover, there was an increase in the expression levels of Perilipin 1 (PLIN1), PLIN3, Perilipin 4 (PLIN4) and Perilipin 5 (PLIN5) in the luminal A and luminal B subgroups. On the other hand, the expression of Perilipin 2 (PLIN2) was elevated in the human epidermal growth factor receptor 2 (HER2) positive and basal-like subgroups. Furthermore, Kaplan-Meier Plotter analysis demonstrated that high expression of PLIN1 might predict a longer Overall Survival (OS) in patients with breast cancer while overexpression of PLIN2 indicated poor OS of breast cancer patients. CONCLUSIONThe findings from this study indicated that genes in the PLIN family were aberrantly expressed in breast cancer and may serve as novel therapeutic targets as well as prognostic biomarkers for the disease.
The ratio of free fatty acid (FFA) turnover decreases significantly with the expansion of white adipose tissue. Adipose tissue and dietary saturated fatty acid levels significantly correlate with an ...increase in fat cell size and number. Inhibition of adipose triglyceride lipase leads to an accumulation of triglyceride, whereas inhibition of hormone-sensitive lipase leads to the accumulation of diacylglycerol. The G0/G1 switch gene 2 increases lipid content in adipocytes and promotes adipocyte hypertrophy through the restriction of triglyceride turnover. Excess triacylglycerols (TAGs), sterols and sterol esters are surrounded by the phospholipid monolayer surface and form lipid droplets. Following the release of lipid droplets from endoplasmic reticulum, cytoplasmic lipid droplets increase their volume either by local TAG synthesis or by homotypic fusion. The number and the size of lipid droplet distribution is correlated with obesity. Obesity-associated adipocyte death exhibits feature of necrosis-like programmed cell death. NOD-like receptors family pyrin domain containing 3 (NLRP3) inflammasome-dependent caspase-1 activation in hypertrophic adipocytes induces obese adipocyte death by pyroptosis. Actually adipocyte death may be a prerequisite for the transition from hypertrophic to hyperplastic obesity. Major transcriptional factors, CCAAT/enhancer-binding proteins beta and delta, play a central role in the subsequent induction of critical regulators, peroxisome-proliferator-activated receptor gamma, CCAAT/enhancer-binding protein alpha and sterol regulatory element-binding protein 1, in the transcriptional control of adipogenesis in obesity.Collectively, in this chapter the concept of adipose tissue remodeling in response to adipocyte death or adipogenesis, and the complexity of lipid droplet interactions with the other cellular organelles are reviewed. Furthermore, in addition to lipid droplet growth, the functional link between the adipocyte-specific lipid droplet-associated protein and fatty acid turn-over is also debated.
Cytoplasmic lipid droplets are highly dynamic storage organelles that are critical for cellular lipid homeostasis. While the molecular details of lipid droplet dynamics are a very active area of ...investigation, this work has been primarily performed in cultured cells. Taking advantage of the powerful transgenic and in vivo imaging opportunities available in zebrafish, we built a suite of tools to study lipid droplets in real time from the subcellular to the whole organism level. Fluorescently tagging the lipid droplet-associated proteins, perilipin 2 and perilipin 3, in the endogenous loci permits visualization of lipid droplets in the intestine, liver, and adipose tissue. Using these tools, we found that perilipin 3 is rapidly loaded on intestinal lipid droplets following a high-fat meal and later replaced by perilipin 2. These powerful new tools will facilitate studies on the role of lipid droplets in different tissues, under different genetic and physiological manipulations, and in a variety of human disease models.
Fibroblast growth factor 21 (FGF21) is active in murine adipocytes and has beneficial metabolic effects in animal models of type 2 diabetes mellitus. We assessed whether FGF21 influences lipolysis in ...human adipocytes and 3T3-L1 cells. FGF21 had no short-time effect (h) while a 3-day incubation with FGF21 attenuated hormone-stimulated lipolysis. FGF21 did not influence the mRNA expression of genes involved in regulating lipolysis, but significantly reduced the expression of the lipid droplet-associated phosphoprotein perilipin without affecting differentiation. Via reduced release of fatty acids into the circulation, the anti-lipolytic effect could be a mechanism through which FGF21 promotes insulin sensitivity in man.
Variations in the perilipin (PLIN) gene have been suggested to be associated with obesity and its related alterations, but a different nutritional status seems to contribute to differences in these ...associations. In our study, we examined the association of several polymorphisms at the PLIN locus with obesity and lipid profile in children, and then analyzed the mediation of plasma leptin levels on these associations. The single-nucleotide polymorphisms (SNPs) rs894160, rs1052700, and rs2304795 in PLIN1, and rs35568725 in PLIN2, were analyzed by RT-PCR in 1264 children aged 6–8 years. Our results showed a contrasting association of PLIN1 rs1052700 with apolipoprotein (Apo) A-I levels in boys and girls, with genotype TT carriers showing significantly higher Apo A-I levels in boys and significantly lower Apo A-I levels in girls. Significant associations of the SNP PLIN2 rs35568725 with high-density lipoprotein cholesterol (HDL-cholesterol), Apo A-I, and non-esterified fatty acids (NEFA) were observed in boys but not in girls. The associations of the SNPs studied with body mass index (BMI), NEFA, and Apo A-I in boys and girls were different depending on leptin concentration. In conclusion, we describe the mediation of plasma leptin levels in the association of SNPs in PLIN1 and PLIN2 with BMI, Apo A-I, and NEFA. Different leptin levels by sex may contribute to explain the sex-dependent association of the PLIN SNPs with these variables.
Cholesterol ester droplets and steroidogenesis Kraemer, Fredric B.; Khor, Victor K.; Shen, Wen-Jun ...
Molecular and cellular endocrinology,
05/2013, Volume:
371, Issue:
1-2
Journal Article
Peer reviewed
Open access
► Cholesteryl ester-rich and triacylglycerol-rich lipid droplets have unique expression of perilipin family members. ► Vimentin is associated with lipid droplets. ► Vimentin deficiency results in ...defective ACTH-stimulated corticosterone production. ► Vimentin deficiency impairs cholesterol movement to mitochondria.
Intracellular lipid droplets (LDs) are dynamic organelles that contain a number of associated proteins including perilipin (Plin) and vimentin. Cholesteryl ester (CE)-rich LDs normally accumulate in steroidogenic cells and their mobilization is the preferred initial source of cholesterol for steroidogenesis. Plin1a, 1b and 5 were found to preferentially associate with triacylglycerol-rich LDs and Plin1c and Plin4 to associate with CE-rich LDs, but the biological significance of this remains unanswered. Vimentin null mice were found to have decreased ACTH-stimulated corticosterone levels, and decreased progesterone levels in females, but normal hCG-stimulated testosterone levels in males. Smaller LDs were seen in null cells. Lipoprotein cholesterol delivery to adrenals and ovary was normal, as was the expression of steroidogenic genes; however, the movement of cholesterol to mitochondria was reduced in vimentin null mice. These results suggest that vimentin is important in the maintenance of CE-rich LDs and in the movement of cholesterol for steroidogenesis.
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