Accumulation Of Lipid Droplets Research Articles

Reducing microglial lipid load enhances β amyloid phagocytosis in an Alzheimer’s disease mouse model

Macrophages accumulate lipid droplets (LDs) under stress and inflammatory conditions. Despite the presence of LD-loaded macrophages in many tissues, including the brain, their contribution to neurodegenerative disorders remains elusive. This study investigated the role of lipid metabolism in Alzheimer’s disease (AD) by assessing the contribution of LD-loaded brain macrophages, including microglia and border-associated macrophages (BAMs), in an AD mouse model. Particularly, BAMs and activated CD11c + microglia localized near β amyloid (Aβ) plaques exhibited a pronounced lipid-associated gene signature and a high LD load. Having observed that elevated intracellular LD content correlated inversely with microglial phagocytic activities, we subsequently inhibited LD formation specifically in CX3CR1 + brain macrophages using an inducible APP-KI/ Fit2 i Δ M φ transgenic mouse model. We demonstrated that reducing LD content in microglia and CX3CR1 + BAMs remarkably improved their phagocytic ability. Furthermore, lowering microglial LDs consistently enhanced their efferocytosis capacities and notably reduced Aβ deposition in the brain parenchyma. Therefore, mitigating LD accumulation in brain macrophages provides perspectives for AD treatment.

Acetoacetate Ameliorates Hepatic Fibrosis by Targeting Peroxisome Proliferator-Activated Receptor Gamma to Restore Lipid Droplets in Activated Hepatic Stellate Cells

Background: Hepatic fibrosis (HF) is a progressive liver disease characterized by the activation of hepatic stellate cells (HSCs) and changes in lipid metabolism. Abnormal ketone body (KD) levels, including acetoacetate (AcAc) and beta-hydroxybutyrate (BHB), have been observed in patients with HF, but the mechanisms linking ketone metabolism to fibrosis progression remain unclear. Objectives: This study aimed to investigate the role of AcAc in modulating HSCs activation and its potential mechanisms in HF. Methods: We examined the effects of AcAc on HSCs activation by Western blot analysis and RT-PCR both in vivo and in vitro. The impact of AcAc on lipid droplet accumulation in HSCs was assessed using total cholesterol (TC), triglyceride (TG), and Retinol (RET) kits, along with Nile Red and Oil Red O staining. RT-PCR screening was performed to analyze the expression of genes involved in lipid droplet formation and lipid metabolism. Results: Our findings show that AcAc inhibited HSCs activation by restoring LD levels. Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) was identified as a key regulator through gene screening. AcAc primarily regulated PPARγ expression, and knocking down PPARγ significantly aggravated HF progression. Conclusions: The ability of AcAc to restore LD levels and regulate PPARγ suggests that it may represent a promising therapeutic strategy for HF by inhibiting HSCs activation.

Cyanidin 3-O-β-d-Glucoside from Black Bean Inhibits the Migration of Vascular Smooth Muscle Cells in the Presence of Adipocytes

Background The potential of cyanidin 3- O-β-D-glucoside (C3G), known for its anti-obesity and anti-diabetic properties, in suppressing arteriosclerosis progression remains unexplored. Purpose This study aimed to elucidate whether C3G prevents or ameliorates arteriosclerosis by investigating the effects of C3G on the transformation, proliferation, and migration of vascular smooth muscle cells (SMCs). Herein, we evaluated the effects of C3G on the migratory ability of SMCs in the presence of adipocytes. Materials and Methods SMCs and 3T3-L1 adipocytes were cocultured in a Boyden chamber, with SMCs positioned in the upper chamber and pre-adipocytes in the lower chamber. Pre-adipocytes were initially seeded in the lower chamber and prompted to undergo differentiation over days 0, 2, 4, 6, and 8. SMCs were seeded in the upper chamber. The quantification of cells that migrated through the membrane was carried out. The migratory potential of SMCs within the SMC/adipocyte coculture (SACC) setup was assessed by placing the upper chamber into wells containing adipocytes, with or without 0.1% C3G. Results The findings indicated that the accumulation of lipid droplets in adipocytes increased as the differentiation stage progressed. The amount of lipid droplets that accumulated upon the addition of C3G was significantly lower than that in the control. C3G was found to inhibit the active form of plasminogen activator inhibitor-1 (PAI-1) while enhancing the levels of the anti-inflammatory adipocytokine adiponectin. In the SACC, SMC migration increased alongside lipid droplet accumulation in adipocytes. We revealed that C3G decreased the active form of PAI-1 in the SACC and suppressed vascular SMC migration. Conclusion C3G inhibited the migration of SMCs in the SACC, highlighting its potential as a compound that can prevent arteriosclerosis and thrombus formation progression by suppressing hyperplasia of the vascular intima.

Coconut oil reduces steroidogenic enzymes and imbalances estrogen receptors in the adrenal cortex of Mongolian gerbils.

This study aims to verify the effects of prolonged ingestion of coconut oil on the adrenal glands of Mongolian gerbils. Mongolian gerbils were used as an experimental model due to the morphological similarity of the adrenal glands to those of primates. Male Mongolian gerbils, 3 months of age, were divided into three experimental groups (n=12): an intact control group, which received no treatment, a gavage control group, which received 0.1ml of water daily by gavage, and a coconut oil-treated group, which received 0.1ml of coconut oil daily for 12 months. The results showed that prolonged consumption of coconut oil caused an increase in cell area and thickness of the zona reticularis and the accumulation of lipid droplets, as well as reducing the amount of steroidogenic enzymes, such as CYP17, 3BHSD, and 17BHSD. It was also observed that the oil increased the expression of estrogen receptor alpha and their isoforms. These alterations allow us to conclude that changes in the lipid diet can cause alterations in the morphophysiology of the adrenal gland and, consequently, impact its functionality.

Vasoactive intestinal peptide induces metabolic rewiring of human-derived cytotrophoblast cells to promote cell migration.

The placenta has an extraordinary metabolic rate with high oxygen consumption. Extravillous cytotrophoblast cells (EVT) metabolism and function are critical to sustain their invasive phenotype supporting fetal development. Deficient EVT function underlies pregnancy complications as preeclampsia (PE) and fetal growth restriction (FGR). The vasoactive intestinal peptide (VIP) promotes human cytotrophoblast cell migration and invasion through mTOR signaling pathways suggesting its crucial role during placentation. Here we explored fatty acid uptake as well as lipid and glucose metabolism in human-derived cytotrophoblast cell function upon VIP stimulation. We found that VIP induced long chain fatty acid (LCFAs) uptake along with the expression of FATP2 transporter, CPT1 fatty acid oxidation (FAO)-rate limiting step importer, and lipid droplet accumulation. VIP induced the expression of glucose 6-P-dehydrogenase, a rate-limiting enzyme of the pentose phosphate pathway (PPP) and pyruvate dehydrogenase complex enzyme DLAT E2, without altering lactate secretion. This metabolic rewiring of trophoblast cells induced by VIP takes place without compromising mitochondrial function or reactive oxygen species (ROS) production. Moreover, cytotrophoblast cell migration induced by VIP required the three glycolysis, oxidative phosphorylation (OXPHOS) and FAO pathways. Our results provide evidence supporting VIP as a metabolic regulatory peptide in cytotrophoblast cells sustaining proper placentation and fetal growth.

Modulation of the local angiotensin II: Suppression of ferroptosis and radiosensitivity in nasopharyngeal carcinoma via the HIF-1α-HILPDA axis.

Radiotherapy presents a curative approach for nasopharyngeal carcinoma (NPC); however, the cellular radiosensitivity heterogeneity limits its efficacy. Thus, investigating the specific mechanisms of radioresistance in NPC is crucial for identifying and employing effective radiosensitizing agents to enhance treatment success. Radioresistant NPC cell lines HONE1-RR and SUNE1-RR were established. Quantitative reverse transcription-PCR (qRT-PCR), western blot, and enzyme-linked immuno sorbent assay (ELISA) were employed to detect the activation of the angiotensinogen (AGT) and local angiotensin II (Ang II). Transmission electron microscopy, ferrous ion detection, and lipid oxidation levels were utilized to detect radiation-induced ferroptosis in NPC. Bioinformatics analysis, along with qRT-PCR, western blotting, co-immunoprecipitation, and dual-luciferase assays were employed to explore downstream mechanisms. Colony formation assay, Cell Counting Kit-8 (CCK-8) assay, and a nude mouse xenograft model were utilized to assess NPC radiosensitivity. The expression of AGT, hypoxia-inducible factor-1 alpha (HIF-1α), hypoxia-inducible lipid droplet-associated protein (HILPDA), and glutathione peroxidase 4 (GPX4) in NPC tissues was detected through immunohistochemistry. Activation of local Ang II was revealed to play a critical role in driving radioresistance in NPC cells modulating ferroptosis. This local Ang II established a positive feedback loop with HIF-1α through two parallel pathways; Ang II stabilizes HIF-1α by activating the MAPK pathway, and AGT directly binds HIF-1α to prevent its degradation. This AGT-HIF-1α loop regulated NPC cell ferroptosis via transcriptional regulation of HILPDA expression. Moreover, the co-administration of Ang II receptor antagonist (ARB) and ferroptosis inducers markedly increased NPC radiosensitivity.Additionally, the expression of AGT, HIF-1α, and HILPDA was closely correlated with the intensity of ferroptosis, radiosensitivity, and prognosis in NPC. Our findings suggest that the AGT-HIF-1α-HILPDA pathway promotes radioresistance in NPC by enhancing lipid droplet accumulation, thereby suppressing ferroptosis. Targeting local Ang II alongside ferroptosis induction offers a promising strategy to improve radiosensitivity in NPC.

Upregulation of LXRβ/ABCA1 pathway alleviates cochlear hair cell senescence of C57BL/6J mice via reducing lipid droplet accumulation.

Senescence and loss of cochlear hair cells is an important pathologic basis of age-related hearing loss. Lipid droplet accumulation has previously been shown to play an important role in neurodegeneration; however, its role in age-related hearing loss has not yet been investigated. LXRβ/ABCA1 is a key pathway that regulates lipid metabolism, while its dysfunction can cause abnormal accumulation of lipid droplets in neurons, leading to neurodegeneration. In this study, we found that decreased expression of LXRβ/ABCA1, elevated levels of lipid droplet accumulation, and increased activation of the NLRP3 inflammasome were demonstrated in senescent cochlear hair cells in both animal and cellular models of age-related hearing loss. We then manipulated the LXRβ/ABCA1 pathway transduction of cochlear hair cells. Upregulation of LXRβ/ABCA1 in senescent hair cells was found to reduce the accumulation of lipid droplets, inhibit NLRP3 inflammasome activation, and ultimately alleviate cochlear hair cell senescence. In our study, we also found that NLRP3 inflammasome activation can abrogate the alleviated effect of LXRβ/ABCA1 pathway on the senescence of cochlear hair cells but did not affect the expression of LXRβ/ABCA1.Our study are the first to demonstrate that abnormal lipid droplet accumulation and decreased LXRβ/ABCA1 pathway are observed in cochlear hair cells following the occurrence of age-related hearing loss. Upregulation of LXRβ/ABCA1 in senescent cochlear hair cells can reduce lipid droplet accumulation in cochlear hair cells and alleviate their senescence, which may be related to the inhibition of NLRP3 inflammasome activation. These findings provide potential targets for the treatment of age-related hearing loss.

The cholesterol metabolite 25-hydroxycholesterol suppresses porcine deltacoronavirus via lipophagy inhibition and mTORC1 modulation

25-Hydroxycholesterol (25HC) is a hydroxylated cholesterol with multiple antiviral activities, however, little is known about the mechanisms by which 25HC correlates antiviral ability with lipid droplet (LD) dynamic balance to ensure cholesterol homeostasis. In the present study, 25HC was applied to porcine deltacoronavirus (PDCoV)-infected LLC-PK1 (Lilly Laboratories Culture-Porcine Kidney 1) cells and piglets to explore its antiviral capacity and underlying mechanism. The results revealed that 25HC decreased free cholesterol (FC) levels but increased triglyceride (TG) levels in PDCoV-infected cells and piglets. The accumulation of LDs induced by oleic acid (OA) impedes PDCoV replication. In addition, 25HC administration increases LD accumulation and declines protein expression associated with lipophagy and lysosomes to facilitate LD accumulation. Moreover, 25HC inhibited TFEB (transcription factor-EB) expression, blocked its translocation into the nucleus and reversed Mechanistic Target of Rapamycin Complex 1 (mTORC1) activity, which in turn hindered lipophagy and PDCoV replication. Additionally, 25HC treatment ameliorated the clinical symptoms and intestinal injury of PDCoV-infected piglets. These findings reveal the beneficial effect of lipophagy on PDCoV infection and uncover the antiviral mechanism of 25HC, by which lipophagy and mTOR activity are tightly controlled by 25HC.Graphical

Estrogen-dependent activation of TRX2 reverses oxidative stress and metabolic dysfunction associated with steatotic disease

Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses a spectrum of hepatic disorders, ranging from simple steatosis to steatohepatitis, with the most severe outcomes including cirrhosis, liver failure, and hepatocellular carcinoma. Notably, MASLD prevalence is lower in premenopausal women than in men, suggesting a potential protective role of estrogens in mitigating disease onset and progression. In this study, we utilized preclinical in vitro models—immortalized cell lines and hepatocyte-like cells derived from human embryonic stem cells—exposed to clinically relevant steatotic-inducing agents. These exposures led to lipid droplet (LD) accumulation, increased reactive oxygen species (ROS) levels, and mitochondrial dysfunction, along with decreased expression of markers associated with hepatocyte functionality and differentiation. Estrogen treatment in steatotic-induced liver cells resulted in reduced ROS levels and LD content while preserving mitochondrial integrity, mediated by the upregulation of mitochondrial thioredoxin 2 (TRX2), an antioxidant system regulated by the estrogen receptor. Furthermore, disruption of TRX2, either pharmacologically using auranofin or through genetic interference, was sufficient to counteract the protective effects of estrogens, highlighting a potential mechanism through which estrogens may prevent or slow MASLD progression.

Ovarian premature aging: VIP as key regulator of fibro-inflammation and foamy macrophages generation.

Ovarian aging is associated with fibro-inflammation, contributing to the decline in oocyte count and quality. Given the immunomodulatory properties of the vasoactive intestinal peptide (VIP) in the reproductive tract, we investigated its role in maintaining ovarian immune homeostasis and preventing premature aging. We evaluated young VIP knockout (KO) mice, comparing them to young wild type (WT) females, for signs of premature aging. Histological staining revealed aberrant ovarian morphology in VIP KO mice, characterized by increased atretic follicles and decreased ovarian reserve compared to WT controls. Moreover, VIP KO ovaries showed reduced vascularization, increased collagen deposition and elevated ROS and IL-1β levels. Foamy macrophages were significantly predominant, indicating premature aging in young VIP KO ovaries. To determine potential mechanisms behind these pathogenic changes, we conditioned peritoneal macrophages from young WT or VIP KO mice in vitro with ovarian-conditioned media from young WT or VIP KO mice to mimic the respective ovarian microenvironment. When WT or VIP KO peritoneal macrophages were conditioned with ovarian media from their respective genotypes, lipid droplet accumulation increased compared to control medium. In cross-genotype experiments, WT macrophages conditioned with media from VIP KO ovaries selectively accumulated higher levels of lipid droplets, whereas no differences were observed in VIP KO macrophages conditioned with WT ovarian media. This suggests that VIP KO macrophages are uniquely sensitized to the inflammatory environment of VIP KO ovaries, implicating both ovarian factors and macrophage status. These findings highlight the role of VIP in preventing fibro-inflammation, thereby preserving ovarian health and preventing premature aging.

Cold induces brain region-selective cell activity-dependent lipid metabolism.

It has been well documented that cold is an enhancer of lipid metabolism in peripheral tissues, yet its effect on central nervous system lipid dynamics is underexplored. It is well recognized that cold acclimations enhance adipocyte functions, including white adipose tissue lipid lipolysis and beiging, and brown adipose tissue thermogenesis in mammals. However, it remains unclear whether and how lipid metabolism in the brain is also under the control of ambient temperature. Here, we show that cold exposure predominantly increases the expressions of the lipid lipolysis genes and proteins within the paraventricular nucleus of the hypothalamus (PVH) in male mice. Mechanistically, by using innovatively combined brain-region selective pharmacology and in vivo time-lapse photometry monitoring of lipid metabolism, we find that cold activates cells within the PVH and pharmacological inactivation of cells blunts cold-induced effects on lipid peroxidation, accumulation of lipid droplets, and lipid lipolysis in the PVH. Together, these findings suggest that PVH lipid metabolism is cold sensitive and integral to cold-induced broader regulatory responses.

Cold induces brain region-selective cell activity-dependent lipid metabolism

It has been well documented that cold is an enhancer of lipid metabolism in peripheral tissues, yet its effect on central nervous system lipid dynamics is underexplored. It is well recognized that cold acclimations enhance adipocyte functions, including white adipose tissue lipid lipolysis and beiging, and brown adipose tissue thermogenesis in mammals. However, it remains unclear whether and how lipid metabolism in the brain is also under the control of ambient temperature. Here, we show that cold exposure predominantly increases the expressions of the lipid lipolysis genes and proteins within the paraventricular nucleus of the hypothalamus (PVH) in male mice. Mechanistically, by using innovatively combined brain-region selective pharmacology and in vivo time-lapse photometry monitoring of lipid metabolism, we find that cold activates cells within the PVH and pharmacological inactivation of cells blunts cold-induced effects on lipid peroxidation, accumulation of lipid droplets, and lipid lipolysis in the PVH. Together, these findings suggest that PVH lipid metabolism is cold sensitive and integral to cold-induced broader regulatory responses.

Inhibition of CD36 ameliorates mouse spinal cord injury by accelerating microglial lipophagy.

Spinal cord injury (SCI) is a serious trauma of the central nervous system (CNS). SCI induces a unique lipid-dense environment that results in the deposition of large amounts of lipid droplets (LDs). The presence of LDs has been shown to contribute to the progression of other diseases. Lipophagy, a selective type of autophagy, is involved in intracellular LDs degradation. Fatty acid translocase CD36, a multifunctional transmembrane protein that facilitates the uptake of long-chain fatty acids, is implicated in the progression of certain metabolic diseases, and negatively regulates autophagy. However, the precise mechanisms of LDs generation and degradation in SCI, as well as whether CD36 regulates SCI via lipophagy, remain unknown. In this study, we investigated the role of LDs accumulation in microglia for SCI, as well as the regulatory mechanism of CD36 in microglia lipophagy during LDs elimination in vivo and in vitro. SCI was induced in mice by applying moderate compression on spina cord at T9-T10 level. Locomotion recovery was evaluated at days 0, 1, 3, 7 and 14 following the injury. PA-stimulated BV2 cells wasestablished as the in vitro lipid-loaded model. We observed a marked buildup of LDs in microglial cells at the site of injury post-SCI. More importantly, microglial cells with excessive LDs exhibited elevated activation and stimulated inflammatory response, which drastically triggered the pyroptosis of microglial cells. Furthermore, we found significantly increased CD36 expression, and the breakdown of lipophagy in microglia following SCI. Sulfo-N-succinimidyl oleate sodium (SSO), a CD36 inhibitor, has been shown to promote the lipophagy of microglial cells in SCI mice and PA-treated BV2 cells, which enhanced LDs degradation, ameliorated inflammatory levels and pyroptosis of microglial cells, and ultimately promoted SCI recovery. As expected, inhibition of lipophagy with Baf-A1 reversed the effects of SSO. We conclude that microglial lipophagy is essential for the removal of LDs during SCI recovery. Our research implies that CD36 could be a potential therapeutic target for the treatment and management of SCI.

Effect of afzelin on inflammation and lipogenesis in particulate matter-stimulated C. acnes-treated SZ95 sebocytes

BackgroundAfzelin, a flavonoid (kaempferol 3-O-α-L-rhamnopyranoside) isolated from Thesium chinense, is known for its potent anti-inflammatory properties. However, its effects on the molecular aspects of inflammation and lipogenesis in SZ95 sebocytes has not been investigated.ObjectiveThis study aimed to (i) investigate inflammatory and sebum secretion changes when a Cutibacterium acnes-treated immortalized human sebocyte cell line (SZ95) is exposed to particulate matter (PM) and (ii) examine the effects of afzelin on these.MethodsTo investigate the effect of afzelin on PM- and C. acnes-treated SZ95 sebocytes, we injected heat-killed C. acnes into SZ95 cells to induce acne-like status. Thereafter, the SZ95 sebocytes were treated with PM and subsequently with afzelin. The gene expression profile was determined using real-time polymerase chain reaction analysis, and protein expression was confirmed via western blotting and immunofluorescence. Intracellular lipid droplet formation was investigated using Nile Red O staining.ResultsPM treatment upregulated the mRNA and protein expression levels of inflammatory cytokine and lipogenic genes in C. acnes-treated SZ95 sebocytes. Furthermore, intracellular lipid-droplet accumulation increased when C. acnes-stimulated SZ95 cells were exposed to PM. Interestingly, the upregulated inflammatory and lipogenic gene expression induced by C. acnes and PM was attenuated by afzelin treatment.ConclusionsThis study's findings indicate that PM potentially aggravates acne by acting on both inflammation and sebum secretion. They also reveal afzelin's ability to suppress these phenomena by not only suppressing inflammatory cytokine expression but also inhibiting sebogenesis. These findings confirm afzelin's potential therapeutic role in improving PM-exacerbated acne.

Bisphenol A attenuates testosterone synthesis via increasing apolipoprotein A1-mediated reverse cholesterol transport in mice

Bisphenol A (BPA), a widely used chemical compound in plastic manufacturing, has become ubiquitous in the environment. Previous studies have highlighted its adverse effects on reproductive function, as BPA exposure reduces testosterone levels. Cholesterol is involved in testosterone synthesis in Leydig cells. However, research on the mechanisms by which BPA affects testosterone synthesis from the perspective of reverse cholesterol transport (RCT) remains limited. This study aimed to investigate the effects of BPA on cholesterol levels, lipid droplet accumulation, and testosterone synthesis in TM3 cells and mice via Apolipoprotein A1 (APOA1)-mediated RCT. Adult male mice were treated by intraperitoneal injection of corn oil containing BPA (20 mg/kg) for 7 days. Testes were collected for protein extraction, RNA extraction, Oil red O staining or for Biochemical analysis. Serums were collected for detection of testosterone levels. flow cytometry, CCK8 assay, immunofluorescence or Filipin III staining was used to detect the effect of BPA on the TM3 cells. It was observed that serum and testicular testosterone levels were drastically reduced in BPA-treated mice. Moreover, lipid droplets accumulation and testicular total (TC) and free cholesterol (FC) levels were reduced in the mouse testes. Conversely, testicular high-density lipoprotein (HDL) content was partially elevated. Furthermore, BPA markedly enhanced Apoa1 mRNA and protein expression in the mouse model. Notably, BPA significantly upregulated Apoa1 mRNA and protein level, reduced cholesterol levels and lipid droplets accumulation, and attenuated testosterone synthesis in TM3 cells. In addition, exogenous supplement with 22-hydoxycholesterol promoted testosterone synthesis and alleviated the inhibitory effect of BPA on testosterone synthesis. Taken together, these results suggest that BPA upregulates APOA1 expression, enhances RCT, and ultimately reduces TC and FC levels in the testis. This cholesterol reduction likely led to testosterone synthesis disorders in the model, indicating that BPA inhibits testosterone synthesis in mice by disrupting cholesterol transport.

Perilipin2-dependent lipid droplets accumulation promotes metastasis of oral squamous cell carcinoma via epithelial-mesenchymal transition

Emerging evidence shows that lipid metabolic reprogramming plays a vital role in tumor metastasis. The effect and mechanism of fatty acids and lipid droplets (LDs), the core products of lipid metabolism, on the metastasis of oral squamous cell carcinoma (OSCC), need further exploration. In this study, the influence of palmitic acid (PA) and oleic acid (OA) on the migration and invasion ability of OSCC cells was determined by in vitro experiments. Genetic manipulation of PLIN2 was performed to explore its effect on the accumulation of LDs and OSCC metastasis. Possible mechanisms of these biological effects were clarified by detecting the levels of epithelial-mesenchymal transition (EMT) markers and phosphatidylinositol 3-kinase (PI3K) pathway proteins as well as conducting various bioinformatics analyses. The results indicated that PA/OA promoted the migration and invasion of OSCC cells and induced PLIN2-dependent LDs accumulation in vitro. Knockdown of PLIN2 inhibited the LDs accumulation and the migration and invasion of OSCC cells in vitro, while overexpression of PLIN2 enhanced those of OSCC cells in vitro and also promoted the metastasis of OSCC in vivo. Besides, PLIN2 up-regulation activated the PI3K pathway and subsequently enhanced EMT in OSCC cells in vitro. OSCC patients with higher PLIN2 expression possessed poorer prognosis and higher sensitivity to chemotherapy drugs (1S,3 R)-RSL3 and ML-210. In conclusion, PLIN2-dependent LDs accumulation could promote the metastasis of OSCC cells by regulating EMT. PLIN2 might be a potential therapeutic target for OSCC patients, especially those with obesity.

Mechanisms of combined deer antler polysaccharides and postbiotics supplementation for regulating obesity in mice

Objective: This study investigated the mechanisms related to lipid metabolism regulation after combined supplementation with deer antler polysaccharides and postbiotics. Methods: Thirty-two male mice were divided into high-fat diet, HD + deer antler polysaccharides, HD + Bacillus coagulans postbiotics, and HD + deer antler polysaccharides + B. coagulans postbiotics groups. The diets contained 60% fat. After 9 weeks, the effects of deer antler polysaccharides and postbiotics on lipid metabolism were assessed through blood biochemical, histological tissue staining, and polymerase chain reaction analyses. Results: Supplementation with deer antler polysaccharides and postbiotics significantly inhibited weight gain in obese mice, reduced serum total cholesterol, triglyceride, and low-density lipoprotein levels and markedly increased the serum high-density lipoprotein level. Additionally, hepatic lipid droplet accumulation and adipocyte hypertrophy improved. The expressions of the lipid synthesis genes, sterol regulatory element-binding protein 1 (i.e. SREBP-1c), and fatty acid synthase (i.e. FAS), significantly decreased, while peroxisome proliferator-activated receptor alpha (i.e. PPAR-α) and acyl-CoA oxidase 1 (i.e. ACOX1) expression significantly increased. The expressions of the inflammation-related genes, tumor necrosis factor-alpha (i.e. TNF-α), interleukin (IL)-6, and IL-1 also significantly decreased. Conclusion: Thus, combined deer antler polysaccharides and postbiotic supplementation regulated obesity in mice, potentially by modulating lipid synthesis and inflammation-related gene expression.

Unveiling Lipid Droplet Transport Dynamics as Biomarkers of Senescence Using Label-Free, Time-Lapse Holotomography.

Accumulation and density of lipid droplets (LDs) in cells have been identified as a potential biomarker to detect senescent cells. However, their intracellular dynamic transport and alterations during senescence remain largely unclear. To address this knowledge gap, senescence was induced in human microglia cells using hydrogen peroxide (H2O2) to investigate both short-term and long-term effects of H2O2 treatment on LD dynamics. We captured time-lapse holotomograms of LDs using label-free refractive index (RI)-based holotomography and quantified 11 dynamic parameters of LDs through single-particle tracking. These quantified parameters were then compared across healthy cells, short-term H2O2-treated pre-senescent cells (H2O2-treated cells), and long-term H2O2-induced senescent cells (senescent cells). The results revealed that LD dynamics are significantly altered in both H2O2-treated pre-senescent cells and H2O2-induced senescent cells, though with differing trends. Healthy cells exhibited higher values in all LD dynamic parameters compared to senescent cells, with the exception of the mean directional change rate, which is lower. In addition, H2O2-treated cells showed higher values in dynamic parameters such as total displacement, mean straight-line velocity, and confinement ratio compared to healthy and senescent cells, due to the observed linear migration of LDs during H2O2 treatment. We found that the altered movement of LDs is closely related to H2O2-induced damage to microtubule networks. These findings suggest that altered LD dynamics, along with associated molecules and pathways, may serve as potential biomarkers for identifying senescent cells, thereby aiding in the development of novel therapeutic targets and senolytics.

Acute lipid droplet accumulation induced by the inhibition of the phospholipase DDHD2 does not affect the level, solubility, or phosphoserine-129 status of α-synuclein.

α-Synuclein (αS) is a 140 amino-acid neuronal protein highly enriched in presynaptic nerve terminals. Its progressive accumulation in Lewy bodies and neurites is the hallmark of Parkinson's disease (PD). A growing number of studies highlights a critical interplay between lipid metabolism and αS biology. Some of these works postulate a physical interaction between αS and lipid droplets (LDs), but further clarity is needed, not least because typically exogenous αS and/or heterologous systems have been studied. Here, we investigated the effects of acute LD accumulation on endogenous wild-type αS in primary rat cortical neurons. To induce robust LD accumulation within hours, we inhibited the neuronal triacylglycerol hydrolase DDHD2, a phospholipase, using the compound KLH45. KLH45-induced LD accumulation did not affect total levels, phosphoserine-129 status, or solubility of αS, and no co-localization between LDs and αS was observed under these conditions. These findings suggest that a "second hit" and/or a specific LD lipid composition may be necessary for lipid excess to affect αS homeostasis. Our work thus contributes to the debate on αS structure and lipid interaction.

BDH1 identified by transcriptome has a negative effect on lipid metabolism in mammary epithelial cells of dairy goats

BackgroundThe 3-hydroxybutyrate dehydrogenase 1 (BDH1) mainly participates in the regulation of milk fat synthesis and ketone body synthesis in mammary epithelial cells. In our previous study, BDH1 was identified as a key candidate gene regulating lipid metabolism in mammary glands of dairy goats by RNA-seq. This study aimed to investigate the effect of BDH1 on lipid metabolism in mammary epithelial cells of dairy goats (GMECs).ResultsThe results suggest that BDH1 plays a significant role in reducing triacylglycerol content and lipid droplet accumulation in GMECs (p < 0.05). Overexpression of BDH1 significantly decreased the expression of lipid metabolism-related genes (SREBF1 and GPAM) and reduced the levels of C14:0 and C17:1, while increasing FABP3 expression and C10:0 concentration (p < 0.05). Interference with BDH1 significantly increased the expression of SREBF1 and GPAM and the concentration of C14:0, C15:1, and C20:1, but significantly decreased FABP3 and C18:0 (p < 0.05). Treatment of GMECs with β-hydroxybutyric acid (R-BHBA) significantly decreased the expression of FASN, ACACA, LPL, SREBF1, FABP3, ACSL1, GPAM, DGAT1, and triacylglycerol content, while significantly increasing the expression of BDH1 (p < 0.05). Interference with BDH1 rescued the reduction of cellular TAG content and the expression of FASN, LPL, SREBF1, ACSL1, and GPAM in BHBA-treated GMECs.ConclusionIn conclusion, BDH1 negatively regulates lipid metabolism in mammary glands of dairy goats. Furthermore, it may mitigate the inhibitory effect of R-BHBA on lipid metabolism in GMECs.Graphical BDH1 serves as a negative regulator of milk lipid synthesis in GMECs, and BDH1 counteracts the inhibitory effect of R-BHBA on lipid synthesis in mammary epithelial cells of dairy goats.