NME4 mediates metabolic reprogramming and promotes nonalcoholic fatty liver disease progression.

Nonalcoholic fatty liver disease (NAFLD) is mainly characterized by excessive fat accumulation in the liver, and it is associated with liver-related complications and adverse systemic diseases. NAFLD has become the most prevalent liver disease; however, effective therapeutic agents for NAFLD are still lacking. We combined clinical data with proteomics and metabolomics data, and found that the mitochondrial nucleoside diphosphate kinase NME4 plays a central role in mitochondrial lipid metabolism. Nme4 is markedly upregulated in mice fed with high-fat diet, and its expression is positively correlated with the level of steatosis. Hepatic deletion of Nme4 suppresses the progression of hepatic steatosis. Further studies demonstrated that NME4 interacts with several key enzymes in coenzyme A (CoA) metabolism and increases the level of acetyl-CoA and malonyl-CoA, which are the major lipid components of the liver in NAFLD. Increased level of acetyl-CoA and malonyl-CoA  lead to increased triglyceride levels and lipid accumulation in the liver. Taken together, these findings reveal that NME4 is a critical regulator of NAFLD progression and a potential therapeutic target for NAFLD.

Histone demethylase KDM1A promotes hepatic steatosis and inflammation by increasing chromatin accessibility in NAFLD.

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease without specific Food and Drug Administration-approved drugs. Recent advances suggest that chromatin remodeling and epigenetic alteration contribute to the development of NAFLD. The functions of the corresponding molecular modulator in NAFLD, however, are still elusive. KDM1A, commonly known as lysine-specific histone demethylase 1, has been reported to increase glucose uptake in hepatocellular carcinoma. In addition, a recent study suggests that inhibition of KDM1A reduces lipid accumulation in primary brown adipocytes. We here investigated the role of KDM1A, one of the most important histone demethylases, in NAFLD. In this study, we observed a significant upregulation of KDM1A in NAFLD mice, monkeys, and humans compared to the control group. Based on these results, we further found that the KDM1A can exacerbate lipid accumulation and inflammation in hepatocytes and mice. Mechanistically, KDM1A exerted its effects by elevating chromatin accessibility, subsequently promoting the development of NAFLD. Furthermore, the mutation of KDM1A blunted its capability to promote the development of NAFLD. In summary, our study discovered that KDM1A exacerbates hepatic steatosis and inflammation in NAFLD via increasing chromatin accessibility, further indicating the importance of harnessing chromatin remodeling and epigenetic alteration in combating NAFLD. KDM1A might be considered as a potential therapeutic target in this regard.

The role of PCSK9 in glomerular lipid accumulation and renal injury in diabetic kidney disease.

AIMS/HYPOTHESIS: Glomerular lipid accumulation is a defining feature of diabetic kidney disease (DKD); however, the precise underlying mechanism requires further elucidation. Recent evidence suggests a role for proprotein convertase subtilisin/kexin type 9 (PCSK9) in intracellular lipid homeostasis. Although PCSK9 is present in kidneys, its role within kidney cells and relevance to renal diseases remain largely unexplored. Therefore, we investigated the role of intracellular PCSK9 in regulating lipid accumulation and homeostasis in the glomeruli and podocytes under diabetic conditions. Furthermore, we aimed to identify the pathophysiological mechanisms responsible for the podocyte injury that is associated with intracellular PCSK9-induced lipid accumulation in DKD. METHODS: In this study, glomeruli were isolated from human kidney biopsy tissues, and glomerular gene-expression analysis was performed. Also, db/db and db/m mice were used to perform glomerular gene-expression profiling. We generated DKD models using a high-fat diet and low-dose intraperitoneal streptozocin injection in C57BL/6 and Pcsk9 knockout (KO) mice. We analysed cholesterol and triacylglycerol levels within the kidney cortex. Lipid droplets were evaluated using BODIPY staining. We induced upregulation and downregulation of PCSK9 expression in conditionally immortalised mouse podocytes using lentivirus and siRNA transfection techniques, respectively, under diabetic conditions. RESULTS: A significant reduction in transcription level of PCSK9 was observed in glomeruli of individuals with DKD. PCSK9 expression was also reduced in podocytes of animals under diabetic conditions. We observed significantly higher lipid accumulation in kidney tissues of Pcsk9 KO DKD mice compared with wild-type (WT) DKD mice. Additionally, Pcsk9 KO mouse models of DKD exhibited a significant reduction in mitochondria number vs WT models, coupled with a significant increase in mitochondrial size. Moreover, albuminuria and podocyte foot process effacement were observed in WT and Pcsk9 KO DKD mice, with KO DKD mice displaying more pronounced manifestations. Immortalised mouse podocytes exposed to diabetic stimuli exhibited heightened intracellular lipid accumulation, mitochondrial injury and apoptosis, which were ameliorated by Pcsk9 overexpression and aggravated by Pcsk9 knockdown in mouse podocytes. CONCLUSIONS/INTERPRETATION: The downregulation of PCSK9 in podocytes is associated with lipid accumulation, which leads to mitochondrial dysfunction, cell apoptosis and renal injury. This study sheds new light on the potential involvement of PCSK9 in the pathophysiology of glomerular lipid accumulation and podocyte injury in DKD.

Advances and challenges in measuring hepatic glucose uptake with FDG PET: implications for diabetes research.

The liver plays a crucial role in the control of glucose homeostasis and is therefore of great interest in the investigation of the development of type 2 diabetes. Hepatic glucose uptake (HGU) can be measured through positron emission tomography (PET) imaging with the tracer [18F]-2-fluoro-2-deoxy-D-glucose (FDG). HGU is dependent on many variables (e.g. plasma glucose, insulin and glucagon concentrations), and the metabolic state for HGU assessment should be chosen with care and coherence with the study question. In addition, as HGU is influenced by many factors, protocols and measurement conditions need to be standardised for reproducible results. This review provides insights into the protocols that are available for the measurement of HGU by FDG PET and discusses the current state of knowledge of HGU and its impairment in type 2 diabetes. Overall, a scanning modality that allows for the measurement of detailed kinetic information and influx rates (dynamic imaging) may be preferable to static imaging. The combination of FDG PET and insulin stimulation is crucial to measure tissue-specific insulin sensitivity. While the hyperinsulinaemic-euglycaemic clamp allows for standardised measurements under controlled blood glucose levels, some research questions might require a more physiological approach, such as oral glucose loading, with both advantages and complexities relating to fluctuations in blood glucose and insulin levels. The available approaches to address HGU hold great potential but await more systematic exploitation to improve our understanding of the mechanisms underlying metabolic diseases. Current findings from the investigation of HGU by FDG PET highlight the complex interplay between insulin resistance, hepatic glucose metabolism, NEFA levels and intrahepatic lipid accumulation in type 2 diabetes and obesity. Further research is needed to fully understand the underlying mechanisms and potential therapeutic targets for improving HGU in these conditions.

Effects of physical activity on the levels of remnant cholesterol: A population-based study.

Physical activity (PA) has the potential to bring about favourable changes in plasma lipid profile. However, the relationship between PA and remnant cholesterol (RC) remains unclear. We aimed to study the link between PA and RC using the database of the 2007-2020 National Health and Nutrition Examination Survey (NHANES). PA was categorized based on Physical Activity Guidelines for Americans. A multivariate linear regression model was used to determine the correlations between PA and RC. The study involved a total of 18,396 participants and revealed that individuals whose PA met the guidelines by engaging in moderate-intensity PA at least 150 min per week had lower body mass index and showed decreased levels of triglyceride, TC, and haemoglobin A1c compared to those who were physically inactive, exercising <150 min per week. Participants whose intensity of PA meets PA guidelines had a lower level of RC than those who did not met PA guidelines (ß = -1.3, 95% confidence interval [CI]: -1.9 to -0.7, p < 0.001), even after adjusting for confounders. During subgroup analysis, we observed that race (pinteraction = 0.0089) emerged as a significant factor of interaction.

SGK1 promotes the lipid accumulation via regulating the transcriptional activity of FOXO1 in bovine.

OBJECTIVES: Serum/glucocorticoid-inducible kinase 1 (SGK1) gene encodes a serine/threonine protein kinase that plays an essential role in cellular stress response and regulation of multiple metabolic processes. However, its role in bovine adipogenesis remains unknown. In this study, we aimed to clarify the role of SGK1 in bovine lipid accumulation and improvement of meat quality. METHODS: Preadipocytes were induced to differentiation to detect the temporal expression pattern of SGK1. Heart, liver, lung, spleen, kidney, muscle and fat tissues were collected to detect its tissue expression profile. Recombinant adenovirus and the lentivirus were packaged for overexpression and knockdown. Oil Red O staining, quantitative real-time PCR, Western blot analysis, Yeast two-hybrid assay, luciferase assay and RNA-seq were performed to study the regulatory mechanism of SGK1. RESULTS: SGK1 showed significantly higher expression in adipose and significantly induced expression in differentiated adipocytes. Furthermore, overexpression of SGK1 greatly promoted adipogenesis and inhibited proliferation, which could be shown by the remarkable increasement of lipid droplet, and the expression levels of adipogenic marker genes and cell cycle-related genes. Inversely, its knockdown inhibited adipogenesis and facilitated proliferation. Mechanistically, SGK1 regulates the phosphorylation and expression of two critical proteins of FoxO family, FOXO1/FOXO3. Importantly, SGK1 attenuates the transcriptional repression role of FOXO1 for PPARγ via phosphorylating the site S256, then promoting the bovine fat deposition. CONCLUSIONS: SGK1 is a required epigenetic regulatory factor for bovine preadipocyte proliferation and differentiation, which contributes to a better understanding of fat deposition and meat quality improvement in cattle.

Impaired cholesterol efflux in retinal pigment epithelium of individuals with juvenile macular degeneration.

Macular degeneration (MD) is characterized by the progressive deterioration of the macula and represents one of the most prevalent causes of blindness worldwide. Abnormal intracellular accumulation of lipid droplets and pericellular deposits of lipid-rich material in the retinal pigment epithelium (RPE) called drusen are clinical hallmarks of different forms of MD including Doyne honeycomb retinal dystrophy (DHRD) and age-related MD (AMD). However, the appropriate molecular therapeutic target underlying these disorder phenotypes remains elusive. Here, we address this knowledge gap by comparing the proteomic profiles of induced pluripotent stem cell (iPSC)-derived RPEs (iRPE) from individuals with DHRD and their isogenic controls. Our analysis and follow-up studies elucidated the mechanism of lipid accumulation in DHRD iRPE cells. Specifically, we detected significant downregulation of carboxylesterase 1 (CES1), an enzyme that converts cholesteryl ester to free cholesterol, an indispensable process in cholesterol export. CES1 knockdown or overexpression of EFEMP1R345W, a variant of EGF-containing fibulin extracellular matrix protein 1 that is associated with DHRD and attenuated cholesterol efflux and led to lipid droplet accumulation. In iRPE cells, we also found that EFEMP1R345W has a hyper-inhibitory effect on epidermal growth factor receptor (EGFR) signaling when compared to EFEMP1WT and may suppress CES1 expression via the downregulation of transcription factor SP1. Taken together, these results highlight the homeostatic role of cholesterol efflux in iRPE cells and identify CES1 as a mediator of cholesterol efflux in MD.

Regulation of genes involved in the metabolic adaptation of murine microglial cells in response to elevated HIF-1α mediated activation.

Microglia cells are activated in response to different stress signals. Several metabolic adaptations underlie microglia activation in the brain. Among these, in conditions like ischemic stroke and, hypoxic stress stimuli activate microglia cells. Hypoxic stress is mediated by HIF-1α. Although HIF-1α has been implicated in the alteration of metabolic pathways, changes in microglia lipid metabolism during M1 activation of microglia induced by elevated HIF-1α levels are yet to be understood. This can also merit interest in the development of novel targets to mitigate chronic inflammation. Our study aims to elucidate the transcriptional regulation of metabolic pathways in microglia cells during HIF-1α mediated activation. To study the adaptations in the metabolic pathways we induced microglia activation, by activating HIF-1α. Here, we show that microglia cells activated in response to elevated HIF-1α require ongoing lipogenesis and fatty acid breakdown. Notably, autophagy is activated during the initial stages of microglia activation. Inhibition of autophagy in activated microglia affects their viability and phagocytic activity. Collectively, our study expands the understanding of the molecular link between autophagy, lipid metabolism, and inflammation during HIF-1α mediated microglial activation that can lead to the development of promising strategies for controlling maladaptive activation states of microglia responsible for neuroinflammation. Together, our findings suggest that the role of HIF-1α in regulating metabolic pathways during hypoxia in microglia is beyond optimization of glucose utilization and distinctly regulates lipid metabolism during pro-inflammatory activation.

The anti-atherosclerotic effect of Paeonol against the lipid accumulation in macrophage-derived foam cells by inhibiting ferroptosis via the SIRT1/NRF2/GPX4 signaling pathway.

Atherosclerosis (AS) is the underlying cause of many severe vascular diseases and is primarily characterized by abnormal lipid metabolism. Paeonol (Pae), a bioactive compound derived from Paeonia Suffruticosa Andr., is recognized for its significant role in reducing lipid accumulation. Our research objective is to explore the link between lipid buildup in foam cells originating from macrophages and the process of ferroptosis, and explore the effect and mechanism of Pae on inhibiting AS by regulating ferroptosis. In our animal model, ApoE-deficient mice, which were provided with a high-fat regimen to provoke atherosclerosis, were administered Pae. The treatment was benchmarked against simvastatin and ferrostatin-1. The results showed that Pae significantly reduced aortic ferroptosis and lipid accumulation in the mice. In vitro experiments further demonstrated that Pae could decrease lipid accumulation in foam cells induced by oxidized low-density lipoprotein (LDL) and challenged with the ferroptosis inducer erastin. Crucially, the protective effect of Pae against lipid accumulation was dependent on the SIRT1/NRF2/GPX4 pathway, as SIRT1 knockdown abolished this effect. Our findings suggest that Pae may offer a novel therapeutic approach for AS by inhibiting lipid accumulation through the suppression of ferroptosis, mediated by the SIRT1/NRF2/GPX4 pathway. Such knowledge has the potential to inform the creation of novel therapeutic strategies aimed at regulating ferroptosis within the context of atherosclerosis.

Sesamin alleviates lipid accumulation induced by oleic acid via PINK1/Parkin-mediated mitophagy in HepG2 cells.

Sesamin, a special compound present in sesame and sesame oil, has been reported a role in regulating lipid metabolism, while the underlying mechanisms remain unclear. Autophagy has been reported associated with lipid metabolism and regarded as a key modulator in liver steatosis. The present work aimed to investigate whether sesamin could exert its protective effects against lipid accumulation via modulating autophagy in HepG2 cells stimulated with oleic acid (OA). Cell viability was evaluated using the CCK-8 method, and triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein, cholesterol (LDL-C), alanine aminotransferase (ALT), along with aspartate aminotransferase (AST) were assessed by oil red O staining, transmission electron microscopy (TEM), and biochemical kits to investigate the lipid-lowering effects of sesamin. Differentially expressed genes were screened by RNA sequencing and validated using real-time quantitative PCR and Western blot. Autophagy and mitophagy related molecules were analyzed employing TEM, Western blot, and immunofluorescence. The data shows that in HepG2 cells stimulated by OA, sesamin reduces levels of TG, TC, LDL-C, ALT, and AST while elevating HDL-C, alleviates the lipid accumulation and improves fatty acid metabolism through modulating the levels of fat metabolism related genes including PCSK9, FABP1, CD36, and SOX4. Sesamin restores the suppressed autophagy in HepG2 cells caused by OA, which could be blocked by autophagy inhibitors. This indicates that sesamin improves fatty acid metabolism by enhancing autophagy levels, thereby mitigating the intracellular lipid accumulation. Furthermore, sesamin significantly enhances the mitophagy and improves mitochondrial homeostasis via activating the PINK/Parkin pathway. These data suggest that sesamin alleviates the excessive lipid accumulation in HepG2 caused by OA by restoring the impaired mitophagy via the PINK1/Parkin pathway, probably playing a preventive or therapeutic role in hepatic steatosis.

Glycoprotein non-metastatic melanoma protein B (GPNMB): An attractive target in atherosclerosis.

Atherosclerosis (AS), the leading cause of cardiovascular diseases, is heavily influenced by inflammation, lipid accumulation, autophagy, and aging. The expression of glycoprotein non-metastatic melanoma B (GPNMB) has been observed to correlate with lipid content, inflammation, and aging, progressively increasing as atherosclerosis advances through its various stages, from baseline to early and advanced phases. However, the interaction between GPNMB and AS is controversial. Knockout of GPNMB has been shown to increase atherosclerotic plaque burden in mice. Conversely, targeted elimination of GPNMB-positive cells reduced atherosclerotic burden. These seemingly contradictory findings underscore the complexity of the issue and highlight the need for further research to reconcile these discrepancies and to elucidate the precise role of GPNMB in the pathogenesis of AS.

MLPH is a novel adipogenic factor controlling redox homeostasis to inhibit lipid peroxidation in adipocytes.

Abnormal adipose tissue formation is associated with metabolic disorders such as obesity, diabetes, and liver and cardiovascular diseases. Thus, identifying the novel factors that control adipogenesis is crucial for understanding these conditions and developing targeted treatments. In this study, we identified the melanosome-related factor MLPH as a novel adipogenic factor. MLPH was induced during the adipogenesis of 3T3-L1 cells and human mesenchymal stem cells. Although MLPH did not affect lipid metabolism, such as lipogenesis or lipolysis, adipogenesis was severely impaired by MLPH depletion. We observed that MLPH prevented excess reactive oxygen species (ROS) accumulation and lipid peroxidation during adipogenesis and in mature adipocytes. In addition, increased MLPH expression was observed under cirrhotic conditions in liver cancer cells and its overexpression also reduced ROS and lipid peroxidation. Our findings demonstrate that MLPH is a novel adipogenic factor that maintains redox homeostasis by preventing lipid peroxidation and ROS accumulation, which could lead to metabolic diseases.

Integrating network pharmacology and animal experimental validation to investigate the action mechanism of oleanolic acid in obesity.

BACKGROUND: Obesity, a condition associated with the development of widespread cardiovascular disease, metabolic disorders, and other health complications, has emerged as a significant global health issue. Oleanolic acid (OA), a pentacyclic triterpenoid compound that is widely distributed in various natural plants, has demonstrated potential anti-inflammatory and anti-atherosclerotic properties. However, the mechanism by which OA fights obesity has not been well studied. METHOD: Network pharmacology was utilized to search for potential targets and pathways of OA against obesity. Molecular docking and molecular dynamics simulations were utilized to validate the interaction of OA with core targets, and an animal model of obesity induced by high-fat eating was then employed to confirm the most central of these targets. RESULTS: The network pharmacology study thoroughly examined 42 important OA targets for the treatment of obesity. The key biological processes (BP), cellular components (CC), and molecular functions (MF) of OA for anti-obesity were identified using GO enrichment analysis, including intracellular receptor signaling, intracellular steroid hormone receptor signaling, chromatin, nucleoplasm, receptor complex, endoplasmic reticulum membrane, and RNA polymerase II transcription Factor Activity. The KEGG/DAVID database enrichment study found that metabolic pathways, PPAR signaling pathways, cancer pathways/PPAR signaling pathways, insulin resistance, and ovarian steroidogenesis all play essential roles in the treatment of obesity and OA. The protein-protein interaction (PPI) network was used to screen nine main targets: PPARG, PPARA, MAPK3, NR3C1, PTGS2, CYP19A1, CNR1, HSD11B1, and AGTR1. Using molecular docking technology, the possible binding mechanism and degree of binding between OA and each important target were validated, demonstrating that OA has a good binding potential with each target. The molecular dynamics simulation's Root Mean Square Deviation (RMSD), and Radius of Gyration (Rg) further demonstrated that OA has strong binding stability with each target. Additional animal studies confirmed the significance of the core target PPARG and the core pathway PPAR signaling pathway in OA anti-obesity. CONCLUSION: Overall, our study utilized a multifaceted approach to investigate the value and mechanisms of OA in treating obesity, thereby providing a novel foundation for the identification and development of natural drug treatments.

Chemically synthesized osteocalcin alleviates NAFLD via the AMPK-FOXO1/BCL6-CD36 pathway.

Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease worldwide. Osteocalcin plays an important role in energy metabolism. In this study, we investigated the mechanism of action of chemically synthesized osteocalcin (csOCN) in ameliorating NAFLD. We demonstrated for the first time that csOCN attenuates lipid accumulation in the liver and hepatocytes by modulating CD36 protein expression. In addition, we found that the expression of p-AMPK, FOXO1 and BCL6 decreased and the expression of CD36 increased after OA/PA induction compared to the control group, and these effects were reversed by the addition of csOCN. In contrast, the therapeutic effect of csOCN was inhibited by the addition of AMPK inhibitors and BCL6 inhibitors. This finding suggested that csOCN regulates CD36 expression via the AMPK-FOXO1/BCL6 axis. In NAFLD mice, oral administration of csOCN also activated the AMPK pathway and reduced CD36 expression. Molecular docking revealed that osteocalcin has a docking site with CD36. Compared to oleic acid and palmitic acid, osteocalcin bound more strongly to CD36. Laser confocal microscopy results showed that osteocalcin colocalized with CD36 at the cell membrane. In conclusion, we demonstrated the regulatory role of csOCN in fatty acid uptake pathways for the first time; it regulates CD36 expression via the AMPK-FOXO1/BCL6 axis to reduce fatty acid uptake, and it affects fatty acid transport by may directly binding to CD36. There are indications that csOCN has potential as a CD36-targeted drug for the treatment of NAFLD.

A WRI1-dependent module is essential for the accumulation of auxin and lipid in somatic embryogenesis of Arabidopsis thaliana.

The potential for totipotency exists in all plant cells; however, the underlying mechanisms remain largely unknown. Earlier findings have revealed that the overexpression of LEAFY COTYLEDON 2 (LEC2) can directly trigger the formation of somatic embryos on the cotyledons of Arabidopsis. Furthermore, cotyledon cells that overexpress LEC2 accumulate significant lipid reserves typically found in seeds. The precise mechanisms and functions governing lipid accumulation in this process remain unexplored. In this study, we demonstrate that WRINKLED1 (WRI1), the key regulator of lipid biosynthesis, is essential for somatic embryo formation, suggesting that WRI1-mediated lipid biosynthesis plays a crucial role in the transition from vegetative to embryonic development. Our findings indicate a direct interaction between WRI1 and LEC2, which enhances the enrichment of LEC2 at downstream target genes and stimulates their induction. Besides, our data suggest that WRI1 forms a complex with LEC1, LEC2, and FUSCA3 (FUS3) to facilitate the accumulation of auxin and lipid for the somatic embryo induction, through strengthening the activation of YUCCA4 (YUC4) and OLEOSIN3 (OLE3) genes. Our results uncover a regulatory module controlled by WRI1, crucial for somatic embryogenesis. These findings provide valuable insights into our understanding of plant cell totipotency.

Saturation Effect of Lipid Accumulation Product (LAP) Index on Spinal Bone Mineral Density: A Population-Based Study.

Lipid accumulation product (LAP) has a positive effect on spinal bone mineral density (BMD). However, once LAP levels exceed 27.26, the rate of spinal BMD increase slow down or even decline. This indicates a biphasic relationship between lipid metabolism and BMD, suggesting potential benefits within a certain range and possible adverse effects beyond that range. This study aimed to investigate the potential association between LAP index and BMD in US adults, as well as to explore the presence of a potential saturation effect in this relationship. This study analyzed data from the National Health and Nutrition Examination Survey (NHANES) spanning from 2007 to 2018. A multiple stepwise regression model was employed to examine the association between LAP index and total spinal BMD. Additionally, a generalized additive model and a smooth curve fitting algorithm were utilized to examine the relationship, and saturation effect study was conducted to determine the saturation level. The calculation formula of LAP used in the study was: (LAP = (waist circumstances (WC) (cm) - 58) × triglyceride (TG) (mmol/L)) for women, and (LAP = (WC (cm) - 65) × TG (mmol/L)) for men. The study involved a total of 7913 participants aged 20 years or older. Through multiple stepwise regression analysis, it was found that individuals with higher LAP scores exhibited higher total spinal BMD. In both the crude and partially adjusted models, total spinal BMD was significantly higher in the highest LAP quartile (Q4) compared to the lowest LAP quartile (Q1) (P < 0.05). Utilizing a generalized additive model and smooth curve, a nonlinear relationship between LAP and total spinal BMD was observed. Furthermore, the study identified the saturation value of LAP to be 27.26, indicating a saturation effect. This research highlights a nonlinear relationship between LAP and total spinal BMD, along with the presence of a saturation effect.

Melatonin ameliorates simulated-microgravity-induced mitochondrial dysfunction and lipid metabolism dysregulation in hepatocytes.

The liver is an essential multifunctional organ, which constantly communicates with nearly all tissues. It has raised the concern that microgravity exposure can lead to liver dysfunction and metabolic syndromes. However, molecular mechanisms and intervention measures of the adverse effects of microgravity on hepatocytes are limited. In this study, we utilized the random positioning machine culture system to investigate the adverse effects on hepatocytes under simulated microgravity (SMG). Our results showed that SMG impaired hepatocyte viability, causing cell cycle arrest and apoptosis. Compared to normal gravity, it also triggered lipid accumulation, elevated triglyceride (TG) and ROS levels, and impaired mitochondria function in hepatocytes. Furthermore, RNA sequencing results showed that SMG upregulated genes implicated in lipid metabolisms, including PPARγ, PLIN2, CD36, FABPs, etc. Importantly, all these defects can be suppressed by melatonin, a potent antioxidant secreted by the pineal gland, suggesting its potential use of therapeutic intervention.

Traumatic acid inhibits ACSL4 associated lipid accumulation in adipocytes to attenuate high-fat diet-induced obesity.

Obesity is a major health concern that lacks effective intervention strategies. Traumatic acid (TA) is a potent wound-healing agent in plants, considered an antioxidant food ingredient. This study demonstrated that TA treatment significantly reduced lipid accumulation in human adipocytes and prevented high-fat diet induced obesity in zebrafish. Transcriptome sequencing revealed TA-activated fatty acid (FA) degradation and FA metabolism signaling pathways. Moreover, western blotting and quantitative polymerase chain reaction showed that TA inhibited the expression of long-chain acyl-CoA synthetase-4 (ACSL4). Overexpression of ACSL4 resulted in the reversal of TA beneficiary effects, indicating that the attenuated lipid accumulation of TA was regulated by ACSL4 expression. Limited proteolysis-mass spectrometry and microscale thermophoresis were then used to confirm hexokinase 2 (HK2) as a direct molecular target of TA. Thus, we demonstrated the molecular basis of TA in regulating lipid accumulation and gave the first evidence that TA may function through the HK2-ACSL4 axis.

Mice harboring a R133L heterozygous mutation in LMNA exhibited ectopic lipid accumulation, aging, and mitochondrial dysfunction in adipose tissue.

The LMNA gene encodes for the nuclear envelope proteins lamin A and C (lamin A/C). A novel R133L heterozygous mutation in the LMNA gene causes atypical progeria syndrome (APS). However, the underlying mechanism remains unclear. Here, we used transgenic mice (LmnaR133L/+ mice) that expressed a heterozygous LMNA R133L mutation and 3T3-L1 cell lines with stable overexpression of LMNA R133L (by lentiviral transduction) as in vivo and in vitro models to investigate the mechanisms of LMNA R133L mutations that mediate the APS phenotype. We found that a heterozygous R133L mutation in LMNA induced most of the metabolic disturbances seen in patients with this mutation, including ectopic lipid accumulation, limited subcutaneous adipose tissue (SAT) expansion, and insulin resistance. Mitochondrial dysfunction and senescence promote ectopic lipid accumulation and insulin resistance. In addition, the FLAG-mediated pull-down capture followed by mass spectrometry assay showed that p160 Myb-binding protein (P160 MBP; Mybbp1 a $$ a $$ ), the critical transcriptional repressor of PGC-1α, was bound to lamin A/C. Increased Mybbp1 a $$ a $$ levels in tissues and greater Mybbp1 a $$ a $$ -lamin A/C binding in nuclear inhibit PGC-1α activity and promotes mitochondrial dysfunction. Our findings confirm that the novel R133L heterozygous mutation in the LMNA gene caused APS are associated with marked mitochondrial respiratory chain impairment, which were induced by decreased PGC-1α levels correlating with increased Mybbp1a levels in nuclear, and a senescence phenotype of the subcutaneous fat.

Targeting foamy macrophages by manipulating ABCA1 expression to facilitate lesion healing in the injured spinal cord.

Spinal cord injury (SCI) triggers a complex cascade of events, including myelin loss, neuronal damage, neuroinflammation, and the accumulation of damaged cells and debris at the injury site. Infiltrating bone marrow derived macrophages (BMDMϕ) migrate to the epicenter of the SCI lesion, where they engulf cell debris including abundant myelin debris to become pro-inflammatory foamy macrophages (foamy Mϕ), participate neuroinflammation, and facilitate the progression of SCI. This study aimed to elucidate the cellular and molecular mechanisms underlying the functional changes in foamy Mϕ and their potential implications for SCI. Contusion at T10 level of the spinal cord was induced using a New York University (NYU) impactor (5 g rod from a height of 6.25 mm) in male mice. ABCA1, an ATP-binding cassette transporter expressed by Mϕ, plays a crucial role in lipid efflux from foamy cells. We observed that foamy Mϕ lacking ABCA1 exhibited increased lipid accumulation and a higher presence of lipid-accumulated foamy Mϕ as well as elevated pro-inflammatory response in vitro and in injured spinal cord. We also found that both genetic and pharmacological enhancement of ABCA1 expression accelerated lipid efflux from foamy Mϕ, reduced lipid accumulation and inhibited the pro-inflammatory response of foamy Mϕ, and accelerated clearance of cell debris and necrotic cells, which resulted in functional recovery. Our study highlights the importance of understanding the pathologic role of foamy Mϕ in SCI progression and the potential of ABCA1 as a therapeutic target for modulating the inflammatory response, promoting lipid metabolism, and facilitating functional recovery in SCI.