Excessive Lipid Accumulation Research Articles

Very low-density lipoprotein receptor mediates triglyceride-rich lipoprotein-induced oxidative stress and insulin resistance.

Obesity is associated with excess lipid deposition in nonadipose tissues, leading to increased oxidative stress and insulin resistance. Very low-density lipoprotein receptor (VLDLR), a member of the LDL receptor family, binds and increases the catabolism of triglyceride-rich lipoproteins. Although VLDLR is highly expressed in the heart, its role in obesity-associated oxidative stress and insulin resistance is unclear. Here, we used lean (wild type), genetically obese leptin-deficient (ob/ob), and leptin-VLDLR double-null (ob/ob-VLDLR-/-) mice to determine the impact of VLDLR deficiency on obesity-induced oxidative stress and insulin resistance in the heart. Although insulin sensitivity and glucose uptake were reduced in the hearts of ob/ob mice, VLDLR expression was upregulated and was associated with increased VLDL uptake and excess lipid deposition. This was accompanied by an upregulation of cardiac NADPH oxidase (Nox) expression and increased production of Nox-dependent superoxides. Silencing the VLDLR in ob/ob mice had reduced VLDL uptake and prevented excess lipid deposition in the heart, in addition to a reduction of superoxide overproduction and the normalization of insulin sensitivity and glucose uptake. In isolated cardiomyocytes, VLDLR deficiency had prevented VLDL-mediated induction of Nox activity and superoxide overproduction while improving insulin sensitivity and glucose uptake. Our findings indicate that VLDLR deficiency prevents excess lipid accumulation and moderates oxidative stress and insulin resistance in the hearts of obese mice. This effect is linked to the active role of VLDLR in VLDL uptake, which triggers a cascade of events leading to increased Nox activity, superoxide overproduction, and insulin resistance.NEW & NOTEWORTHY Obesity is associated with excess lipid deposition in muscles, which is considered as a leading cause of metabolic dysfunction and oxidative stress. Cellular uptake of lipids is regulated by several membrane receptors, among which is the very low-density lipoprotein receptor (VLDLR). This article provides information on the role of VLDLR in cardiac muscle and how its expression regulates insulin resistance and oxidative stress in the obese mouse model.

Biosynthetic deficiency of docosahexaenoic acid causes nonalcoholic fatty liver disease and ferroptosis-mediated hepatocyte injury

Exogenous omega-3 fatty acids, particularly docosahexaenoic acid (DHA), have shown to exert beneficial effects on nonalcoholic fatty liver disease (NAFLD), which is characterized by the excessive accumulation of lipids and chronic injury in the liver. However, the effect of endogenous DHA biosynthesis on the lipid homeostasis of liver is poorly understood. In this study, we used a DHA biosynthesis-deficient zebrafish model, elovl2 mutant, to explore the effect of endogenously biosynthesized DHA on hepatic lipid homeostasis. We found the pathways of lipogenesis and lipid uptake were strongly activated, while the pathways of lipid oxidation and lipid transport were inhibited in the liver of elovl2 mutants, leading to lipid droplet accumulation in the mutant hepatocytes and NAFLD. Furthermore, the elovl2 mutant hepatocytes exhibited disrupted mitochondrial structure and function, activated endoplasmic reticulum (ER) stress, and hepatic injury. We further unveiled that the hepatic cell death and injury was mainly mediated by ferroptosis, rather than apoptosis, in elovl2 mutants. Elevating DHA content in elovl2 mutants, either through introduction of an omega-3 desaturase (fat1) transgene or feeding with a DHA-rich diet, could strongly alleviate NAFLD features and ferroptosis-mediated hepatic injury. Together, our study elucidates the essential role of endogenous DHA biosynthesis in maintaining hepatic lipid homeostasis and liver health, highlighting that DHA deficiency can lead to NAFLD and ferroptosis-mediated hepatic injury.

Lipidomic Assessment of the Inhibitory Effect of Standardized Water Extract of Hydrangea serrata (Thunb.) Ser. Leaves during Adipogenesis.

Obesity is primarily exacerbated by excessive lipid accumulation during adipogenesis, with triacylglycerol (TG) as a major lipid marker. However, as the association between numerous lipid markers and various health conditions has recently been revealed, investigating the lipid metabolism in detail has become necessary. This study investigates the lipid metabolic effects of Hydrangea serrata (Thunb.) Ser. hot water leaf extract (WHS) on adipogenesis using LC-MS-based lipidomics analysis of undifferentiated, differentiated, and WHS-treated differentiated 3T3-L1 cells. WHS treatment effectively suppressed the elevation of glycerolipids, including TG and DG, and prevented a molecular shift in fatty acyl composition towards long-chain unsaturated fatty acids. This shift also impacted glycerophospholipid metabolism. Additionally, WHS stabilized significant lipid markers such as the PC/PE and LPC/PE ratios, SM, and Cer, which are associated with obesity and related comorbidities. This study suggests that WHS could reduce obesity-related risk factors by regulating lipid markers during adipogenesis. This study is the first to assess the underlying lipidomic mechanisms of the adipogenesis-inhibitory effect of WHS, highlighting its potential in developing natural products for treating obesity and related conditions. Our study provides a new strategy for the development of natural products for the treatment of obesity and related diseases.

Lactobacillus casei-fermented Amomum xanthioides ameliorates metabolic dysfunction in high-fat diet-induced obese mice.

Amomum xanthioides (AX) has been used as an edible herbal medicine to treat digestive system disorders in Asia. Additionally, Lactobacillus casei is a well-known probiotic commonly used in fermentation processes as a starter. The current study aimed to investigate the potential of Lactobacillus casei-fermented Amomum xanthioides (LAX) in alleviating metabolic disorders induced by high-fat diet (HFD) in a mouse model. LAX significantly reduced the body and fat weight, outperforming AX, yet without suppressing appetite. LAX also markedly ameliorated excessive lipid accumulation and reduced inflammatory cytokine (IL-6) levels in serum superior to AX in association with UCP1 activation and adiponectin elevation. Furthermore, LAX noticeably improved the levels of fasting blood glucose, serum insulin, and HOMA-IR through positive regulation of glucose transporters (GLUT2, GLUT4), and insulin receptor gene expression. In conclusion, the fermentation of AX demonstrates a pronounced mitigation of overnutrition-induced metabolic dysfunction, including hyperlipidemia, hyperglycemia, hyperinsulinemia, and obesity, compared to non-fermented AX. Consequently, we proposed that the fermentation of AX holds promise as a potential candidate for effectively ameliorating metabolic disorders.

Reactive oxygen species-responsive nano-platform with dual-targeting and fluorescent lipid-specific imaging capabilities for the management of atherosclerotic plaques

Atherosclerosis (AS), a pathological cause of cardiovascular disease, results from endothelial injury, local progressive inflammation, and excessive lipid accumulation. AS plaques rich in foam cells are prone to rupture and form thrombus, which can cause life-threatening complications. Therefore, the assessment of atherosclerotic plaque vulnerability and early intervention are crucial in reducing the mortality rates associated with cardiovascular disease. In this work, A fluorescent probe FC-TPA was synthesized, which switches the fluorescence state between protonated and non-protonated, reducing background fluorescence and enhancing imaging signal-to-noise ratio. On this basis, FC-TPA is loaded into cyclodextrin (CD) modified with phosphatidylserine targeting peptide (PTP) and coated with hyaluronic acid (HA) to construct the intelligent responsive diagnostic nanoplatform (HA@PCFT). HA@PCFT effectively targets atherosclerotic plaques, utilizing dual targeting mechanisms. HA binds strongly to CD44, while PTP binds to phosphatidylserine, enabling nanoparticle aggregation at the lesion site. ROS acts as a smart release switch for probes. Both in vitro and in vivo evaluations confirm impressive lipid-specific fluorescence imaging capabilities of HA@PCFT nanoparticles (NPs). The detection of lipid load in atherosclerotic plaque by fluorescence imaging will aid in assessing the vulnerability of atherosclerotic plaque. Statement of significanceCurrently, numerous fluorescent probes have been developed for lipid imaging. However, some challenges including inadequate water solubility, nonspecific distribution patterns, and fluorescence background interference, have greatly limited their further applications in vivo. To overcome these limitations, a fluorescent molecule has been designed and synthesized, thoroughly investigating its photophysical properties through both theoretical and experimental approaches. Interestingly, this fluorescent molecule exhibits the reversible fluorescence switching capabilities, mediated by hydrogen bonds, which effectively mitigate background fluorescence interference. Additionally, the fluorescent molecules has been successfully loaded into nanocarriers functionalized with the active targeting abilities, which has significantly improved the solubility of the fluorescent molecules and reduced their nonspecific distribution in vivo for an efficient target imaging in atherosclerosis. This study provides a valuable reference for evaluating the performance of such fluorescent dyes, and offers a promising perspective on the design of the target delivery systems for atherosclerosis.

Assessing the ability of dihydrosterculic acid to activate PPARα

Peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated transcription factor associated with the expression of specific target genes involved in fatty acid β-oxidation. Activation of PPARα could potentially be utilized to treat diseases associated with the accumulation of hepatic lipids such as non-alcoholic fatty liver disease (NAFLD), which currently impacts approximately 25% of the world’s population. At present, a class of synthetic ligands called fibrates can be prescribed to help manage NAFLD but are weak agonists for PPARα and therefore have limited effcacy. Consequently, alternative ligands for PPARα must be established and no natural endogenous ligands have been conclusively identified. This study expands on our previous work and aims to identify the direct effects of dihydrosterculic acid (DHSA), a cyclopropyl fatty acid found in cottonseed oil (CSO), on PPARα activity. To identify downstream effects of DHSA, male mice were placed on a CSO- (DHSA-containing) or isocaloric oil-enriched diet for 6 weeks and tissues were sent for genome-wide RNA sequencing analysis. CSO-fed mice demonstrated increased PPARα gene expression in the liver and concomitant decreased triglyceride in plasma (-75.1±11.5 milligrams/deciliter (mg/dL); p<0.01) and liver (-86.7±71.7 mg/gram (g) protein; p=0.1) and decreased free fatty acid in liver (-16.5±3.4 micromolar (μM)/g protein; p<0.01) relative to the oil-enriched control diet. Confirmational tissue analysis of liver samples show an increase in PPARα target gene expression in the DHSA containing groups compared to control diet groups, indicating that DHSA could potentially serve as an endogenous ligand for PPARα to increase its transcriptional activity to increase fat oxidation. To further test this hypothesis, female PPARα knockout mice were fed a DHSA containing diet or control diet for 4 weeks (n=8). Following the 4-week period, the chow-fed wild type females gained more weight (1.3±0.6 g; p<0.05) than the PPARα knockout mice. Otherwise, there were no significant differences in body weight or food intake between diets or genotypes. Additional in vitro studies show increased PPARα target gene expression following treatments with DHSA, specifically for CPT1a (2.7±0.2 fold increase; p<0.01), ACOX1 (1.3±0.1 fold increase; p<0.05), and ACADVL (1.6±0.1 fold increase, p<0.01), which encode key enzymes in lipid oxidation pathways. SCD1, the rate limiting enzyme in lipogenesis, was also downregulated (0.5±0.03 fold decrease, p<0.01) in response to a 24-hour treatment with DHSA indicating a reduction in endogenous lipogenesis. From these results, we believe that DHSA could function through a PPARα-dependent mechanism. Further analysis of the tissues collected from the PPARα knockout mouse model will aid in determining the mechanism of DHSA as well as identifying its potential for the treatment of excess lipid accumulation. This project is funded by Cotton Incorporated. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Increased FGF-21 Improves Ectopic Lipid Deposition in the Liver and Skeletal Muscle.

Obesity can lead to excessive lipid accumulation in non-adipose tissues, such as the liver and skeletal muscles, leading to ectopic lipid deposition and damaging target organ function through lipotoxicity. FGF-21 is a key factor in regulating lipid metabolism, so we aim to explore whether FGF-21 is involved in improving ectopic lipid deposition. We observed the characteristics of ectopic lipid deposition in the liver and skeletal muscles of obesity-resistant mice, detected the expression of FGF-21 and perilipin, and found that obesity-resistant mice showed a decrease in ectopic lipid deposition in the liver and skeletal muscles and increased expression of FGF-21. After inhibiting the expression of FGF-21, a more severe lipid deposition in liver cells and skeletal muscle cells was found. The results indicate that inhibiting FGF-21 can exacerbate ectopic lipid deposition via regulating lipid droplet synthesis and decomposition, as well as free fatty acid translocation and oxidation. In conclusion, FGF-21 is involved in improving ectopic lipid deposition caused by obesity in the liver and skeletal muscles.

GPR1 and CMKLR1 Control Lipid Metabolism to Support the Development of Clear Cell Renal Cell Carcinoma.

Clear cell renal cell carcinoma (ccRCC), the most common type of kidney cancer, is largely incurable in the metastatic setting. ccRCC is characterized by excessive lipid accumulation that protects cells from stress and promotes tumor growth, suggesting that the underlying regulators of lipid storage could represent potential therapeutic targets. Here, we evaluated the regulatory roles of GPR1 and CMKLR1, two G protein-coupled receptors of the protumorigenic adipokine chemerin that is involved in ccRCC lipid metabolism. Both genetic and pharmacologic suppression of either receptor suppressed lipid formation and induced multiple forms of cell death, including apoptosis, ferroptosis, and autophagy, thereby significantly impeding ccRCC growth in cell lines and patient-derived xenograft models. Comprehensive lipidomic and transcriptomic profiling of receptor competent and depleted cells revealed overlapping and unique signaling of the receptors granting control over triglyceride synthesis, ceramide production, and fatty acid saturation and class production. Mechanistically, both receptors enforced suppression of adipose triglyceride lipase, but each receptor also demonstrated distinct functions, such as the unique ability of CMKLR1 to control lipid uptake through regulation of sterol regulatory element-binding protein 1c and the CD36 scavenger receptor. Treating patient-derived xenograft models with the CMKLR1-targeting small molecule 2-(α-naphthoyl) ethyltrimethylammonium iodide (α-NETA) led to a dramatic reduction in tumor growth, lipid storage, and clear-cell morphology. Together, these findings provide mechanistic insights into lipid regulation in ccRCC and identify a targetable axis at the core of the histologic definition of this tumor that could be exploited therapeutically. Significance: Extracellular control of lipid accumulation via G protein receptor-mediated cell signaling is a metabolic vulnerability in clear cell renal cell carcinoma, which depends on lipid storage to avoid oxidative toxicity.

Revealing Molecular Mechanisms of the Bioactive Saponins from Edible Root of Platycodon grandiflorum in Combating Obesity.

Obesity has emerged as a significant health concern, as it is a disease linked to metabolic disorders in the body and is characterized by the excessive accumulation of lipids. As a plant-derived food, Platycodon grandiflorum (PG) was reported by many studies, indicating that the saponins from PG can improve obesity effectively. However, the anti-obesity saponins from PG and its anti-obesity mechanisms have not been fully identified. This study identified the active saponins and their molecular targets for treating obesity. The TCMSP database was used to obtain information on 18 saponins in PG. The anti-obesity target of the PG saponins was 115 targets and 44 core targets. GO and KEGG analyses using 44 core anti-obesity genes and targets of PG-active saponins screened from GeneCards, OMIM, Drugbank, and DisGeNet showed that the PI3K-Akt pathway, the JAK-STAT pathway, and the MAPK pathway were the major pathways involved in the anti-obesity effects of PG saponins. BIOVIA Discovery Studio Visualizer and AutoDock Vina were used to perform molecular docking and process the molecular docking results. The molecular docking results showed that the active saponins of PG could bind to the major therapeutic obesity targets to play an obesity-inhibitory role. The results of this study laid the foundation for further research on the anti-obesity saponins in PG and their anti-obesity mechanism and provided a new direction for the development of functional plant-derived food. This research studied the molecular mechanism of PG saponins combating obesity through various signaling pathways, and prosapogenin D can be used to develop as a new potential anti-obesity drug.

Mechanistic insights into the role of USP14 in adipose tissue macrophage recruitment and insulin resistance in obesity

Diet-induced obesity can cause metabolic syndromes. The critical link in disease progression is adipose tissue macrophage (ATM) recruitment, which drives low-level inflammation, triggering adipocyte dysfunction. It is unclear whether ubiquitin-specific proteinase 14 (USP14) affects metabolic disorders by mediating adipose tissue inflammation. In the present study, we showed that USP14 is highly expressed in ATMs of obese human patients and diet-induced obese mice. Mouse USP14 overexpression aggravated obesity-related insulin resistance by increasing the levels of pro-inflammatory ATMs, leading to adipose tissue inflammation, excessive lipid accumulation, and hepatic steatosis. In contrast, USP14 knockdown in adipose tissues alleviated the phenotypes induced by a high-fat diet. Co-culture experiments showed that USP14 deficiency in macrophages led to decreased adipocyte lipid deposition and enhanced insulin sensitivity, suggesting that USP14 plays an important role in ATMs. Mechanistically, USP14 interacted with TNF receptor-associated 6, preventing K48-linked ubiquitination as well as proteasome degradation, leading to increased pro-inflammatory polarization of macrophages. In contrast, the pharmacological inhibition of USP14 significantly ameliorated diet-induced hyperlipidemia and insulin resistance in mice. Our results demonstrated that macrophage USP14 restriction constitutes a key constraint on the pro-inflammatory M1 phenotype, thereby inhibiting obesity-related metabolic diseases.

Probiotic Mixture Ameliorates a Diet-Induced MASLD/MASH Murine Model through the Regulation of Hepatic Lipid Metabolism and the Gut Microbiome.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent metabolic disease that has no effective treatment. Our proprietary probiotic mixture, Prohep, has been proven in a previous study to be helpful in reducing hepatocellular carcinoma (HCC) in vivo. However, its prospective benefits on the treatment of other liver diseases such as MASLD, which is one of the major risk factors in the development of HCC, are unclear. To investigate the potential of Prohep in modulating the development and progression of MASLD, we first explored the effect of Prohep supplementation via voluntary intake in a high-fat diet (HFD)-induced MASLD/metabolic dysfunction-associated steatohepatitis (MASH) murine model. Our results indicated that Prohep alleviated HFD-induced liver steatosis and reduced excessive hepatic lipid accumulation and improved the plasma lipid profile when compared with HFD-fed control mice through suppressing hepatic de novo lipogenesis and cholesterol biosynthesis gene expressions. In addition, Prohep was able to modulate the gut microbiome, modify the bile acid (BA) profile, and elevate fecal short-chain fatty acid (SCFA) levels. Next, in a prolonged HFD-feeding MASLD/MASH model, we observed the effectiveness of Prohep in preventing the transition from MASLD to MASH via amelioration in hepatic steatosis, inflammation, and fibrosis. Taken together, Prohep could ameliorate HFD-induced MASLD and control the MASLD-to-MASH progression in mice. Our findings provide distinctive insights into the development of novel microbial therapy for the management of MASLD and MASH.

Raman-AFM-fluorescence-guided impact of linoleic and eicosapentaenoic acids on subcellular structure and chemical composition of normal and cancer human colon cells

The regular overconsumption of high-energy food (rich in lipids and sugars) results in elevated nutrient absorption in intestine and consequently excessive accumulation of lipids in many organs e.g.: liver, adipose tissue, muscles. In the long term this can lead to obesity and obesity-associated diseases e.g. type 2 diabetes, non-alcoholic fatty liver disease, cardiovascular disease, inflammatory bowel disease (IBD). In the presented paper based on RI data we have proved that Raman maps can be used successfully for subcellular structures visualization and analysis of fatty acids impact on morphology and chemical composition of human colon single cells – normal and cancer. Based on Raman data we have investigated the changes related to endoplasmic reticulum, mitochondria, lipid droplets and nucleus. Analysis of ratios calculated based on Raman bands typical for proteins (1256, 1656 cm−1), lipids (1304, 1444 cm−1) and nucleic acids (750 cm−1) has confirmed for endoplasmic reticulum the increased activity of this organelle in lipoproteins synthesis upon FAs supplementation; for LDs the changes of desaturation of accumulated lipids with the highest unsaturation level for CaCo-2 cells upon EPA supplementation; for mitochondria the stronger effect of FAs supplementation was observed for CaCo-2 cells confirming the increased activity of this organelle responsible for energy production necessary for tumor development; the weakest impact of FAs supplementation was observed for nucleus for both types of cells and both types of acids. Fluorescence imaging was used for the investigations of changes in LDs/ER morphology. Our measurements have shown the increased area of LDs/ER for CaCo-2 cancer cells, and the strongest effect was noticed for CaCo-2 cells upon EPA supplementation. The increased participation of lipid structures for all types of cells upon FAs supplementation has been confirmed also by AFM studies. The lowest YM values have been observed for CaCo-2 cells including samples treated with FAs.

Surfactant protein A promotes western diet-induced hepatic steatosis and fibrosis in mice

Metabolic dysfunction-associated steatotic liver disease (MASLD) remains the most common cause of liver disease in the United States due to the increased incidence of metabolic dysfunction and obesity. Surfactant protein A (SPA) regulates macrophage function, strongly binds to lipids, and is implicated in renal and idiopathic pulmonary fibrosis (IPF). However, the role of SPA in lipid accumulation, inflammation, and hepatic fibrosis that characterize MASLD remains unknown. SPA deficient (SPA−/−) and age-matched wild-type (WT) control mice were fed a Western diet for 8 weeks to induce MASLD. Blood and liver samples were collected and used to analyze pathological features associated with MASLD. SPA expression was significantly upregulated in livers of mice with MASLD. SPA deficiency attenuated lipid accumulation along with downregulation of genes involved in fatty acid uptake and reduction of hepatic inflammation as evidenced by the diminished macrophage activation, decreased monocyte infiltration, and reduced production of inflammatory cytokines. Moreover, SPA−/− inhibited stellate cell activation, collagen deposit, and liver fibrosis. These results highlight the novel role of SPA in promoting fatty acid uptake into hepatocytes, causing excessive lipid accumulation, inflammation, and fibrosis implicated in the pathogenesis of MASLD.

(−)-Epigallocatechin-3-O-gallate or (−)-epicatechin enhances lipid catabolism and antioxidant defense in common carp (Cyprinus carpio L.) fed a high-fat diet: Mechanistic insights from the AMPK/Sirt1/PGC-1α signaling pathway

Long-term high-fat diets (HF) lead to lipid accumulation and an oxidative stress response, which deteriorates the chemical and physical characteristics of fish muscle. Green tea extracts, such as (−)-epigallocatechin-3-O-gallate (EGCG) and (−)-epicatechin (EC), have been found to regulate antioxidant ability and lipid metabolism. However, the effects of EGCG and EC on alleviating oxidative stress and lipid metabolism disorders caused by HF are unclear. Furthermore, the underlying mechanisms remain unknown. In this study, a total of 360 carp (average weight: 9.75 ± 0.09 g) were provided with four experimental diets: a control diet (CN, 6.15% dietary lipids), a high-fat diet (HF, 14.05% dietary lipids), HF supplemented with EGCG (HF + EGCG, 14.05% dietary lipids +50 mg/kg EGCG), and a HF diet supplemented with EC (HF + EC, 14.05% dietary lipids +1000 mg/kg EC) for a duration of 84 days. The results indicated that EGCG or EC ameliorated the negative effects of the HF diet on muscle tissue. Apart from muscle physical characteristics, EGCG decreased yellowness (b*), redness (a*), and dripping loss (P < 0.05). Apart from muscle nutritional composition and antioxidant status, EC mitigated the reduction in protein levels in the muscle induced by the HF diet. Similarly, EGCG and EC mitigated the excessive accumulation of lipids and reactive oxygen species (ROS) in the muscle induced by the HF diet (P < 0.05). Further study showed that EGCG or EC facilitated the phosphorylation of AMP-activated protein kinase (AMPK) and increased silent information regulator 1 (Sirt1) and PPARγ coactivator-1 alpha (PGC-1α) expression in muscle. Taken together, the results of this study revealed that EGCG or EC enhance lipid metabolism and antioxidant capacity in the muscle of common carp (Cyprinus carpio L.) via the AMPK/Sirt1/PGC-1α pathway.

Deciphering adipose development: Function, differentiation and regulation.

The overdevelopment of adipose tissues, accompanied by excess lipid accumulation and energy storage, leads to adipose deposition and obesity. With the increasing incidence of obesity in recent years, obesity is becoming a major risk factor for human health, causing various relevant diseases (including hypertension, diabetes, osteoarthritis and cancers). Therefore, it is of significance to antagonize obesity to reduce the risk of obesity-related diseases. Excess lipid accumulation in adipose tissues is mediated by adipocyte hypertrophy (expansion of pre-existing adipocytes) or hyperplasia (increase of newly-formed adipocytes). It is necessary to prevent excessive accumulation of adipose tissues by controlling adipose development. Adipogenesis is exquisitely regulated by many factors in vivo and in vitro, including hormones, cytokines, gender and dietary components. The present review has concluded a comprehensive understanding of adipose development including its origin, classification, distribution, function, differentiation and molecular mechanisms underlying adipogenesis, which may provide potential therapeutic strategies for harnessing obesity without impairing adipose tissue function.

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.

Phthalate Biomarkers Composition in Relation to Fatty Liver: Evidence from Epidemiologic and in vivo studies

Phthalates, classified as environmental endocrine disruptors, pose potential toxicity risks to human health. Metabolic dysfunction-associated fatty liver disease is one of the most widespread liver diseases globally. Compared to studies focusing on metabolic disorders in relation to pollutants exposure, the impact of individual factors such as fatty liver on the in vivo metabolism of pollutants is always overlooked. Therefore, this study measured concentrations and composition of phthalate monoesters (mPAEs) in human urine samples, particularly those from fatty liver patients. Furthermore, we induced fatty liver in male Wistar rats by formulating a high-fat diet for twelve weeks. After administering a single dose of DEHP at 500 mg/kg bw through gavage, we compared the levels of di-2-ethylhexyl phthalate (DEHP), its metabolites (mDEHPs) and three hepatic metabolic enzymes, namely cytochrome P450 enzymes (CYP450), UDP glucuronosyltransferase 1 (UGT1), and carboxylesterase 1 (CarE1), between the normal and fatty liver rat groups. Compared to healthy individuals (n = 75), fatty liver patients (n = 104) exhibited significantly lower urinary concentrations of ∑mPAEs (median: 106 vs. 166 ng/mL), but with a higher proportion of mono-2-ethylhexyl phthalate in ∑mDEHPs (25.7 % vs. 9.9 %) (p < 0.05). In the animal experiment, we found that fatty liver in rats prolonged the elimination half-life of DEHP (24.61 h vs. 18.89 h) and increased the contents of CYP450, CarE1, and UGT1, implying the common but differentiated metabolism of DEHP as excess lipid accumulation in liver cells. This study provides valuable information on how to distinguish populations in biomonitoring studies across a diverse population and in assigning exposure classifications of phthalates or similar chemicals in epidemiologic studies.

Pla2g12b drives expansion of triglyceride-rich lipoproteins

Vertebrates transport hydrophobic triglycerides through the circulatory system by packaging them within amphipathic particles called Triglyceride-Rich Lipoproteins. Yet, it remains largely unknown how triglycerides are loaded onto these particles. Mutations in Phospholipase A2 group 12B (PLA2G12B) are known to disrupt lipoprotein homeostasis, but its mechanistic role in this process remains unclear. Here we report that PLA2G12B channels lipids within the lumen of the endoplasmic reticulum into nascent lipoproteins. This activity promotes efficient lipid secretion while preventing excess accumulation of intracellular lipids. We characterize the functional domains, subcellular localization, and interacting partners of PLA2G12B, demonstrating that PLA2G12B is calcium-dependent and tightly associated with the membrane of the endoplasmic reticulum. We also detect profound resistance to atherosclerosis in PLA2G12B mutant mice, suggesting an evolutionary tradeoff between triglyceride transport and cardiovascular disease risk. Here we identify PLA2G12B as a key driver of triglyceride incorporation into vertebrate lipoproteins.

Pennogenin 3-O-β-Chacotrioside Attenuates Hypertrophied Lipid Accumulation by Enhancing Mitochondrial Oxidative Capacity.

Excessive lipid accumulation in adipocytes is a primary contributor to the development of metabolic disorders, including obesity. The consumption of bioactive compounds derived from natural sources has been recognized as being safe and effective in preventing and alleviating obesity. Therefore, we aimed to explore the antilipidemic effects of pennogenin 3-O-β-chacotrioside (P3C), a steroid glycoside, on hypertrophied 3T3-L1 adipocytes. Oil Red O and Nile red staining demonstrated a P3C-induced reduction in lipid droplet accumulation. Additionally, the increased expression of adipogenic and lipogenic factors, including PPARγ and C/EBPα, during the differentiation process was significantly decreased by P3C treatment at both the protein and mRNA levels. Furthermore, P3C treatment upregulated the expression of fatty acid oxidation-related genes such as PGC1α and CPT1a. Moreover, mitochondrial respiration and ATP generation increased following P3C treatment, as determined using the Seahorse XF analyzer. P3C treatment also increased the protein expression of mitochondrial oxidative phosphorylation in hypertrophied adipocytes. Our findings suggest that P3C could serve as a natural lipid-lowering agent, reducing lipogenesis and enhancing mitochondrial oxidative capacity. Therefore, P3C may be a promising candidate as a therapeutic agent for obesity-related diseases.

FOXO3/Rab7-Mediated Lipophagy and Its Role in Zn-Induced Lipid Metabolism in Yellow Catfish (Pelteobagrus fulvidraco).

Lipophagy is a selective autophagy that regulates lipid metabolism and reduces hepatic lipid deposition. However, the underlying mechanism has not been understood in fish. In this study, we used micronutrient zinc (Zn) as a regulator of autophagy and lipid metabolism and found that Ras-related protein 7 (rab7) was involved in Zn-induced lipophagy in hepatocytes of yellow catfish Pelteobagrus pelteobagrus. We then characterized the rab7 promoter and identified binding sites for a series of transcription factors, including Forkhead box O3 (FOXO3). Site mutation experiments showed that the -1358/-1369 bp FOXO3 binding site was responsible for Zn-induced transcriptional activation of rab7. Further studies showed that inhibition of rab7 significantly inhibited Zn-induced lipid degradation by lipophagy. Moreover, rab7 inhibitor also mitigated the Zn-induced increase of cpt1α and acadm expression. Our results suggested that Zn exerts its lipid-lowering effect partly through rab7-mediated lipophagy and FA β-oxidation in hepatocytes. Overall, our findings provide novel insights into the FOXO3/rab7 axis in lipophagy regulation and enhance the understanding of lipid metabolism by micronutrient Zn, which may help to reduce excessive lipid accumulation in fish.