Sterol Regulatory Element-binding Protein Research Articles

Effects of celastrol on the heart and liver galaninergic system expression in a mouse model of Western-type diet-induced obesity and metabolic dysfunction-associated steatotic liver disease and steatohepatitis

BackgroundThe complexity of the galaninergic system is still not fully understood, especially under specific pre-existing comorbidities related to metabolic dysfunction. A plant-derived triterpenoid celastrol was demonstrated to exert a complex effect on the galaninergic system and to have hepatoprotective and anti-obesity properties. However, the exact molecular mechanisms responsible for these effects remain unclear. Specifically, there are no data on the impact of celastrol on the heart and liver galaninergic system. Therefore, this study aimed to investigate the effects of celastrol on the galaninergic system expression in the heart and liver of mice suffering from diet-induced obesity and metabolic dysfunction-associated steatotic liver disease and steatohepatitis (MASLD/MASH).MethodsThe male mice C57BL/6J were fed a Western-type high-fat diet for 16 and 20 weeks to induce obesity and MASLD/MASH. Celastrol was administered along with a specific diet for the last 4 weeks to evaluate its impact on the progression of these conditions. Moreover, the inhibitor of sterol regulatory element-binding protein 1/2 (SREBP1/2), fatostatin, was also tested to compare its influence on the galaninergic system with celastrol.ResultsThe study demonstrates that celastrol treatment was safe and led to a reduction in food and energy intake, body fat and liver weights, and MASLD-to-MASH progression and improved glucose tolerance, serum biochemistry markers, and hepatic lipid peroxidation in mice. Quantitative gene expression originally showed significant regulation of galanin and all three of its receptors (GalR1/2/3) in the heart ventricles and only GalR2 in the liver of obese mice. Celastrol influenced the gene expression of galanin receptors: it downregulated Galr1 in the heart and upregulated Galr2 in the liver and Galr3 in the heart ventricles, potentially affecting energy metabolism, oxidative stress, and inflammation. Fatostatin suppressed gene expression of all the detected members of the galaninergic system in the heart ventricles, depicting the role of SREBP in this process.ConclusionThese findings suggest that celastrol may beneficially modulate the galaninergic system under obesity and MASLD-to-MASH progression, indicating its potential as a therapeutic agent for disorders associated with metabolic dysfunction.

NPD7426 suppresses sterol regulatory element-binding proteins by promoting the degradation of mature SREBP forms.

Sterol regulatory element-binding proteins (SREBPs) are transcription factors that regulate various genes involved in cholesterol and fatty acid synthesis, playing a central role in lipid metabolism regulation in vivo. SREBP-1c activity is significantly elevated in the liver under conditions of obesity, fatty liver disease, and type II diabetes, while suppression of SREBP-1c activity has been shown to alleviate these symptoms. Consequently, targeting SREBP-1c activity is considered a potential therapeutic approach for these conditions. In this study, we identified NPD7426 as a compound with inhibitory effects on SREBP activity. Furthermore, we demonstrated that NPD7426 promotes the proteasome-mediated degradation of mature SREBP protein forms. These findings provide new insights into the mechanism of SREBP activity suppression by small-molecule compounds containing NPD7426, suggesting that NPD7426 may be a promising candidate for the development of therapeutic drugs targeting SREBPs.

Evaluation of selected indigenous spices- and herbs-derived small molecules as potential inhibitors of SREBP and its implications for breast cancer using MD simulations and MMPBSA calculations.

In this study, we conducted an extensive analysis of 252 bioactive compounds derived from native spices and herbs for their potential anti-breast cancer activity against sterol regulatory element-binding protein (SREBP), using in silico techniques. To evaluate the oral bioavailability, overall pharmacokinetics, and safety profiles of these compounds, we employed Lipinski's rule of five and ADME descriptors, which depicted 66 lead molecules. These molecules were then docked with the SREBP using molecular docking tools, which revealed that diosgenin and smilagenin were the most promising hits compared to the reference inhibitor betulin, with average binding affinities of -7.42 and -7.37kcal/mol and -6.27kcal/mol, respectively. To further assess the stability of these complexes along with betulin, we conducted molecular dynamics simulations over a 100ns simulation period. We employed various parameters, including the root-mean-square deviation, root-mean-square fluctuation, solvent-accessible surface area, free energy of solvation, and radius of gyration, followed by principal component analysis. Furthermore, we evaluated the toxicity of the selected compounds against various anticancer cell lines, as well as their metabolic activity related to CYP450 metabolism and biological activity spectrum. Based on these results, both molecules exhibited promising drug candidate potential and could be utilized for further experimental analysis to elucidate their anticancer potential.

Embelin Elevates Endoplasmic Reticulum Calcium Levels and Blocks the Sterol Regulatory Element-Binding Protein 2 Mediated Proprotein Convertase Subtilisin/Kexin Type 9 Expression and Improves the Low-Density Lipoprotein Receptor Mediated Lipid Clearance on Hepatocytes.

Cardiovascular diseases (CVDs) continue to be one of the leading causes of morbidity and mortality worldwide, with a significant increase in recent years. Atherosclerosis, the pathological basis and prime reason for CVDs is primarily driven by dysregulated lipid metabolism and inflammation. Recently, proprotein convertase subtilisin kexin9 (PCSK9) has been evolved to be highly implicated in the circulatory low-density lipoprotein cholesterol levels by its modulatory effects on the low-density lipoprotein receptor (LDLR) mediated clearance. Even though not economical, the therapies targeting PCSK9 demonstrated appreciable levels of efficiency in managing hyperlipidaemic conditions. Embelin (2,5-dihydroxy-3-undecyl-1,4-benzoquinone) is a naturally occurring para-benzoquinone isolated from dried berries of Embelia ribes, which possess several effects in maintaining the cholesterol homeostasis. In this study, we have analysed the role of embelin in sterol regulatory element-binding protein 2 (SREBP2) mediated PCSK9 expression in cultured hepatocytes. The study showed that the embelin treatment attenuates the endoplasmic reticulum (ER) stress-induced reactive oxygen species levels and ER stress markers on cultured hepatocytes. The treatment of embelin modulates the mRNA and protein level expression of SREBP2 and its downstream targets like PCSK9, LDLR, and HMG-CoA reductase (HMGCR). Interestingly the Ca2+ levels and the calcium binding protein of ER were significantly increased with embelin treatment. The work revealed a putative mechanism of embelin in lowering PCSK9 levels by boosting ER Ca2+ levels, thereby blocking SREBP2 nuclear translocation. Further, this reduces LDLR degradation and increases receptor-mediated circulatory lipid clearance. The study summarized the potential clinical applications of embelin in addressing the cardio vascular diseases.

MiR-18a-5p/PXR/SREBP2 Was Involved in MAFLD Associated With Methyl Tert-Butyl Ether Among Petrol Station Workers.

Metabolic associated fatty liver disease (MAFLD), previously defined as non-alcoholic fatty liver disease (NAFLD), has been shown to be closely related to many environmental pollutants. Lately, we found methyl tert-butyl ether (MTBE), a new environmental pollutant, could increase NAFLD risk in American adults, which still needs more population epidemiological studies to verify, and its pathogenic mechanism is not yet clear. We conducted a cross-sectional study among petrol station workers, diagnosed their MAFLD according to internationally recognised diagnostic criteria, assessed the potential association of MTBE exposure with MAFLD risk, and explored the miR-18a-5p/PXR/SREBP2 pathway as possible pathogenic mechanisms in male Wistar rats and HepaRG cells treated with MTBE. Blood MTBE levels were found to be significantly correlated with an increased risk of MAFLD, and MAFLD risk increased by 24.3% for every 0.1 μg/L increase in blood MTBE. Consistently, we found that MTBE exposure could induce MAFLD in rats and HepaRG cells, and activate pregnane X receptor (PXR) by inhibiting miR-18a-5p to upregulate the expression of sterol regulatory element-binding protein 2 (SREBP2) and its nuclear translocation, thereby upregulating the expression of its downstream target genes. Our study demonstrated that MTBE exposure might be a significant risk factor for MAFLD, and MTBE could promote liver cholesterol synthesis and lipid deposition by activating the miRNA-18a-5p/PXR/SREBP2 pathway.

Copy number amplification of FLAD1 promotes the progression of triple-negative breast cancer through lipid metabolism.

Triple-negative breast cancer (TNBC) is known for frequent copy number alterations (CNAs) and metabolic reprogramming. However, the mechanism by which CNAs of metabolic genes drive distinct metabolic reprogramming and affect disease progression remains unclear. Through an integrated analysis of our TNBC multiomic dataset (n = 465) and subsequent experimental validation, we identify copy number amplification of the metabolic gene flavin-adenine dinucleotide synthetase 1 (FLAD1) as a crucial genetic event that drives TNBC progression. Mechanistically, FLAD1, but not its enzymatically inactive mutant, upregulates the enzymatic activity of FAD-dependent lysine-specific demethylase 1 (LSD1). LSD1 subsequently promotes the expression of sterol regulatory element-binding protein 1 (SREBP1) by demethylating dimethyl histone H3 lysine 9 (H3K9me2). The upregulation of SREBP1 enhances the expression of lipid biosynthesis genes, ultimately facilitating the progression of TNBC. Clinically, pharmacological inhibition of the FLAD1/LSD1/SREBP1 axis effectively suppresses FLAD1-induced tumor progression. Moreover, LSD1 inhibitor enhances the therapeutic effect of doxorubicin and sacituzumab govitecan (SG). In conclusion, our findings reveal the CNA-derived oncogenic signalling axis of FLAD1/LSD1/SREBP1 and present a promising treatment strategy for TNBC.

Antioxidant Peptides from Miiuy Croaker Swim Bladders: Ameliorating Effect and Mechanism in NAFLD Cell Model through Regulation of Hypolipidemic and Antioxidant Capacity

In this work, the hypolipidemic and antioxidative capacity of FSGLR (S7) and GIEWA (S10) from miiuy croaker swim bladders was explored systematically in an oleic acid (OA)-induced nonalcoholic fatty liver disease (NAFLD) model of HepG2 cells. Moreover, the hypolipidemic activity of S7 and S10 and their antioxidative abilities were preliminarily investigated in combination with molecular docking technology. The results indicated that S7 and S10 could decrease the amount of lipid accumulation and the content of triglycerides (TG) and total cholesterol (TC) in the OA-induced NAFLD cell model in a dose-dependent manner. In addition, S7 and S10 exhibited better bile salt binding, pancreatic lipase (PL) inhibition, and cholesterol esterase (CE) inhibition capacities. The hypolipidemic mechanisms of S7 and S10 were connected with the downregulation of the mRNA expression levels of adipogenic factors, including sterol-regulatory element-binding protein-1c (SREBP-1c), acetyl-CoA carboxylase (ACC), sterol-regulatory element-binding protein (SREBP)-2, hydroxymethylglutaryl-CoA reductase (HMGR), and fatty acid synthase (FAS) (p < 0.01), and the upregulation of the mRNA expression of β-oxidation-related factors, including carnitine palmitoyltransferase 1 (CPT-1), acyl-CoA oxidase 1 (ACOX-1), and peroxisome proliferator-activated receptor α (PPARα). Moreover, FSGLR (S7) and GIEWA (S10) could significantly protect HepG2 cells against OA-induced oxidative damage, and their antioxidant mechanisms were related to the increased activity of intracellular antioxidant proteases (superoxide dismutase, SOD; glutathione peroxidase, GSH-PX; catalase, CAT) to remove excess reactive oxygen species (ROS) and decrease the production of malondialdehyde (MDA). The presented findings indicate that the hypolipidemic and antioxidant functions and mechanisms of S7 and S10 could make them potential hypolipidemic and antioxidant candidates for the treatment of NAFLD.

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.

Reconstruction and computer analysis of the structural and functional organization of the gene network regulating cholesterol biosynthesis in humans and the evolutionary characteristics of the genes involved in the network

Cholesterol is an essential structural component of cell membranes and a precursor of vitamin D, as well as steroid hormones. Humans and other animal species can absorb cholesterol from food. Cholesterol is also syn­thesized de novo in the cells of many tissues. We have previously reconstructed the gene network regulating intra­cellular cholesterol levels, which included regulatory circuits involving transcription factors from the SREBP (Sterol Regulatory Element-Binding Proteins) subfamily. The activity of SREBP transcription factors is regulated inversely depending on the intracellular cholesterol level. This mechanism is implemented with the participation of proteins SCAP, INSIG1, INSIG2, MBTPS1/S1P and MBTPS2/S2P. This group of proteins, together with the SREBP factors, is designated as “cholesterol sensor”. An elevated cholesterol level is a risk factor for the development of cardiovas­cular diseases and may also be observed in obesity, diabetes and other pathological conditions. Systematization of information about the molecular mechanisms controlling the activity of SREBP factors and cholesterol biosyn­thesis in the form of a gene network and building new knowledge about the gene network as a single object is extremely important for understanding the molecular mechanisms underlying the predisposition to diseases. With a computer tool, ANDSystem, we have built a gene network regulating cholesterol biosynthesis. The gene network included data on: (1) the complete set of enzymes involved in cholesterol biosynthesis; (2) proteins that function as part of the “cholesterol sensor”; (3) proteins that regulate the activity of the “cholesterol sensor”; (4) genes encod­ing proteins of these groups; (5) genes whose transcription is regulated by SREBP factors (SREBP target genes). The gene network was analyzed and feedback loops that control the activity of SREBP factors were identified. These feedback loops involved the PPARG, NR0B2/SHP1, LPIN1, and AR genes and the proteins they encode. Analysis of the phylostratigraphic age of the genes showed that the ancestral forms of most human genes encoding the enzymes of cholesterol biosynthesis and the proteins of the “cholesterol sensor” may have arisen at early evolutionary stages (Cellular organisms (the root of the phylostratigraphic tree) and the stages of Eukaryota and Metazoa divergence). However, the mechanism of gene transcription regulation in response to changes in cholesterol levels may only have formed at later evolutionary stages, since the phylostratigraphic age of the genes encoding the transcription factors SREBP1 and SREBP2 corresponds to the stage of Vertebrata divergence.

Effect of PCSK9 Inhibitors on Regulators of Lipoprotein Homeostasis, Inflammation and Coagulation

Background: PCSK9 inhibitors (PCSK9i) represent a newer form of atherosclerosis treatment. Inflammation and haemostasis are key processes in the development of atherosclerosis. In this study, we investigated the influence of therapy with PCSK9i in patients with coronary artery disease (CAD) on regulators for lipoprotein homeostasis, inflammation and coagulation. Methods: Using quantitative polymerase chain reaction (qPCR), we measured the expression of the genes involved in lipoprotein homeostasis, namely for sterol regulatory element-binding protein 1 (SREBP1), SREBP2, low-density lipoprotein receptor (LDLR), hepatic lipase type C (LIPC), LDLR-related protein 8 (LRP8), and the genes associated with inflammation and coagulation, such as cluster of differentiation (CD) 36 (CD36), CD63, and CD14 in 96 patients with CAD and 25 healthy subjects. Results: Significant differences in the expression of the investigated genes between patients and healthy controls were found. Treatment with PCSK9i also resulted in significant changes in the expression of all studied genes. Conclusions: We established that PCSK9i may have a significant effect on the gene expression of lipid regulators, inflammatory markers, and coagulation parameters, independent of their lipolytic effect.

Taurine alleviates dysfunction of cholesterol metabolism under hyperuricemia by inhibiting A2AR-SREBP-2/CREB/HMGCR axis.

Dysfunctional cholesterol metabolism is highly prevalent in patients with hyperuricemia. Both uric acid and cholesterol are independent risk factors for atherosclerosis, contributing to an increased incidence of cardiovascular disease in hyperuricemia. Investigating the pathological mechanisms underlying cholesterol metabolism dysfunction in hyperuricemia is essential. This study identified adenosine and inosine, two major purine metabolites, as key regulators of cholesterol biosynthesis. These metabolites up-regulate 3-hydroxy-3-methylglutaryl-CoA (HMGCR). Further mechanistic studies revealed that adenosine/inosine up-regulated the expression of HMGCR by activating adenosine A2A receptor (A2AR) via the sterol-regulatory element binding protein 2 (SREBP-2)/CREB axis in hyperuricemia. Additionally, we found that taurine deficiency contributes to cholesterol metabolism dysfunction in hyperuricemia. Taurine administration in hyperuricemia mice significantly reduced cholesterol elevation by inhibiting A2AR. This study provides a promising strategy for treating comorbid hypercholesterolemia and hyperuricemia.

Effects of Enterococcus faecalis Supplementation on Growth Performance, Hepatic Lipid Metabolism, and mRNA Expression of Lipid Metabolism Genes and Intestinal Flora in Geese.

The effects of Enterococcus faecalis (E. faecalis) at a concentration of 1.0 × 108 CFU/mL on growth performance, hepatic lipid metabolism, and mRNA expression related to lipid metabolism, intestinal morphology, and intestinal flora were investigated in geese. A total of 60 male geese, aged 30 days and of similar weight, were randomly assigned to 2 groups. Each group was divided into six replicates, with five geese per replicate. During the 45-day experiment, the control group received a basal diet, while the experimental group was provided with the same basal diet supplemented with E. faecalis in drinking water at a concentration of 1.0 × 108 CFU/mL. E. faecalis significantly increased the half-eviscerated weight of geese and improved ileal intestinal morphology (p < 0.05). Serum triglyceride (TG) levels were significantly reduced on day 5, while serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels were significantly decreased on day 25 (p < 0.05). By day 45, serum TG and free fatty acid (FFA) levels were also significantly reduced (p < 0.05). Additionally, E. faecalis significantly increased the HDL/LDL ratio and serum high-density lipoprotein cholesterol (HDL-C) levels (p < 0.05). Serum insulin levels were significantly elevated on day 25, and glucagon-like peptide-1 (GLP-1) levels were significantly increased on day 45 (p < 0.05). On day 25 of the trial, hepatic TG levels, FFA levels, and Oil Red O-stained areas in the liver were significantly reduced (p < 0.05), accompanied by significantly decreased mRNA expression of hepatic acetyl-CoA carboxylase (ACCA) (p < 0.05). Conversely, the mRNA expression levels of fatty acid synthase (FASN), farnesoid X receptor (FXR), sterol regulatory element-binding protein 1 (SREBP-1), and peroxisome proliferator-activated receptor-α (PPARα) were significantly elevated (p < 0.05). A 16S rRNA diversity analysis of ileal contents on day 25 revealed significant differences in intestinal flora composition between the control and E. faecalis groups. The 16S rRNA data demonstrated a strong correlation between microbial communities and lipid-related physiological and biochemical indicators (p < 0.05). In conclusion, E. faecalis supplementation promoted fatty acid oxidation, reduced blood lipid levels, alleviated hepatic lipid accumulation, and improved ileal morphology and intestinal flora diversity, thereby enhancing growth performance and lipid metabolism in geese. These findings suggest that E. faecalis is a promising probiotic candidate for development as a feed additive.

Probiotic Supplementation Alleviates Corticosterone-Induced Fatty Liver Disease by Regulating Hepatic Lipogenesis and Increasing Gut Microbiota Diversity in Broilers.

Emerging evidence indicates a close relationship between gut microbiota and fatty liver disease. It has been suggested that gut microbiota modulation with probiotics ameliorates fatty liver disease in rodents and humans, yet it remains unclear whether the same results will also be obtained in poultry. The aim of this study was to investigate whether a mixture of probiotics supplemented after hatching can prevent CORT-induced fatty liver disease in broilers, and to determine how such effects, if any, are associated with hepatic de novo lipogenesis and gut microbiota composition. Ninety-six one-day-old green-legged chickens were divided into a control group (CON) and probiotic group (PB). At 28 days of age, fatty liver was induced in 16 broilers that were randomly selected from the CON or PB group. At the end of the experiment, broilers from four groups, (i) the control group (CON), (ii) corticosterone group (CORT), (iii) probiotic group (PB), and (iv) PB plus CORT group (CORT&PB), were slaughtered for sampling and analysis. The results showed that probiotic administration significantly prevented CORT-induced body weight loss (p < 0.05) but did not alleviate the weight loss of immune organs caused by CORT. Compared to CON, the broilers in the CORT group exhibited a significant increase in triglyceride (TG) levels in plasma and liver (p < 0.01), as well as severe hepatocytic steatosis and hepatocellular ballooning, which was accompanied by the upregulation of hepatic lipogenesis gene expression. However, probiotic supplementation markedly decreased the intrahepatic lipid accumulation and steatosis histological score, which was associated with the downregulation of sterol regulatory element-binding protein-1 (SREBP1) and acetyl-CoA carboxylase (ACC) mRNA (p < 0.05) and the expression of its protein (p = 0.06). The cecal microbiota composition was determined by 16S rRNA high-throughput sequencing. The results showed that CORT treatment induced distinct gut microbiota alterations with a decrease in microbial diversity and an increase in Proteobacteria abundance (p < 0.05). In contrast, probiotic supplementation increased the beta diversity, the community richness, and the diversity index (p > 0.05), as well as the abundance of Intestinimonas (p < 0.05). Our results indicate that CORT treatment induced severe fatty liver disease and altered the gut microbiota composition in broilers. However, post-hatching probiotic supplementation had a beneficial effect on alleviating fatty liver disease by regulating lipogenic gene expression and increasing gut microbiota diversity and the abundance of beneficial bacteria. We demonstrate for the first time that the supplementation of probiotics to chicks had a beneficial effect on preventing fatty liver disease through regulating lipogenic gene expression and improving the gut microbial balance. Thus, our results indicate that probiotics are a potential nutritional agent for preventing fatty liver disease in chickens.

Impact of protein intake from a caloric-restricted diet on liver lipid metabolism in overweight and obese rats of different sexes

In addition to being linked to an excess of lipid accumulation in the liver, being overweight or obese can also result in disorders of lipid metabolism. There is limited understanding regarding whether different levels of protein intake within an energy-restricted diet affect liver lipid metabolism in overweight and obese rats and whether these effects differ by gender, despite the fact that both high protein intake and calorie restriction can improve intrahepatic lipid. The purpose of this study is to explore the effects and mechanisms of different protein intakes within a calorie-restricted diet on liver lipid metabolism, and to investigate whether these effects exhibit gender differences. The Sprague-Dawley rats, which were half female and half male, were used to construct a rat model of overweight and obesity attributed to a high-fat diet. They were then split up into five groups: the normal control (NC) group, the model control (MC) group, the calorie-restricted low protein (LP) group, the calorie-restricted normal protein (NP) group, and the calorie-restricted high protein (HP) group. Body weight was measured weekly. Samples of plasma and liver were obtained after eight weeks and analyzed for glucose, triglycerides, cholesterol, and hormones in the plasma as well as the liver fat and factors involved in the liver’s synthesis and degradation. For the male rats, compared to the HP group, the weight of liver fat in the LP and NP group was significantly higher (P < 0.05). However, for the female rats, there was no significant variation among the three calorie-restricted groups (P > 0.05). There was no significant variation in the concentration of total cholesterol (TC), very low density lipoprotein (VLDL), low density lipoprotein (LDL), and high density lipoprotein (HDL) among the three male calorie-restricted groups (P > 0.05), while the TC and VLDL concentrations in the female LP and NP group were significantly higher compared to those in the HP group (P < 0.05). Moreover, the trend of expression in the signaling pathways of adiponectin/phosphorylated AMP-activated protein kinase (p-AMPK) and adiponectin/peroxisome proliferators-activated receptor alpha (PPARα) in the liver was consistent with that of the liver fat content, and leptin acted in the same way as adiponectin. Compared with the three calorie-restricted groups, the expressions of nuclear sterol-regulatory element-binding protein-2 (nSREBP-2) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) involved in cholesterol synthesis and low-density lipoprotein receptor (LDLR) and cholesterol 7-alpha hydroxylase (CYP7A1) involved in cholesterol clearance in the MC group were significantly lower (P < 0.05). A 40% energy restriction can significantly reduce the body weight, body fat, liver fat, and the blood concentration of TG in both male and female overweight and obese rats, but it can significantly increase the blood concentration of TC in overweight and obese male rats. At the same time of 40% calorie restriction, increasing dietary protein intake to twice the normal protein intake has a stronger effect on promoting hepatic triglyceride oxidation and reducing liver fat content in the male overweight and obese rats by increasing the levels of adiponectin and leptin in the blood, and can also significantly reduce the plasma cholesterol concentration in the female overweight and obese rats through inhibiting cholesterol synthesis most likely by increasing glucagon level in the blood.

Elevated SREBP1 accelerates the initiation and growth of pancreatic cancer by targeting SOX9

Pancreatic cancer is a lethal disease with an insidious onset, and little is known about its early molecular events. Here, we found that the sterol regulatory element-binding protein 1 (SREBP1) expression is gradually upregulated during the initiation of pancreatic cancer. Through in vitro 3D culture of pancreatic acinar cells and experiments in LSL-KrasG12D/+;Pdx1-Cre (KC) mice, we found that pharmacological inhibition of SREBP1 suppressed pancreatic tumorigenesis. In vitro, either knockdown or pharmacological inhibition of SREBP1 suppressed tumor proliferation but SREBP1 overexpression promoted tumor proliferation. In LSL-KrasG12D/+;Trp53fl/+;Pdx1-Cre (KPC) mice, we confirmed the tumor-promoting role of SREBP1 in pancreatic cancer progression. Mechanistically, we revealed SOX9 as a downstream target of SREPB1. SREBP1 inhibition decreased SOX9 expression in both acinar cells and pancreatic cancer cells. Indeed, we identified SREBP1 binding sites in the SOX9 promoter region and reported that SOX9 is transcriptionally regulated by SREBP1. Taken together, our findings demonstrate that SREBP1/SOX9 inhibition suppresses pancreatic cancer initiation and growth, suggesting that SREBP1 could serve as a potential target for cancer screening and treatment.

Fatty Acid Esterification of Octacosanol Attenuates Triglyceride and Cholesterol Synthesis in Mice.

This study aimed to evaluate the cholesterol-regulatory effects of lauric-acid-esterified octacosanol (LEO) and oleic-acid-esterified octacosanol (OEO) compared to their unmodified counterparts and to investigate the underlying mechanisms by partially substituting the fat content in obese C57BL/6J mice induced with a high-fat diet (HFD). Rice bran oil and coconut oil were also investigated as they are rich in oleic acid and lauric acid, respectively. The results showed that all supplemented groups significantly inhibited weight gain induced by the HFD, but the groups treated with esterified octacosanol exhibited a more pronounced effect. Esterified octacosanol inhibited fatty acid synthesis via the Sirtuin 1/AMP-activated protein kinase/Sterol regulatory element-binding protein 1 (SIRT1/AMPK/SREBP-1c) pathway by decreasing fatty acid synthase (FASN) (0.78 fold ±0.09, p < 0.05) transcription and affecting the phospho-acetyl-coA carboxylase/acetyl-coA carboxylase (p-ACC/ACC) (1.42 fold ±0.18, p < 0.05) ratio, as well as by inhibiting cholesterol synthesis by reducing sterol regulatory element-binding protein 2 (SREBP-2) (0.75 fold ±0.08, p < 0.05) and low-density lipoprotein receptor (LDL-R) (1.24 fold ±0.1, p < 0.05), which are responsible for cholesterol uptake. Our findings indicate that OEO had a greater influence on fatty acid and cholesterol synthesis compared to the other agents.

The TRPV1-PKM2-SREBP1 axis maintains microglial lipid homeostasis in Alzheimer’s disease

Microglia are progressively activated by inflammation and exhibit phagocytic dysfunction in the pathogenesis of neurodegenerative diseases. Lipid-droplet-accumulating microglia were identified in the aging mouse and human brain; however, little is known about the formation and role of lipid droplets in microglial neuroinflammation of Alzheimer’s disease (AD). Here, we report a striking buildup of lipid droplets accumulation in microglia in the 3xTg mouse brain. Moreover, we observed significant upregulation of PKM2 and sterol regulatory element binding protein 1 (SREBP1) levels, which were predominantly localized in microglia of 3xTg mice. PKM2 dimerization was necessary for SREBP1 activation and lipogenesis of lipid droplet-accumulating microglia. RNA sequencing analysis of microglia isolated from 3xTg mice exhibited transcriptomic changes in lipid metabolism, innate inflammation, and phagocytosis dysfunction; these changes were improved with capsaicin-mediated pharmacological activation of TRPV1 via inhibition of PKM2 dimerization and reduction of SREBP1 activation. Lipid droplet-accumulating microglia exhibited increased mitochondrial injury accompanied by impaired mitophagy, which was abrogated upon of TRPV1 activation. Capsaicin also rescued neuronal loss, tau pathology, and memory impairment in 3xTg mice. Our study suggests that TRPV1-PKM2-SREBP1 axis regulation of microglia lipid metabolism could be a therapeutic approach to alleviate the consequences of AD.

SREBF1 facilitates pathological retinal neovascularization by reprogramming the fatty acid metabolism of endothelial cells.

Retinopathy of prematurity (ROP) is a proliferative retinal vascular disorder that critically affects the visual development of premature infants, potentially leading to irreversible vision loss or even blindness. Despite its significance, the underlying mechanisms of this disease remain insufficiently understood. In this study, we utilized the oxygen-induced retinopathy (OIR) mouse model and conducted endothelial functional assays to explore the role of Sterol Regulatory Element-Binding Protein 1 (SREBF1) in ROP pathogenesis. SREBF1 expression levels, along with its downstream targets, were investigated through Western blotting, RT-qPCR, and immunofluorescence staining techniques. Furthermore, Co-Immunoprecipitation (Co-IP) was employed to examine the molecular mechanisms involved. Our results demonstrated a significant increase in SREBF1 expression in both the OIR mouse model and hypoxic primary human retinal microvascular endothelial cells (HRMECs). Interventions conducted both in vivo and in vitro showed notable efficacy in reducing pathological neovascularization. Importantly, we discovered that SREBF1 plays a key role in modulating lipid metabolism in HRMECs by regulating the expression of ACC1 and FASN, leading to cellular reprogramming. This reprogramming influences HRMEC proliferation, migration, and tube formation through the HIF-1α/TGF-β signaling pathway, ultimately contributing to pathological retinal neovascularization. These findings provide new insights into the role of SREBF1 in angiogenesis within the context of ROP, offering potential therapeutic targets for the management and treatment of this disease.

Dendrobium nobile Lindl. alkaloids improve lipid metabolism by increasing LDL uptake through regulation of the LXRα/IDOL/LDLR pathway and inhibition of PCSK9 expression in HepG2 cells.

Dendrobium nobile Lindl. alkaloids (DNLA) are active ingredients that can be extracted from the traditional Chinese herb Dendrobium Nobile Lindl. DNLA exhibits hypoglycemic and antihyperlipidemia effects. However, to the best of our knowledge, the specific molecular mechanism by which DNLA can regulate lipid metabolism remains unclear. The aim of the present study was to investigate the effect of DNLA on lipopolysaccharide (LPS)-induced lipid metabolism in HepG2 cells and its potential mechanism. HepG2 cells were treated with LPS with or without different concentrations of DNLA (0, 0.035, 0.35 and 3.5 µg/ml) for 48 h. Cell viability was then detected using the Cell Counting Kit-8 assay. The 1,1'-dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanideperchlorate-low-density lipoprotein (LDL) uptake assay was used to examine LDL uptake. In addition, possible mechanisms were explored using western blot analysis. The effect of the combination of DNLA with rosuvastatin calcium on the expression levels of the LDL receptor (LDLR) and proprotein convertase subtilisin/Kexin type 9 (PCSK9) was examined. The results indicated that LPS stimulation reduced the uptake of LDL by HepG2 cells, decreased the intracellular LDLR content, and increased the expression levels of inducible degrader of the LDLR (IDOL) and liver X receptor (LXR)α. DNLA intervention reversed all of the aforementioned LPS-induced effects in HepG2 cells. Additional mechanistic experiments revealed that DNLA exerted its effects mainly by regulating the LXRα/IDOL/LDLR pathway. It was shown that DNLA also reduced the expression levels of PCSK9, sterol regulatory element binding protein 2 and hepatocyte nuclear factor 1α. In addition, DNLA decreased the expression levels of PCSK9 in rosuvastatin calcium-induced HepG2 cells. Notably, DNLA was able to decrease 3-hydroxy-3-methylglutaryl-coenzyme A reductase and increase cytochrome p450 7A1 expression at the protein level, which are rate-limiting enzymes in cholesterol synthesis and metabolism. Collectively, these data suggested that DNLA could enhance LDL uptake of HepG2 cells by increasing LDLR expression through the LXRα/IDOL/LDLR pathway to alleviate the effects induced by LPS, suggesting the potential benefit of DNLA in improving lipid metabolism disorders.

Bisphenol S Induces Lipid Metabolism Disorders in HepG2 and SK-Hep-1 Cells via Oxidative Stress.

Bisphenol S (BPS) is a typical endocrine disruptor associated with obesity. To observe BPS effects on lipid metabolism in HepG2 and SK-Hep-1 human HCC cells, a CCK-8 assay was used to assess cell proliferation in response to BPS, and the optimal concentration of BPS was selected. Biochemical indices such as triglyceride (TG) and total cholesterol (T-CHO), and oxidative stress indices such as malondialdehyde (MDA) and catalase (CAT) were measured. ROS and MDA levels were significantly increased after BPS treatment for 24 h and 48 h (p < 0.05), indicating an oxidative stress response. Alanine aminotransferase (ALT), T-CHO, and low-density lipoprotein cholesterol (LDL-C) levels also increased significantly after 24 or 48 h BPS treatments (p < 0.05). RT-PCR and Western blot analyses detected mRNA or protein expression levels of peroxisome proliferator-activated receptor α (PPARα) and sterol regulatory element-binding protein 1c (SREBP1C). The results indicated that BPS could inhibit the mRNA expression of PPARα and carnitine palmitoyl transferase 1B (CPT1B), reduce lipid metabolism, promote mRNA or protein expression of SREBP1C and fatty acid synthase (FASN), and increase lipid synthesis. Increased lipid droplets were observed using morphological Oil Red O staining. Our study demonstrates that BPS may cause lipid accumulation by increasing oxidative stress and perturbing cellular lipid metabolism.