Targeting the glucose dependent insulinotropic polypeptide receptor (GIPR) is of growing interest for treating type 2 diabetes and obesity, though the optimal approach remains unclear. Both GIPR agonism and antagonism, respectively, incorporated into drugs like tirzepatide and maridebart cafraglutide, have paradoxically both shown significant weight loss effects in humans. In this study, the metabolic impacts of a GIPR agonist (GIP108) and antagonist (NN-GIPR-Ant) were evaluated in lean and high-fat diet (HFD)-induced obese male mice. We assessed the impacts on food intake, body weight, glucose and insulin tolerance, liver triglyceride levels, bone markers and adipose tissue lipolytic gene expression. In lean mice, neither peptide affected food intake or body weight, but GIP108 improved glucose tolerance. In obese mice, both agents reduced food intake and body weight, with NN-GIPR-Ant producing more sustained appetite suppression. Energy expenditure remained unchanged, as weight loss matched that of pair-fed controls. GIP108 improved glucose tolerance independently of weight loss, whereas NN-GIPR-Ant reduced insulin sensitivity compared to pair-fed controls. Both treatments slightly increased liver triglyceride content compared to their pair-fed controls, and no treatment significantly affected plasma bone marker levels. Finally, NN-GIPR-Ant reduced the expression of adipose tissue lipolytic genes. Our data highlights the distinct metabolic effects of GIPR agonism and antagonism, offering insights for their future application in personalised metabolic disease treatments. Further human studies are needed to understand the long-term metabolic impacts of these therapies.

Maternal exposure to high level of ursodeoxycholic acid during pregnancy promotes hepatic lipid deposition in the offspring by reducing the methylation level of Fasn gene.

Background/Objectives: Plants and fruits of Physalis philadelphica Lam. Solanacea are commonly used in traditional medicine to improve some illnesses such as diabetes, in North and Central American countries. The aim was to evaluate the effects of aqueous maceration (He-M) and ultrasound-assisted (He-US) extracts of P. philadelphica husk on hyperglycemia, insulin resistance, hepatic steatosis, and oxidative stress in obese rats. Methods: The effects of husk extracts on carbohydrate and lipid absorption were evaluated using oral starch and lipid tolerance tests in healthy male Wistar rats. Obesity was then induced using a high-fructose and saturated fat diet, followed by 16 weeks of extract administration. Results: He-US significantly reduced the postprandial glycemic spike, while both extracts lowered serum triglyceride levels (~50%) following lipid loading, compared with the negative control. In obese rats, both extracts reduced body weight gain (~10%) and lowered fasting glucose levels (22% for He-M and 15% for He-US), compared with the obese control. He-US also reduced insulin levels (~32%), insulin resistance (~53%), and free fatty acids (~52%), while He-M improved hepatic steatosis and reduced liver triglycerides (~26%). Both extracts reduced hepatic nitrite levels, although only He-M significantly decreased lipid peroxidation (~32%). Additionally, both treatments enhanced hepatic antioxidant enzyme activity. Conclusions: Husk extracts exerted beneficial effects on hyperglycemia, insulin resistance, hepatic steatosis, and oxidative stress markers in obese rats.

Disclosure: M. Mirabelli: None. M. Greco: None. F.S. Brunetti: None. E. Chiefari: None. D.P. Foti: None. A. Brunetti: None.Background: Thrombospondin-1 (TSP1) is a multimeric glycoprotein mainly stored in platelet (PLT) granules but also secreted by various cell types, contributing to metabolic, inflammatory, and thrombotic processes. Although TSP1 has been linked to adipose tissue dysfunction and insulin resistance (IR), its precise role in obesity remains unclear. Endothelin-1 (ET1), a potent vasoconstrictor, interacts with TSP1 for receptor binding and may underlie the heightened cardiometabolic risks observed in obesity. This study investigates the association between the severity of obesity and circulating levels of TSP1 and ET1, as well as their potential implications in obesity-related pathophysiology. Methods: The study enrolled 58 nondiabetic obese individuals (median age: 37 years, predominantly female) without established cardiovascular disease. Anthropometric, clinical, metabolic, inflammatory, and hemato-coagulative parameters were measured, with serum TSP1 and ET1 levels assessed using automated ELISA. Participants were stratified into two groups based on BMI (<35 vs. ≥35 kg/m²). Correlations between TSP1, ET1, and other laboratory markers were analyzed. Results: The median BMI was 33.8 kg/m², with 46% of participants classified as severely obese. IR was prevalent in 69.6% of participants. TSP1 and ET1 levels tended to be lower in those with severe obesity. TSP1 correlated positively with white blood cell count (r = 0.360, p < 0.01), PLT (r = 0.403, p < 0.01), and HbA1c (r = 0.373, p < 0.01), highlighting its involvement in both inflammatory and glycemic control pathways. In contrast, ET1 exhibited positive correlations with liver enzymes and triglycerides, while being negatively correlated with PLT and D-dimer. Severe obesity was associated with higher IR indices, elevated D-dimer, and increased inflammatory markers, alongside a decreased TSP1-to-PLT ratio (89.56 vs. 118.33, p = 0.022)—an index created to account for platelet activation. Further supporting the link to visceral adipose tissue, in vitro 3T3-L1 adipocyte experiments under hypoxic conditions, simulating the microenvironment of enlarged visceral fat, revealed reduced TSP1 transcription and secretion. Conclusions: Severe obesity is characterized by reduced circulating levels of TSP1 and ET1, which display distinct relationships with metabolic, inflammatory, and thrombotic parameters. The hypoxia-induced decrease in TSP1, associated with expanded visceral fat, along with the concurrent reduction in circulating ET1, may serve as compensatory mechanisms to mitigate vascular dysfunction in severe obesity. TSP1 emerges as a promising biomarker for cardiometabolic risk in obesity, meriting further investigation into its therapeutic potential for preventing obesity-related complications.Presentation: Sunday, July 13, 2025

Disclosure: P. Patel: None. E. de Groot: None. P. Saha: None. S.M. Hartig: None.N-acetylaspartate (NAA) is the second most abundant metabolite in the brain, and the metabolites generated from its catabolism direct the myelination of nerves. Despite abundant circulating NAA, roles outside the brain remain unknown. The hydrolysis of NAA by the enzyme aspartoacylase (ASPA) leads to the generation of acetate and aspartate, supplying rate-limiting metabolites for essential cellular processes, including lipogenesis. Lipogenesis occurs in the liver to store excess carbohydrates in times of nutrient overload. However, excessive fat accumulation in the liver can lead to fatty liver disease. Interestingly, we found that Aspa expression and NAA abundance are decreased in the livers of mice placed on a high-fat diet. To better understand NAA’s function in the liver, we utilized a whole-body ASPA knockout (KO) mouse model that accure NAA. As such, we find that ASPA KO mice are resistant to fatty liver. ASPA KO livers were larger when normalized to body weight, accumulated less triglycerides, and expressed lower levels of key lipogenic genes relative to age-matched littermate controls. These mice also had increased serum free fatty acids that do not appear in the liver. As an alternative method to increase NAA levels in the liver, we overexpressed N-acetylaspartate synthetase (Nat8l), the enzyme that synthesizes NAA from acetate and aspartate. Consistent with our findings in the ASPA-deficient mice, Nat8l overexpression in the liver resulted in decreased liver triglycerides. In parallel, we find that per orem NAA in wild-type (WT) mice decreases cytidine diphosphate (CDP) and glyceraldehyde 3-phosphate (G3P), both of which contribute to lipid synthesis in the liver. From these data, we can hypothesize that NAA provides an acetate pool for lipogenesis, and the presence of ASPA determines whether the liver can accumulate pathological amounts of fat.Presentation: Saturday, July 12, 2025

A 42-day feeding trial was conducted to determine the effects of different lipid and phospholipid (PL) levels on growth performance, fatty acid composition, fat deposition, antioxidant capacity, and liver health of largemouth bass (Micropterus salmoides) larvae. Six diets were designed: 6% lipids and 0% PLs (L6/PL0), 3% lipids and 3% PLs (L6/PL50), 0% lipids and 6% PLs (L6/PL100), 12% lipids and 0% PLs (L12/PL0), 6% lipids and 6% PLs (L12/PL50), and 0% lipids and 12% PLs (L12/PL100). These correspond to gradient designs for PLs replacing 0%, 50%, and 100% lipids at the 6% and 12% lipids levels. Results showed that dietary PL supplementation significantly enhanced body weight gain (BWG) and specific growth rate (SGR), with the highest BWG in L12/PL100. PL supplementation reduced both the hepatosomatic index (HSI) and viscerosomatic index (VSI), with the L6/PL100 having the lowest levels. The PL supplementation efficiently reduced liver fat deposition and neutral lipid/polar lipid ratio. The n-3 polyunsaturated fatty acid content in the polar lipid fraction was significantly higher than that in the neutral lipid fraction. Dietary PL supplement significantly increased hepatopancreatic catalase and glutathione activities and decreased malondialdehyde content in the hepatopancreas. PL supplementation significantly reduced liver triglyceride and total cholesterol levels, with the lowest levels observed in the L6/PL100 and L12/PL100 groups. These findings demonstrate that graded PL replacement (up to 100%) at the 6% lipid level optimized growth, reduced fat deposition, increased antioxidant capacity, and avoided the metabolic burden induced by high fat (12% lipids), enhancing LB larval health.

Abstract Disclosure: A. Tsay: None. I. Su: None. K. Lam: None. J. Wang: None. The prevalence of Metabolic Dysfunction-Associate Steatotic Liver Disease (MASLD) has rapidly increased over the past two decades. Genetic factors play important roles in the development of MASLD. Genome-wide association studies (GWAS) have been valuable in identifying novel genes involved in developing various diseases, including MASLD. A single nucleotide polymorphism (SNP) in GATA zinc finger domain containing 2A (GATAD2A) gene, rs59148799, has been shown to be associated with MASLD in Japanese and Korean populations. However, the mechanism of how this GATAD2A SNP affects the development of MASLD is unknown. GATAD2A is a transcriptional coregulator and component of the nucleosome remodeling and deacetylase (NuRD) complex. The metabolic function of GATAD2A has not been identified. To learn whether hepatic GATAD2A affects lipid metabolism, we infected 8 weeks old male C57BL/6J mice with adeno-associated virus (AAV) expressing either scramble small hairpin RNA (shRNA, as a control) or shRNA targeting Gatad2a. We found that mice infected with AAV expressing Gatad2a shRNA had lower expression of Gatad2a in the liver but not in epididymal white adipose tissue and gastrocnemius muscle. Under chow diet feeding, hepatic Gatad2a knockdown resulted in lower fasting plasma and liver triglyceride levels. Looking into signaling pathways involved in lipid homeostasis regulation, we found that Gatad2a knockdown mice had significantly increased activity of hepatic AMP-activated protein kinase (AMPK) and decreased Acetyl-CoA Carboxylase (ACC1) activity, leading to inhibition of lipogenesis and promotion of fatty acid oxidation. Reducing Gatad2a expression in mouse AML12 hepatocytes also increased AMPK activity and reduced ACC1 activity, thus showing that this effect is cell autonomous. We performed liver RNA-sequencing and identified that N-myc downstream regulated gene 1 (Ndrg1) expression was reduced by Gatad2a knockdown. Ndrg1 expression was also reduced by Gatad2a knockdown in mouse AML12 hepatocytes, and, importantly, Ndrg1 depletion augmented AMPK activity. Moreover, overexpressing Gatad2a in mouse liver resulted in increased expression of Ndrg1 and liver TG levels. Chromatin immunoprecipitation (ChIP) revealed that Gatad2a was recruited to the promoter of mouse Ndrg1 gene. Based on these results, we propose that Gatad2a is a transcriptional coactivator promoting Ndrg1 transcription, which in turn suppresses AMPK to regulate lipid homeostasis. These results elucidate the novel function of GATAD2A in lipid metabolism and will provide important insights into the mechanism of MASLD development. Presentation: Saturday, July 12, 2025

Objective:The Western diet promotes obesity and metabolic disease by increasing caloric intake and systemic inflammation. The typical Western diet is high in saturated fats, sugars, and salt. In pre-clinical rodent studies, the “Western” diet (also called the high-fat high-sucrose diet (HFHS)) is high in saturated fats and sugars (typically sucrose) but low in salt (<1% salt). As such, we sought investigate the impact of a chronic 3% NaCl Western diet (high-fat, high-sucrose + high salt (HFHS + Salt)) diet on systemic organ metabolism, liver mitochondrial function, and adipose tissue.Methods:Thirty-six 8 week-old C57Bl/6J male mice were fed either a low-fat diet (LFD), a HFHS, or a HFHS + Salt diet for 16 weeks. Body weight, body composition, and food intake were monitored weekly. Glucose tolerance tests (GTT) and insulin concentrations were measured after 8 weeks of diet intervention to assess glucose and insulin homeostasis. Mice were euthanized at 16 weeks for liver mitochondrial respiration and tissue analysis.Results:Over 16 weeks, the HFHS fed group gained significantly more weight than the other diet groups. Liver weights were similar in LFD and HFHS + Salt groups but higher in the HFHS group. Liver triglycerides (TAGs) were also similar between LFD and HFHS + Salt groups, while HFHS had elevated liver TAGs. Inguinal and brown adipose tissue depots were larger in both HFHS and HFHS + Salt vs. LFD. Surprisingly, the gonadal adipose tissue was significantly larger in the HFHS + Salt compared to HFHS and LFD groups – suggesting that a HFHS + Salt exacerbates gonadal adipose expansion more than typical rodent HFHS. Paradoxically, the addition of salt appears to have dampened expression of inflammation related genes (Ccl2 & Adgre1) in adipose tissue compared to HFHS alone. Metabolically, the HFHS+ Salt fed mice showed the highest glucose intolerance, followed by HFHS and then LFD groups. Liver mitochondrial respiration, assessed by changing ATP/ADP ratios, showed the HFHS group with the highest oxygen consumption, followed by HFHS + Salt, then LFD groups, highlighting differences in respiration with additional salt (HFHS vs HFHS + Salt).Conclusion:While the excess salt mitigated some HFHS effects on weight gain and hepatic lipid accumulation, it exacerbated gonadal adipose expansion and impaired glucose tolerance. HFHS increased mitochondrial respiration, but salt addition appeared to dampen this effect. Dietary salt, within a high-fat/high-sucrose context, has differential impacts on metabolic outcomes compared to HFHS alone, underscoring the need for further research to fully understand how Western diets (high-fat, high-sucrose, and high salt) impact all aspects of metabolic health.

Being born small-for-gestational-age (SGA), is associated with an increased risk of cardiometabolic disease in adulthood. We studied the influence of birth size on hepatocellular lipid (HCL) concentrations in prepubertal children. A total of 195 prepubertal Caucasian children (4.4-9.7 years) were studied in three cohorts. Twenty-one children were born small-for-gestational-age (SGA), 132 were appropriate-for-gestational-age (AGA), and 42 were large-for-gestational-age (LGA). The outcomes were body fat by dual-energy X-ray absorptiometry (DXA), liver fat MRI and MR spectroscopy (MRS), anthropometric measurements at examination, and biochemical markers of metabolism and inflammation. MRS revealed higher HCL in SGA children, as determined from the methylene (-CH2-) resonance (p = 0.02). The high-sensitivity c-reactive protein (hs-CRP) level was also significantly higher in the SGA group than in the AGA (p = 0.01) or LGA groups (p = 0.002). The HCL concentrations were correlated with hs-CRP values in the whole cohort (R = 0.51, p = 0.03), independently of traditional anthropometric markers. Other laboratory parameters were not associated with HCL. Our study shows a link between SGA status, elevated hs-CRP, and elevated MRS-detectable HCL. MRS may thus be important in identifying prepubertal children at risk for metabolic sequelae. Prepubertal children born small-for-gestational-age (SGA), although still shorter and leaner than their peers, exhibit elevated liver triglyceride concentrations on proton MR spectroscopy associated with elevated hs-CRP levels. Elevated hs-CRP and liver triglyceride concentrations can be early indicators of pathological metabolic changes associated with later cardiometabolic abnormalities.

BackgroundThe causes of acute liver injury (ALI) are complex and diverse, including alcohol, drugs, infections, and toxic substances, and it has become a major global health issue. Traditional Chinese medicine (TCM), with advantages such as broad-spectrum biological activity, low toxicity, and minimal side effects, has been widely used in drug research and development as well as disease management. Some TCMs have shown significant efficacy in treating ALI: Ganoderma lucidum polysaccharides, monoterpene glycosides from Paeonia lactiflora, glycyrrhizic acid saponins, and flavonoids all exhibit liver-protective effects; however, the protective effects of their compound preparations on liver injury remain unclear.MethodsThe study optimized the water extraction process using orthogonal experiments with AHP-entropy weight scoring. The preparation process was verified by single-factor experiments, Plackeett–Burman and Box–Bohnken tests. The mechanism of action was validated using network pharmacology methods and a CCl4-induced acute liver injury animal model.ResultsThe developed extraction and granule formation processes were reliable after validation. The contents of active components in CEHG determined by HPLC were as follows: albiflorin 1.26%, paeoniflorin 5.42%, liquiritin 0.43%, glycyrrhizic acid 1.30%, and ganoderic acid A 0.14%, with batch-to-batch variation coefficients (RSD) of 1.66%, 0.87%, 2.32%, 1.60%, and 4.03%, respectively. The dry extract ratio was 18.23% with an RSD of 2.11%. Network pharmacology revealed that CEHG improved liver injury by regulating the HIF-1, p53, and FoxO signaling pathways. Animal experiments indicated that CEHG granules reduce liver function-related aspartate transaminase (AST), alanine transaminase (ALT), total cholesterol (TC), triglyceride (TG), total bilirubin (TBIL), and LDH levels, decrease the levels of inflammatory factors IL-6, IL-1β, and TNF-α and of oxidative stress-related MDA and ROS, and down-regulated the mRNA and protein levels of P53, Bax, and HIF-1α in rats with liver injury. Meanwhile, CEHG improved liver function-related Total Protein (TP), raised the levels of oxidative stress-related SOD, GSH-Px, and GSH, and up-regulated mRNA and protein expression of Bcl-2.ConclusionThis study successfully optimized the extraction and granule-formation of CEHG and revealed its hepatoprotective mechanism through network pharmacology and animal studies, providing scientific evidence supporting the further development and clinical use of CEHG.

Simple SummaryFish farming plays a key role in producing healthy food and meeting the growing demand for animal protein. However, producers face challenges in maintaining fish health while reducing the use of synthetic additives. Olive leaves, a by-product of olive oil production, are rich in natural compounds that may improve fish health and product quality. In this study, we tested whether adding small amounts of olive leaf extract to the diet of Nile tilapia juveniles could improve their growth, body composition, and health indicators. The fish were fed for 46 days with diets containing different amounts of olive leaf extract. Fish growth was not affected, but the lowest amount tested improved the proportion of healthy nutrients in the fish’s body, balanced certain blood parameters, and reduced fat oxidation in the liver, which is linked to better health. These results suggest that olive leaf extract can be used as a natural feed additive to promote fish health and make aquaculture more sustainable, while also adding value to an agricultural by-product that would otherwise be discarded.This study evaluated the effects of dietary olive leaf extract (OLE) on Nile tilapia (Oreochromis niloticus) juveniles, focusing on growth parameters, centesimal composition, biochemical responses, and lipid peroxidation. OLE was extracted with 60% ethanol (1:20 w/v). Five diets, containing 34% crude protein and 8% lipids, were tested: a control (0 g/kg) and four with increasing OLE levels (0.25, 0.5, 1, and 2 g/kg). The 46-day trial included 225 fish (0.56 ± 0.11 g) distributed in 15 tanks. Growth performance was not affected, except for a higher condition factor in OLE0.25. This dose also resulted in lower moisture and higher lipid content, while all OLE treatments increased crude protein in fish. Muscle glycogen decreased in all OLE-fed groups, and liver glycogen was reduced in OLE0.25. Plasma triglycerides decreased in OLE0.5 and OLE0.25, while total plasma protein was lower in OLE2.0. Liver triglycerides were lower in OLE0.25 and higher in OLE0.5, whereas glucose showed a glycemic peak in OLE2.0. Hepatic lipid peroxidation was reduced in OLE2.0. Overall, dietary OLE did not compromise the growth performance of Nile tilapia, and 0.25 g/kg promoted beneficial effects on centesimal composition, biochemical parameters, and lipid peroxidation, highlighting its potential as a functional ingredient in aquafeeds.

Effect of metabolic disturbances on the plasma concentration and hepatic expression of the appetite-reducing hormone growth differentiation factor-15 (GDF15) in dairy cows.

A cross sectional study was conducted among 79 children and adolescents in Paediatric Endocrine Outpatient Department (OPD) of Bangladesh Institute of Research and Rehabilitation in Diabetes, Endocrine and Metabolic Disorders (BIRDEM) General Hospital, a tertiary care centre in Dhaka, Bangladesh. Children and adolescents of 8 to 18 years of age with simple obesity who visited during the period of 1st January 2018 to 30th June 2018 were included in this study. The study was done to determine the percentage of different grades of fatty liver disease and to compare metabolic profiles and anthropometric measurements among obese children and adolescents with different grades of fatty liver disease. Fatty liver disease was identified and it's grading was done by Real-time ultrasonography of hepatobiliary system. Total 24 obese children (30.4%) had fatty liver disease among 79 patients. Majority of them (54.2%) had mild fatty liver disease followed by moderate fatty liver disease (41.6%). Severe fatty liver disease was found in only one child. Fasting blood sugar (p=0.031) and SGPT level (p=0.001) were significantly higher among children and adolescents with fatty liver disease in comparison to children without it. When comparison was done in different grades of fatty liver disease, triglyceride level (p=0.033) and diastolic hypertension (p=0.016) was significantly higher in children having moderate fatty liver disease. There was no significant difference in anthropometric measurements among children having different grades of fatty liver disease.

PNPLA3-I148M is a neomorph that interferes with two primary hepatic triglyceride clearance pathways.

Regulation of alternative splicing of retinol metabolism in lipid abnormality of PCOS liver by Cyp4a32 and Hsd17b6.

Background: The aim of this study was to investigate the effects of matcha on lipid metabolism, insulin resistance (IR), inflammation, and gut dysbiosis in non-alcoholic fatty liver disease (NAFLD) induced by a cafeteria diet. Methods: Forty-eight 7-week-old male Wistar rats were divided into six groups (n = 8), including a control group (C), C + 0.2% matcha group (C + 0.2%), C + 1% matcha group (C + 1%), cafeteria group (Caf), Caf + 0.2% matcha group (Caf + 0.2%), and Caf + 1% matcha group (Caf + 1%). All rats were sacrificed at the end of the 12th week of the experiment. A one-way analysis of variance (ANOVA), followed by a Fisher's post hoc test, was used to determine the significant differences among each of the groups. Results: The results indicated that plasma experiment triglycerides (TGs) significantly increased in the Caf group compared to the C group, and significantly decreased TG levels were found in the Caf + 1% group compared to the Caf group. In addition, the liver total cholesterol and TG had significantly increased in the Caf group, while the 0.2% Matcha intervention can mitigate hepatic lipid accumulation. Blood sugar, serum insulin, the homeostasis model assessment of IR (HOMA-IR), and plasma leptin significantly increased in the Caf group and were significantly lower in the Caf + 0.2% and Caf + 1% groups. Hepatic cytokines significantly increased in the Caf group, while, on the other hand, significantly lower concentrations were found in the Caf + 1% group. In addition, beneficial bacteria including Akkermansia, Faecalibacterium, and Parabacteroides increased after matcha supplementation. Conclusions: These results suggested that 12 weeks of a cafeteria diet can induce abnormal lipid metabolism, IR, liver inflammation, and an altered gut microbiotic composition, while both the 0.2% and 1% matcha interventions might regulate obesity, lipid accumulation, IR, and inflammatory responses, and help maintain a healthier gut microbiota, which may then ameliorate the development of NAFLD.

IntroductionObesity is caused by excessive storage of adipose tissue and leads to metabolic disorders. Uridine exerts modulatory effects on lipid metabolism, but the regulatory mechanism in obesity needs further research.MethodsIn this study, the effects of uridine supplementation on lipid metabolism were investigated in high-fat diet-induced obese mice. Mice aged at 8 weeks were randomly grouped to receive a control diet (CON, n = 10) or a high-fat diet (HF, n = 24). After 6 weeks of feeding, the HF group was further divided, with half receiving 0.4 mg/mL uridine supplementation in drinking water (HUR, n = 12) for an additional 4 weeks, while the remaining HF mice continued without intervention.ResultsThe results showed that the uridine supplement reduced the liver weight and intra-abdominal white adipose tissue weight in obese mice (p < 0.05). Treatment with uridine and free fatty acid resulted in a significant increase in late and total apoptosis, accompanied by a decrease in early apoptosis of mouse liver organoids (p < 0.05). Moreover, uridine lowered serum levels of triglycerides (TG), total cholesterol (TC), high-density lipoprotein (HDL), leptin, and liver TG content (p < 0.05). In obese mice fed with uridine, the expression of key genes involved in lipid transport [activated fatty acid translocase/cd36 (Fat/cd36) and low-density lipid receptor (Ldlr)], pyrimidine de novo synthesis [dihydroorotate dehydrogenase (Dhodh)], pyrimidine metabolism [uridine phosphorylase 2 (Upp2), ribonucleoside-diphosphate reductase subunit M2 (Rrm2), and thymidine kinase 1 (Tk1)] was improved (p < 0.05). Furthermore, liver metabolomic analysis identified 37 differential metabolites between the HF and HUR groups, primarily enriched in arachidonic acid metabolism and α-linolenic acid metabolism.DiscussionThese findings indicated that uridine supplementation can improve lipid metabolism in obese mice by regulating hepatic gene expression and metabolic pathways.

Alisol A 24-acetate protects against NASH-associated fibrosis via suppression of Kupffer cell-derived SPHK1/S1P axis.

As a widespread environmental pollutant, di(2-ethylhexyl) phthalate (DEHP) mainly leaches from plastic products into food and is ultimately absorbed by living organisms. DEHP and its metabolites pose potential threats to human and animal health, particularly through metabolic disorders. While existing studies have explored DEHP's impact on lipid metabolism, investigations in aged mice remain scarce. This study aimed to investigate the effects of DEHP exposure on hepatic lipid metabolism and gut microbiota in mice. Male senescence-accelerated (SAMP8) were orally exposed to DEHP (0, 0.2, and 200 mg/kg/day) for 5 weeks. Results showed that DEHP exposure significantly interfered with hepatic lipid profiles, leading to elevated liver triglyceride (TG) levels. Furthermore, DEHP exposure influenced the alpha and beta diversity of the gut microbiota. An increase in the Firmicutes/Bacteroidota ratio suggests that DEHP exposure causes changes in the composition of the gut microbiota. The association between hepatic lipidomics and gut microbiota showed a positive correlation between specific genera like Alloprevotella and various hepatic lipids. Finally, we further clarified the molecular mechanism of increased hepatic TG, identifying elevated fatty acid synthase FASN as a key factor. In summary, these results suggest that DEHP exposure disrupts lipid metabolism in the liver, possibly mediated by gut microbiota dysbiosis.

Our previous study suggested that increasing the phospholipid-to-cholesterol intake ratio might mitigate the negative effects of cholesterol intake, based on a comparison of lipid metabolism changes in mice fed chow diets containing egg yolk low-density lipoprotein (LDL) and high-density lipoprotein (HDL). This benefit might stem from the involvement of phospholipids, leading to reduced food efficiency, decreased body weight, and increased bile acid excretion. In this study, we further investigated the effects of this ratio on lipid metabolism under a high-fat diet (HFD) using egg yolk LDL and HDL, which differ in the proportions of phospholipids and cholesterol. Both LDL and HDL intake led to increased body weight and adipose tissue weight in mice, with significant effects observed in the HFD-LDL3 group. Accordingly, these groups exhibited overall increases in food efficiency. Lipid biomarkers indicated that both LDL and HDL intake significantly elevated plasma and liver triglyceride (TG) levels. Cholesterol in the blood might be stored with TGs in adipose tissue. No significant differences were observed in lipid biomarkers between the HFD-LDL and HFD-HDL groups under the same cholesterol dose. Western blot results showed upregulated cholesterol synthesis following LDL and HDL intakes. Bile acid excretion also increased, though not significantly. Fecal metabolite analysis further revealed changes in polyunsaturated fatty acids, pregnane-type steroids, and bile acids. Compared to our previous findings, increasing the phospholipid-to-cholesterol intake ratio under an HFD had a weaker beneficial effect on lipid metabolism than under a chow diet, possibly due to the lower proportion of phospholipids in the total lipids.