Lipid Accumulation In Mice Research Articles

Native corn (Zea mays L., cv. ‘Elotes Occidentales’) polyphenols extract reduced total cholesterol and triglycerides levels, and decreased lipid accumulation in mice fed a high-fat diet

Obesity is a complex disease with numerous molecular and metabolic implications that could be prevented through proper diet and lifestyle. Native corn is a promissory underutilized plant species containing bioactive compounds that could reduce the impact of obesity. This research aimed to characterize and evaluate the anti-obesogenic effect of a polyphenols-rich extract of native corn (‘Elotes Occidentales’) in HFD-fed mice. The powdered extract was administered using gelatins to C57BL/6 J mice randomly divided into four groups (n:8/group) for 13 weeks: standard diet (SD) group, HFD group, HFD+200 mg extract/kg body weight (BW), and HFD+400 mg extract/kg BW/day. Ellagic acid, chlorogenic acid, rutin, and kaempferol were the most abundant phenolics (2022.44–4028.43 µg/g). Among the HFD groups, the highest dose of the extracts promoted the lowest BW gain, and fasting triglycerides and cholesterol levels. Moreover, the HFD+400 mg/kg BW group showed the lowest epididymal and subcutaneous adipose tissue weight and adipocytes’ diameter and area between the HFD-treated animals. The extract administration prevented hepatic lipid accumulation. Rutin demonstrated the highest in silico binding affinity with proteins from the AMPK pathway (ACACA, SIRT1, and SREBP1) (-6.70 to −8.70 kcal/mol). Results indicated beneficial effects in alleviating obesity-associated parameters in vivo due to bioactive compounds from native maize extracts.

Lactiplantibacillus plantarum P101 Alleviated Alcohol-Induced Hepatic Lipid Accumulation in Mice via AMPK Signaling Pathway: Gut Microbiota and Metabolomics Analysis.

Mitigating steatosis is essential for delaying the progression of alcoholic liver disease. The effect and mechanism of Lactiplantibacillus plantarum P101 (LP.P101) on alleviating alcohol-induced hepatic lipid accumulation were investigated in our study. The mouse model was constructed by a short-term (10-day)-plus-binge ethanol feeding and gavaged with 108 CFU/mL of LP.P101 daily. Lipid droplet in the liver was significantly reduced by LP.101 intervention on AMPK activation. However, when AMPK was inhibited by dorsomorphin, the levels of related indicators (ALT, TG, etc.) and the expression levels of AMPK and relevant genes in the liver converged to that of the alcohol-fed group. Compared with the alcohol-fed group, LP.P101 reduced the relative abundance of Firmicutes and increased that of Bacteroidetes. Parabacteroides merdae was negatively correlated with lipid accumulation, and unclassified Negativibacillus was negatively associated with AMPK activation. Importantly, LP.P101 modified the compositions of the serum metabolites. The potential biomarker stercobilinogen was positively correlated with AMPK activation and negatively associated with lipid accumulation. This work confirmed that LP.P101 attenuated alcohol-induced hepatic lipid accumulation in mice through AMPK activation, and the alterations in gut microbiota and metabolites may play a significant role on AMPK activation.

Exercise training alleviates cholesterol and lipid accumulation in mice with non-alcoholic steatohepatitis: Reduction of KMT2D-mediated histone methylation of IDI1

Exercise training is a cornerstone treatment for non-alcoholic fatty liver disease (NAFLD). This study aims to investigate the effects of exercises on lipid accumulation in non-alcoholic steatohepatitis (NASH) and to explore the molecular mechanism. Established NASH mice were remained sedentary or subjected to moderate-intensity continuous training or high-intensity interval training (HIIT). The two training regimens, especially the latter one, reduced liver weight, steatosis, inflammation, lipid accumulation, collagen deposition, and cholesterol content in the mouse liver. Similarly, the HIIT regimen improved clinical presentation of NAFLD patients. RNA sequencing analysis revealed lysine methyltransferase 2D (Kmt2d) and isopentenyl-diphosphate delta isomerase 1 (Idi1) as two important genes downregulated in mice underwent HIIT. By using mouse hepatocytes AML12, we found that KMT2D promoted Idi1 expression by catalyzing H3K4me1 modification near its promoter. Upregulation of either KMT2D or IDI1 blocked the ameliorating effects of HIIT on mice. Meanwhile, in AML12 cells modeled by palmitic acid and oleic acid treatment, KMT2D and IDI1 were found to be correlated with lipid accumulation, cholesterol content, inflammation, and cell death and senescence. In conclusion, this study demonstrates that the ameliorating effects of exercise training on NASH might involve the downregulation of the KMT2D/IDI1 axis.

Study on the Mechanism of GABA-Rich Adzuki Bean Regulating Blood Glucose Based on the IRS/PI3K/AKT Pathway.

The adzuki bean is a mature seed of the red bean leguminous plant, and people like to eat it because of its nutritious properties and moderate proportion of amino acids. Adzuki bean germination and the enrichment of GABA greatly improve the health effects of the adzuki bean. The effects of the GABA-rich adzuki bean on the expression of insulin-pathway-related genes and proteins in the liver of T2DM mice were studied via Western blotting and qPCR. The results showed that a GABA-rich adzuki bean diet could promote glycogen synthesis in the liver of T2DM mice, inhibit the activities of PEPCK and G-6-Pase, and significantly down-regulate the gene expression levels of PEPCK, G6PC and FOXO1 (p < 0.05) and the phosphorylation levels of FOXO1 and GSK3β. In addition, it can also up-regulate the expression of the AMPKα gene and down-regulate the expression of the SREBP1c gene to inhibit the synthesis of triglycerides and cholesterol in T2DM mice. Lipid accumulation in mice can alleviate glucose and lipid metabolism disorders and play an effective role in regulating blood glucose at liver tissue targets. This study suggested that the GABA-rich adzuki bean can improve hyperglycemia in type 2 diabetic mice by activating the IRS/PI3K/AKT signaling pathway in the liver.

Integrated metabolomic and transcriptomic analysis reveals the effects and mechanisms of Jinqi Jiangtang tablets on type 2 diabetes

BackgroundType 2 diabetes (T2DM) is one of the major metabolic diseases and poses a serious challenge to human life and global economic development. Jinqi Jiangtang Tablets (JQJT) is effective in ameliorating the effects of T2DM, but the mechanism of JQJT is unclear. PurposeThis study integrated metabolomics and transcriptomics to reveal the mechanism by which JQJT improves T2DM. MethodsThe T2DM mouse model was established, and the effects of JQJT on improving T2DM were evaluated by determining the levels of blood lipids, fasting blood glucose (FBG), insulin metabolism and hepatic lipid accumulation in mice after JQJT administration for 8 weeks. Serum metabolites were detected using ultra-performance liquid chromatography/quadrupole time-of-flight-tandem mass spectrometry (UPLC-Q-TOF-MS) technology, and mouse liver differential genes were detected using transcriptomic technology. Correlation analysis was used to extract metabolites and RNA with correlations, and potential pathways were enriched and constructed using the common pathway analysis function of MetaboAnalyst 5.0. Finally, the expression of key target proteins and genes was verified by Western blot (WB) and Polymerase Chain Reaction (PCR) to further elucidate the mechanism by which JQJT improves T2DM. ResultsJQJT reduced FBG and lipid levels, improved insulin resistance (IR) and hepatic lipoatrophy in mice. A total of 35 differentially abundant metabolites were identified by metabolomics, and 328 differential genes were detected by transcriptomics. The integrated metabolomics and transcriptomics results suggested that JQJT may ameliorate T2DM mainly by regulating glucose and lipid metabolic pathways. WB and PCR results showed that JQJT regulates the insulin signaling pathway, involved in fatty acid metabolism, glycogen synthesis and catabolism. ConclusionsJQJT improved IR in T2DM mice by regulating the insulin signaling pathway, improving glycogen synthesis and glycolysis, and increasing hepatic triglyceride and fatty acid metabolism.

Ebselen improves lipid metabolism by activating PI3K/Akt and inhibiting TLR4/JNK signaling pathway to alleviate nonalcoholic fatty liver

Nonalcoholic fatty liver disease (NAFLD), a metabolic disease associated with obesity and type 2 diabetes. Due to its complex pathogenesis, there are still limitations in the knowledge of the disease. To date, no drug has been approved to treat NAFLD. This study aims to explore the role and mechanism of Ebselen (EbSe) in NAFLD. A high-fat diet-induced mouse model of NAFLD was employed to investigate EbSe function in NAFLD mice by EbSe gavage and to regularly monitor the mouse body weight. HE and oil red O staining were performed, respectively, to detect the pathological damage and lipid accumulation in mouse liver tissues. The biochemical and ELISA kits were employed to measure the levels of ALT, AST, TG, TC, LDL-C, HDL-C and pro-inflammatory cytokines within mouse serum or liver tissue. The expression of key proteins of PPARα, fatty acid β oxidation-related protein, PI3K/Akt and TLR4/JNK signaling pathway was detected by western blot. EbSe significantly downregulated body weight, liver weight and liver lipid accumulation in NAFLD mice and downregulated ALT, AST, TG, TC, LDL-C and increased HDL-C serum levels. EbSe upregulated the expression levels of PPARα and fatty acid β oxidation-associated proteins CPT1α, ACOX1, UCP2 and PGC1α. EbSe promoted Akt and PI3K phosphorylation, and inhibited TLR4 expression and JNK phosphorylation. EbSe can upregulate PPARα to promote fatty acid β-oxidation and improve hepatic lipid metabolism. Meanwhile, EbSe also activated PI3K/Akt and inhibited TLR4/JNK signaling pathway. EbSe is predicted to be an effective therapeutic drug for treating NAFLD.

Blocking H1R signal aggravates atherosclerosis by promoting inflammation and foam cell formation.

Atherosclerosis (AS) is a chronic inflammatory arterialdisease, in which abnormal lipid metabolism and foam cell formation play key roles. Histamine is a vital biogenic amine catalyzed by histidine decarboxylase (HDC) from L-histidine. Histamine H1receptor (H1R)antagonist is a commonly encountered anti-allergic agent in theclinic. However, the role and mechanism of H1R in atherosclerosis have not been fully elucidated. Here, we explored the effect of H1R on atherosclerosis using ApolipoproteinE-knockout (ApoE-/-)mice with astemizole (AST, a long-acting H1R antagonist) treatment. The results showed that AST increased atherosclerotic plaque area and hepatic lipid accumulation in mice. The result of microarray study identified a significant change of endotheliallipase (LIPG) in CD11b+ myeloid cells derived from HDC-knockout (HDC-/-) mice compared to WT mice. Blocking H1R promoted the formation of foam cells from bone marrow-derived macrophages (BMDMs) of mice by up-regulating p38mitogen-activatedproteinkinase (p38 MAPK) and LIPG signalingpathway. Taken together, these findings demonstrate that blocking H1R signal aggravates atherosclerosis by promoting abnormal lipid metabolism and macrophage-derived foam cell formation via p38 MAPK-LIPG signalingpathway. KEY MESSAGES: Blocking H1R signal with AST aggravated atherosclerosis and increased hepatic lipid accumulation in high-fatdiet (HFD)-fed ApoE-/- mice. Blocking H1R signal promoted macrophage-derived foam cell formation via p38 MAPK-LIPG signalingpathway.

Integrated transcriptome and metabolome study reveal the therapeutic effects of nicotinamide riboside and nicotinamide mononucleotide on nonalcoholic fatty liver disease

Nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) have received considerable attention as anti-aging and anti-metabolic disease nutraceuticals. However, few studies have focused on their role in ameliorating hepatic metabolic disturbances. In the present study, the effects of NMN and NR on the liver of mice with nonalcoholic fatty liver disease (NAFLD) were investigated via transcriptome and metabolome analyses. NMN and NR reduced body weight gain, improved glucose homeostasis, regulated plasma lipid levels, and ameliorated liver injury, oxidative stress, and lipid accumulation in mice with HFD-induced NAFLD. Integrated transcriptome and metabolome analyses indicated that NMN and NR altered the biosynthesis of unsaturated fatty acids, arachidonic acid metabolism, and linoleic acid metabolism pathways, increased saturated fatty acid (palmitic acid, stearate, and arachidic acid) content, and increased polyunsaturated fatty acid (linoleic acid and eicosapentaenoic acid) content. Quantitative reverse transcription PCR (qRT-PCR) showed that NMN and NR primarily promoted arachidonic acid and linoleic acid catabolism via cytochrome P450 (CYP450) enzymes. This study established a theoretical foundation for the potential use of NMN and NR in future clinical settings.

Tamoxifen upregulates the peroxisomal β-oxidation enzyme Enoyl CoA hydratase and 3-hydroxyacyl CoA hydratase ameliorating hepatic lipid accumulation in mice

Tamoxifen is an estrogen receptor modulator that has been reported to alleviate hepatic lipid accumulation in mice, but the mechanism is still unclear. Peroxisome fatty acid β-oxidation is the main metabolic pathway for the overload of long-chain fatty acids. As long-chain fatty acids are a cause of hepatic lipid accumulation, the activation of peroxisome fatty acid β-oxidation might be a novel therapeutic strategy for metabolic associated fatty liver disease. In this study, we investigated the mechanism of tamoxifen against hepatic lipid accumulation based on the activation of peroxisome fatty acid β-oxidation. Tamoxifen reduced liver long-chain fatty acids and relieved hepatic lipid accumulation in high fat diet mice without sex difference. In vitro, tamoxifen protected primary hepatocytes against palmitic acid-induced lipotoxicity. Mechanistically, the RNA-sequence of hepatocytes isolated from the liver revealed that peroxisome fatty acid β-oxidation was activated by tamoxifen. Protein and mRNA expression of enoyl CoA hydratase and 3-hydroxyacyl CoA hydratase were significantly increased in vivo and in vitro. Small interfering RNA enoyl CoA hydratase and 3-hydroxyacyl CoA hydratase in primary hepatocytes abolished the therapeutic effects of tamoxifen in lipid accumulation. In conclusion, our results indicated that tamoxifen could relieve hepatic lipid accumulation in high fat diet mice based on the activation of enoyl CoA hydratase and 3-hydroxyacyl CoA hydratase-mediated peroxisome fatty acids β-oxidation.

Melatonin restores hepatic lipid metabolic homeostasis disrupted by blue light at night in high-fat diet-fed mice.

Artificial light at night (ALAN) is an emerging environmental pollutant that threatens public health. Recently, ALAN has been identified as a risk factor for obesity; however, the role of ALAN and its light wavelength in hepatic lipid metabolic homeostasis remains undetermined. We showed that chronic dim (~5 lx) ALAN (dLAN) exposure significantly promoted hepatic lipid accumulation in obese or diabetic mice, with the most severe effect of blue light and little effect of green or red light. These metabolic phenotypes were attributed to blue rather than green or red dLAN interfering with hepatic lipid metabolism, especially lipogenesis and lipolysis. Further studies found that blue dLAN disrupted hepatic lipogenesis and lipolysis processes by inhibiting hepatic REV-ERBs. Mechanistically, feeding behavior mediated the regulation of dLAN on hepatic REV-ERBs. In addition, different effects of light wavelengths at night on liver REV-ERBs depended on the activation of the corticosterone (CORT)/glucocorticoid receptor (GR) axis. Blue dLAN could activate the CORT/GR axis significantly while other wavelengths could not. Notably, we demonstrated that exogenous melatonin could effectively inhibit hepatic lipid accumulation and restore the hepatic GR/REV-ERBs axis disrupted by blue dLAN. These findings demonstrate that dLAN promotes hepatic lipid accumulation in mice via a short-wavelength-dependent manner, and exogenous melatonin is a potential therapeutic approach. This study strengthens the relationship between ALAN and hepatic lipid metabolism and provides insights into directing ambient light.

Parboiled rice supplementation alleviates high-fat diet-induced hyperlipidemia by regulating genes and gut microbiota in mice

Dietary parboiled rice (PR) has a low risk of disease, but little is known about the contribution of PR to the prevention of hyperlipidemia. The potential role and underlying mechanisms of PR in hyperlipidemia were evaluated in this study. Male C57BL/6J mice were fed with a normal diet, high-fat diet (HFD) containing refined rice (HFDRR) or PR (HFDPR). It was found that PR intervention improved lipid accumulation in mice. Transcriptomic data analysis revealed that 27 genes were up-regulated (mostly involved in lipid breakdown) and 86 genes were down-regulated (mostly involved in inflammatory responses) in the HFDPR group compared to the HFDRR group. And 15 differentially expressed genes (DEGs) were validated by quantitative real-time PCR (RT-qPCR), while protein interaction network showed that protein tyrosine phosphatase receptor type C (PTPRC) has a central role. The gut microbiota of mice was also altered after different dietary treatments, with higher ratio of Firmicutes and Bacteroidetes, increased abundances of Ruminococcaceae, Lachnospiraceae, Christensenellaceae, Porphyromonadaceae, Rikenellaceae and Prevotellaceae, and decreased abundances of Lactobacillaceae, Peptostreptococcaceae, Erysipelotrichaceae and Actinobacteria in the HFDRR group. In addition, it was observed that PPAR signaling pathway may act as a bridge between DEGs and differential gut microbiota. These results suggested that PR can prevent hyperlipidemia by modulating liver genes and gut microbiota.

Role of ADAR1 on Proliferation and Differentiation in Porcine Preadipocytes.

Recent research has identified ADAR1 as a participant in the regulation of lipid accumulation in mice. However, there are no reports on the roles of ADAR1 in proliferation, apoptosis and differentiation of porcine preadipocytes. In this study, we investigated the role of ADAR1 in differentiation, proliferation and apoptosis of porcine preadipocytes using CCK-8, EdU staining, cell cycle detection, RT-qPCR, Western blot, a triglyceride assay and Oil Red O staining. The over-expression of ADAR1 significantly promoted proliferation but inhibited the differentiation and apoptosis of porcine preadipocytes. The inhibition of ADAR1 had the opposite effect on the proliferation, differentiation and apoptosis of porcine preadipocytes with over-expressed ADAR1. Then, the regulation mechanisms of ADAR1 on preadipocyte proliferation were identified using RNA-seq, and 197 DEGs in response to ADAR1 knockdown were identified. The MAPK signaling pathway is significantly enriched, indicating its importance in mediating fat accumulation regulated by ADAR1. The study's findings will aid in uncovering the mechanisms that regulate fat accumulation through ADAR1.

Glutamine prevents high-fat diet-induced hepatic lipid accumulation in mice by modulating lipolysis and oxidative stress

Metabolic-associated fatty liver disease (MAFLD) is related to metabolic dysfunction and is characterized by excess fat storage in the liver. Several studies have indicated that glutamine could be closely associated with lipid metabolism disturbances because of its important role in intermediary metabolism. However, the effect of glutamine supplementation on MAFLD progression remains unclear. Here, we used a high-fat diet (HFD)-induced MAFLD C57BL/6 mouse model, and glutamine was supplied in the drinking water at different time points for MAFLD prevention and reversal studies. A MAFLD prevention study was performed by feeding mice an HFD concomitant with 4% glutamine treatment for 24 weeks, whereas the MAFLD reversal study was performed based on 4% glutamine treatment for 13 weeks after feeding mice an HFD for 10 weeks. In the prevention study, glutamine treatment ameliorated serum lipid storage, hepatic lipid injury, and oxidative stress in HFD-induced obese mice, although glutamine supplementation did not affect body weight, glucose homeostasis, energy expenditure, and mitochondrial function. In the MAFLD reversal study, there were no noticeable changes in the basic physiological phenotype and hepatic lipid metabolism. In summary, glutamine might prevent, but not reverse, HFD-induced MAFLD in mice, suggesting that a cautious attitude is required regarding its use for MAFLD treatment.

The size-dependence and reversibility of polystyrene nanoplastics-induced lipid accumulation in mice: Possible roles of lysosomes

Nanoplastics (NPs) continue to accumulate in global aquatic and terrestrial systems, posing a potential threat to human health through the food chain and/or other pathways. Both in vivo and in vitro studies have confirmed that the liver is one of the main organs targeted for the accumulation of NPs in living organisms. However, whether exposure to NPs induces size-dependent disorders of liver lipid metabolism remains controversial, and the reversibility of NPs-induced hepatotoxicity is largely unknown. In this study, the effects of long-term exposure to environmentally relevant doses of polystyrene nanoplastics (PS-NPs) on lipid accumulation were investigated in terms of autophagy and lysosomal mechanisms. The findings indicated that hepatic lipid accumulation was more pronounced in mice exposed to 100 nm PS-NPs compared to 500 nm PS-NPs. This effect was effectively alleviated after 50 days of self-recovery for 100 nm and 500 nm PS-NPs exposure. Mechanistically, although PS-NPs exposure activated autophagosome formation through ERK (mitogen-activated protein kinase 1)/mTOR (mechanistic target of rapamycin kinase) signaling pathway, the inhibition of Rab7 (RAB7, member RAS oncogene family), CTSB (cathepsin B), and CTSD (cathepsin D) expression impaired lysosomal function, thereby blocking autophagic flux and contributing to hepatic lipid accumulation. After termination of PS-NPs exposure, lysosomal exocytosis was responsible for the clearance of PS-NPs accumulated in lysosomes. Furthermore, impaired lysosomal function and autophagic flux inhibition were effectively alleviated. This might be the main reason for the alleviation of PS-NPs-induced lipid accumulation after recovery. Collectively, we demonstrate for the first time that lysosomes play a dual role in the persistence and reversibility of hepatotoxicity induced by environmental relevant doses of NPs, which provide novel evidence for the prevention and intervention of liver injury associated with nanoplastics exposure.

Hepatoprotective Effect of Annulohypoxylon stygium Melanin on Acute Alcoholic Liver Injury in Mice.

Annulohypoxylon stygium melanin (AsM) has various functional properties such as antioxidant and anti-radiation, but its biological activity in vivo has not been fully investigated. In this study, we researched the effects of AsM on the protection against acute liver injury in mice and its mechanism. The results showed that AsM had no significant effect on body weight in mice but reduced the liver index. It was able to significantly decrease the activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), the contents of triglyceride (TG) and total cholesterol (TC) in mice. Simultaneously, it raised the levels of superoxide dismutase (SOD), peroxidase (CAT), and glutathione peroxidase (GSH-Px), which obviously exceeded those of the EtOH group. AsM could significantly lower the levels of inflammatory factors, with inhibition rates of 68.30%, 29.0%, and 19.50% for IL-1β, IL-6, and TNF-α, respectively. H&E and Oil red O staining also showed that AsM ameliorated liver damage and lipid accumulation in mice. The protective mechanism of AsM may be associated to the nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant signaling pathway, which could activate the downstream antioxidant enzymes heme oxygenase-1 (HO-1), glutamate-cysteine ligase modifier subunit (GCLM), and glutamate-cysteine ligase catalytic subunit (GCLC). These findings confirmed that AsM had an alleviating effect on alcoholic liver injury and provided new thoughts for the development of natural product.

Effect of Tetrastigma hemsleyanum leaves and Extract supplementation on liver metabolomics and the gut microbiota in alcohol-induced liver injury

Alcoholic liver disease (ALD) is caused by chronic heavy alcohol consumption and is characterized by lipid metabolism disorders, oxidative stress, and hypersecretion of proinflammatory cytokines. Tetrastigma hemsleyanum leaves (THL), a popular functional food in China, have good anti-inflammatory, antioxidant, and liver protection effects. However, whether THL extracts improve alcoholic liver disease and the underlying mechanism of action have not been determined. Therefore, in this study, we used a C57BL/6J male mouse model to investigate the effect of THL extract on ALD and to explore the underlying mechanism involved preliminarily. The alleviation of alcohol-induced liver dysfunction and changes in lipid metabolism-related pathways were observed after THL extract administration stimulated fatty acid synthesis and fatty acid β-oxidation by modulating the expression levels of related mRNAs and genes, thereby alleviating lipid accumulation and oxidative stress in the liver. The composition and abundance of the gut microbiota in mice also underwent alterations. Collectively, these findings suggest that supplementation with THL extract can mitigate liver damage and reduce hepatic lipid accumulation in mice with alcoholic fatty liver disease. It regulates hepatic metabolism and generates various metabolites associated with diminished lipid buildup, such as Plafibride, LysoPI (20:4(5Z,8Z,11Z,14Z)/0:0), 1,3,7-trimethyluric acid, and phytol. Moreover, it impacts specific gut microbiota in mice with alcoholic fatty liver disease including Bacteroides and other beneficial microorganisms while enhancing the production of short-chain fatty acids to improve the intestinal microenvironment.

Therapeutic Role of Polyphenol Extract from Prunus cerasifera Ehrhart on Non-Alcoholic Fatty Liver.

Prunus cerasifera Ehrhart (P. cerasifera) flourishes uniquely in the arid landscapes of Xinjiang, China. Preliminary studies have revealed the therapeutic potential of its polyphenol extract (PPE) in mitigating liver lipid accumulation in mice fed a high-fat diet. We established a mouse model that was subjected to a continuous high-fat diet for 24 weeks and administered PPE to investigate the effects of PPE on cholesterol and BA metabolism in NAFLD mice. The results showed that PPE administration (200 and 400 mg/kg/day, BW) led to a reduction in liver TC, an increase in liver T-BAs, and normalization of the disrupted fecal BA profile. Concurrently, it decreased levels of lipotoxic BAs and inhibited hepatic cholesterol synthesis (evidenced by reduced HMGCR activity) and intestinal cholesterol absorption (indicated by lower ACAT2 levels) while enhancing intestinal cholesterol efflux (via LXRα, ABCA1, ABCG5, and ABCG8) and stimulating hepatic BA synthesis (CYP7A1, CYP27A1) and secretion (BSEP). PPE thus led to a significant reduction in lipotoxic BAs metabolized by gut microbiota and a downregulation of the BA secretion pathway under its influence. Our findings reveal the therapeutic effect of PPE on NAFLD mice via regulating cholesterol and BA metabolism, providing a theoretical basis for exploring the potential functions of P. cerasifera.

Effects of riboflavin deficiency and high dietary fat on hepatic lipid accumulation: a synergetic action in the development of non-alcoholic fatty liver disease

BackgroundNon-alcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation in the liver. Riboflavin, one of water soluble vitamins, plays a role in lipid metabolism and antioxidant function. However, the effects of riboflavin deficiency on NAFLD development have not yet to be fully explored.MethodsIn the present study, an animal model of NAFLD was induced by high fat diet feeding in mice and a cellular model of NAFLD was developed in HepG2 cells by palmitic acid (PA) exposure. The effects of riboflavin deficiency on lipid metabolism and antioxidant function were investigated both in vivo and in vitro. In addition, the possible role of peroxisome proliferator-activated receptor gamma (PPARγ) was studied in HepG2 cells using gene silencing technique.ResultsThe results showed that riboflavin deficiency led to hepatic lipid accumulation in mice fed high fat diet. The expressions of fatty acid synthase (FAS) and carnitine palmitoyltransferase 1 (CPT1) were up-regulated, whereas that of adipose triglyceride lipase (ATGL) down-regulated. Similar changes in response to riboflavin deficiency were demonstrated in HepG2 cells treated with PA. Factorial analysis revealed a significant interaction between riboflavin deficiency and high dietary fat or PA load in the development of NAFLD. Hepatic PPARγ expression was significantly upregulated in mice fed riboflavin deficient and high fat diet or in HepG2 cells treated with riboflavin deficiency and PA load. Knockdown of PPARγ gene resulted in a significant reduction of lipid accumulation in HepG2 cells exposed to riboflavin deficiency and PA load.ConclusionsThere is a synergetic action between riboflavin deficiency and high dietary fat on the development of NAFLD, in which PPARγ may play an important role.

Antibiotic altered liver damage induced by aflatoxin B1 exposure in mice by modulating the gut microbiota

Aflatoxins B1 (AFB1) and antibiotic (AN) carry co-exposure risks, with the gut being a target organ for their combined effects. However, the current understanding of the impact of AN on gut and liver injury induced by AFB1 remains limited. In this study, we conducted a 9-week investigation into the implications of AN (ampicillin and penicillin) treatment on AFB1-induced intestinal and liver injury in C57BL/6J male mice fed a normal diet (ND) and a high-fat diet (HFD). The results showed that AN treatment significantly reduce the total number and diversity of intestinal species in both ND and HFD mice exposed to AFB1. Moreover, AN treatment alleviated AFB1-induced liver injury and lipid accumulation in mice on ND and HFD, while improving abnormal lipid metabolism in the liver and serum. However, AN treatment also promoted intestinal damage and reduced the levels of short-chain fatty acids in the gut. Correlation analysis demonstrated that, under the two dietary patterns, microorganisms across various genera were significantly positively or negatively correlated with alterations in liver, serum, and intestinal biochemical indexes. These genera include Akkermansia, Robinsoniella, Parabacteroides, Escherichia-Shigel, and Parabacteroides, Odoribacter. AN may alleviate long-term AFB1-induced liver injury through the regulation of intestinal microorganisms, with the effect being more pronounced in mice following an HFD pattern. These findings provide novel insights into the effects of AFB1 on the gut‒liver axis under complex exposure conditions, as well as the relationship between gut microbial homeostasis and liver injury across different dietary patterns.

Effects of short-term carbohydrate deprivation on glycolipid metabolism and hepatic lipid accumulation in mice.

To investigate the effect of dietary carbohydrate levels on liver glycolipid metabolism, this study used C57BL/6J male mice receiving standard diet (CON), no-carbohydrate high-fat diet (NCD), and high-carbohydrate no-fat diet (HCD). One week after intervention, mice in the NCD group showed lower blood glucose, HbA1c and LDL-C as well as liver weight and liver index compared with the CON group. Further research found that the liver fat synthesis genes of mice in the NCD group were significantly down-regulated at the gene level, and histopathological sections showed that the livers of mice in the NCD group had less lipid accumulation. Furthermore, liver metabolomic analysis showed that primary bile acid levels and acylcarnitine levels in the liver of mice in the NCD group were significantly increased, and conversely, lysophosphatidylcholine and fatty acyl metabolites were significantly decreased. KEGG metabolic pathway analysis showed that metabolic pathways such as biosynthesis of unsaturated fatty acids and starch and sucrose metabolism were significantly inhibited in mice in the NCD group, while metabolic pathways such as primary bile acid biosynthesis, linoleic acid metabolism and glycerophospholipid metabolism were enhanced. Taken together, these results indicate that short-term carbohydrate deprivation improves blood glucose and lipid metabolism levels in mice; the molecular mechanism of action may involve inhibition of de novo lipogenesis and enhancement of bile acid metabolism.