Obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) are linked to numerous chronic conditions, including cardiovascular disease, atherosclerosis, chronic kidney disease, and type II diabetes. Previous research identified the natural flavonoid diosmin, derived from Chrysanthemum morifolium, as a regulator of glucose metabolism. However, its effects on lipid metabolism and underlying mechanisms remained unexplored. The AMP-activated protein kinase (AMPK) pathway serves a critical function in glucose and lipid metabolism. The relationship between diosmin and the AMPK pathway has not been previously documented. This investigation examined diosmin's capacity to reduce lipid content through AMPK pathway activation in hepatoblastoma cell line G2 (HepG2) and 3T3-L1 cells. The study revealed that diosmin inhibits lipogenesis, indicating its potential as an anti-obesity agent in obese mice. Moreover, diosmin demonstrated effective MASLD alleviation in vivo. These findings suggest that diosmin may represent a promising therapeutic candidate for treating obesity and MASLD.
Diosmin/administration & dosage* ; Animals ; AMP-Activated Protein Kinases/genetics* ; Humans ; Non-alcoholic Fatty Liver Disease/enzymology* ; Mice ; Obesity/enzymology* ; Hep G2 Cells ; Male ; 3T3-L1 Cells ; Mice, Inbred C57BL ; Signal Transduction/drug effects* ; Lipid Metabolism/drug effects* ; Chrysanthemum/chemistry* ; Lipogenesis/drug effects*

The aim of this study was to clone the goat RPL29 gene and analyze its effect on lipogenesis in intramuscular adipocytes. Using Jianzhou big-eared goats as the object, the goat RPL29 gene was cloned by reverse transcription-polymerase chain reaction (RT-PCR), the gene structure and expressed protein sequence were analyzed by bioinformatics, and the mRNA expression levels of RPL29 in various tissues and different differentiation stages of intramuscular adipocytes of goats were detected by quantitative real-time PCR (qRT-PCR). The RPL29 overexpression vector pEGFP-N1-RPL29 constructed by gene recombination was used to transfect into goat intramuscular preadipocytes and induce differentiation. Subsequently, the effect of overexpression of RPL29 on fat droplet accumulation was revealed morphologically by oil red O and Bodipy staining, and changes in the expression levels of genes related to lipid metabolism were detected by qRT-PCR. The results showed that the length of the goat RPL29 was 507 bp, including a coding sequence (CDS) region of 471 bp which encodes 156 amino acid residues. It is a positively charged and stable hydrophilic protein mainly distributed in the nucleus of cells. Tissue expression profiling showed that the expression level of this gene was much higher in subcutaneous adipose tissue and inter-abdominal adipose tissue of goats than in other tissues (P < 0.05). The temporal expression profile showed that the gene was expressed at the highest level at 84 h of differentiation in goat intramuscular adipocytes, which was highly significantly higher than that in the undifferentiated period (P < 0.01). Overexpression of RPL29 promoted lipid accumulation in intramuscular adipocytes, and the optical density values of oil red O staining were significantly increased (P < 0.05). In addition, overexpression of RPL29 was followed by a highly significant increase in ATGL and ACC gene expression (P < 0.01) and a significant increase in FASN gene expression (P < 0.05). In conclusion, the goat RPL29 may promote intra-muscular adipocyte deposition in goats by up-regulating FASN, ACC and ATGL.
Animals ; Lipogenesis/genetics* ; Adipogenesis/genetics* ; Goats/genetics* ; Adipocytes ; Cell Differentiation/genetics* ; Sequence Analysis ; Cloning, Molecular

PURPOSE: Sprouts of evening primrose (Oenothera laciniata, OL) were reported to have high contents of flavonoids and potent antioxidant activity. This study examined the antioxidant and antiobesity activities of OL sprouts to determine if they could be a natural health-beneficial resource preventing obesity and oxidative stress.METHODS: OL sprouts were extracted with 50% ethanol, evaporated, and lyophilized (OLE). The in vitro antioxidant activity of OLE was examined using four different tests. The antiobesity activity and in vivo antioxidant activity from OLE consumption were examined using high fat diet-induced obese (DIO) C57BL/6 mice.RESULTS: The IC₅₀ for the 2,2-diphenyl-1-picryl-hydrazyl (DPPH) radical scavenging and superoxide dismutase (SOD)-like activities of OLE were 26.2 µg/mL and 327.6 µg/mL, respectively. OLE exhibited the ferric reducing antioxidant power (FRAP) activity of 56.7 µg ascorbic acid eq./mL at 100 µg/mL, and an increased glutathione level by 65.1% at 200 µg/mL compared to the control in the hUC-MSC stem cells. In an animal study, oral treatment with 50 mg or 100 mg of OLE/kg body weight for 14 weeks reduced the body weight gain, visceral fat content, fat cell size, blood leptin, and triglyceride levels, as well as the atherogenic index compared to the high fat diet control group (HFC) (p < 0.05). The blood malondialdehyde (MDA) level and the catalase and SOD-1 activities in adipose tissue were reduced significantly by the OLE treatment compared to HFC as well (p < 0.05). In epididymal adipose tissue, the OLE treatment reduced the mRNA expression of leptin, PPAR-γ and FAS significantly (p < 0.05) compared to HFC while it increased adiponectin expression (p < 0.05).CONCLUSION: OLE consumption has potent antioxidant and antiobesity activities via the suppression of oxidative stress and lipogenesis in DIO mice. Therefore, OLE could be a good candidate as a natural resource to develop functional food products that prevent obesity and oxidative stress.
Adipocytes ; Adipokines ; Adiponectin ; Adipose Tissue ; Animals ; Ascorbic Acid ; Body Weight ; Catalase ; Diet, High-Fat ; Ethanol ; Flavonoids ; Functional Food ; Glutathione ; In Vitro Techniques ; Intra-Abdominal Fat ; Leptin ; Lipogenesis ; Malondialdehyde ; Mice ; Mice, Obese ; Natural Resources ; Obesity ; Oenothera biennis ; Oxidative Stress ; RNA, Messenger ; Stem Cells ; Superoxide Dismutase ; Triglycerides

BACKGROUND/OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) is a common metabolic disease triggered by epigenetic alterations, including lysine acetylation at histone or non-histone proteins, affecting the stability or transcription of lipogenic genes. Although various natural dietary compounds have anti-lipogenic effects, their effects on the acetylation status and lipid metabolism in the liver have not been thoroughly investigated. MATERIALS/METHODS: Following oleic-palmitic acid (OPA)-induced lipid accumulation in HepG2 cells, the acetylation status of histone and non-histone proteins, HAT activity, and mRNA expression of representative lipogenic genes, including PPARγ, SREBP-1c, ACLY, and FASN, were evaluated. Furthermore, correlations between lipid accumulation and HAT activity for 22 representative natural food extracts (NExs) were evaluated. RESULTS: Non-histone protein acetylation increased following OPA treatment and the acetylation of histones H3K9, H4K8, and H4K16 was accelerated, accompanied by an increase in HAT activity. OPA-induced increases in the mRNA expression of lipogenic genes were down-regulated by C-646, a p300/CBP-specific inhibitor. Finally, we detected a positive correlation between HAT activity and lipid accumulation (Pearson's correlation coefficient = 0.604) using 22 NExs. CONCLUSIONS: Our results suggest that NExs have novel applications as nutraceutical agents with HAT inhibitor activity for the prevention and treatment of NAFLD.
Acetylation ; Dietary Supplements ; Epigenomics ; Hep G2 Cells ; Histone Acetyltransferases ; Histones ; Lipid Metabolism ; Lipogenesis ; Liver ; Lysine ; Metabolic Diseases ; Non-alcoholic Fatty Liver Disease ; RNA, Messenger ; Sterol Regulatory Element Binding Protein 1

No abstract available.
Inflammation ; Lipogenesis

BackgroundA high consumption of fructose leads to hepatic steatosis. About 20-30% of triglycerides are synthesized via de novo lipogenesis. Some studies showed that endoplasmic reticulum stress (ERS) is involved in this process, while others showed that a lipotoxic environment directly influences ER homeostasis. Here, our aim was to investigate the causal relationship between ERS and fatty acid synthesis and the effect of X-box binding protein-1 (XBP-1), one marker of ERS, on hepatic lipid accumulation stimulated by high fructose.

MethodsHepG2 cells were incubated with different concentrations of fructose. Upstream regulators of de novo lipogenesis (i.e., carbohydrate response element-binding protein [ChREBP] and sterol regulatory element-binding protein 1c [SREBP-1c]) were measured by polymerase chain reaction and key lipogenic enzymes (acetyl-CoA carboxylase [ACC], fatty acid synthase [FAS], and stearoyl-CoA desaturase-1 [SCD-1]) by Western blotting. The same lipogenesis-associated factors were then evaluated after exposure of HepG2 cells to high fructose followed by the ERS inhibitor tauroursodeoxycholic acid (TUDCA) or the ERS inducer thapsigargin. Finally, the same lipogenesis-associated factors were evaluated in HepG2 cells after XBP-1 upregulation or downregulation through cell transfection.

ResultsExposure to high fructose increased triglyceride levels in a dose- and time-dependent manner and significantly increased mRNA levels of SREBP-1c and ChREBP and protein levels of FAS, ACC, and SCD-1, concomitant with XBP-1 conversion to an active spliced form. Lipogenesis-associated factors induced by high fructose were inhibited by TUDCA and induced by thapsigargin. Triglyceride level in XBP-1-deficient group decreased significantly compared with high-fructose group (4.41 ± 0.54 μmol/g vs. 6.52 ± 0.38 μmol/g, P < 0.001), as mRNA expressions of SREBP-1c (2.92 ± 0.46 vs. 5.08 ± 0.41, P < 0.01) and protein levels of FAS (0.53 ± 0.06 vs. 0.85 ± 0.05, P = 0.01), SCD-1 (0.65 ± 0.06 vs. 0.90 ± 0.04, P = 0.04), and ACC (0.38 ± 0.03 vs. 0.95 ± 0.06, P < 0.01) decreased. Conversely, levels of triglyceride (4.22 ± 0.54 μmol/g vs. 2.41 ± 0.35 μmol/g, P < 0.001), mRNA expression of SREBP-1c (2.70 ± 0.33 vs. 1.00 ± 0.00, P < 0.01), and protein expression of SCD-1 (0.93 ± 0.06 vs. 0.26 ± 0.05, P < 0.01), ACC (0.98 ± 0.09 vs. 0.43 ± 0.03, P < 0.01), and FAS (0.90 ± 0.33 vs. 0.71 ± 0.02, P = 0.04) in XBP-1s-upregulated group increased compared with the untransfected group.

ConclusionsERS is associated with de novo lipogenesis, and XBP-1 partially mediates high-fructose-induced lipid accumulation in HepG2 cells through augmentation of de novo lipogenesis.

Endoplasmic Reticulum Stress ; physiology ; Fatty Liver ; Fructose ; metabolism ; Hep G2 Cells ; Humans ; Lipogenesis ; physiology ; Liver ; Sterol Regulatory Element Binding Protein 1 ; X-Box Binding Protein 1 ; physiology

BACKGROUND: Hepatic steatosis is caused by metabolic stress associated with a positive lipid balance, such as insulin resistance and obesity. Previously we have shown the anti-obesity effects of inhibiting serotonin synthesis, which eventually improved insulin sensitivity and hepatic steatosis. However, it is not clear whether serotonin has direct effect on hepatic lipid accumulation. Here, we showed the possibility of direct action of serotonin on hepatic steatosis. METHODS: Mice were treated with para-chlorophenylalanine (PCPA) or LP-533401 to inhibit serotonin synthesis and fed with high fat diet (HFD) or high carbohydrate diet (HCD) to induce hepatic steatosis. Hepatic triglyceride content and gene expression profiles were analyzed. RESULTS: Pharmacological and genetic inhibition of serotonin synthesis reduced HFD-induced hepatic lipid accumulation. Furthermore, short-term PCPA treatment prevented HCD-induced hepatic steatosis without affecting glucose tolerance and browning of subcutaneous adipose tissue. Gene expression analysis revealed that the expressions of genes involved in de novo lipogenesis and triacylglycerol synthesis were downregulated by short-term PCPA treatment as well as long-term PCPA treatment. CONCLUSION: Short-term inhibition of serotonin synthesis prevented hepatic lipid accumulation without affecting systemic insulin sensitivity and energy expenditure, suggesting the direct steatogenic effect of serotonin in liver.
Animals ; Diabetes Mellitus ; Diet ; Diet, High-Fat ; Energy Metabolism ; Fatty Liver ; Fenclonine ; Gene Expression ; Glucose ; Insulin Resistance ; Lipogenesis ; Liver ; Mice ; Obesity ; Serotonin* ; Stress, Physiological ; Subcutaneous Fat ; Transcriptome ; Triglycerides

The mechanistic target of rapamycin (mTOR) signaling pathway regulates many metabolic and physiological processes in different organs or tissues. Dysregulation of mTOR signaling has been implicated in many human diseases including obesity, diabetes, cancer, fatty liver diseases, and neuronal disorders. Here we review recent progress in understanding how mTORC1 (mTOR complex 1) signaling regulates lipid metabolism in the liver.
Animals ; Humans ; Lipid Metabolism ; Lipogenesis ; Liver ; cytology ; metabolism ; pathology ; Mechanistic Target of Rapamycin Complex 1 ; metabolism ; Signal Transduction

Cushing's syndrome (CS) is a collection of symptoms caused by prolonged exposure to excess cortisol. Chronically elevated glucocorticoid (GC) levels contribute to hepatic steatosis. We hypothesized that histone deacetylase inhibitors (HDACi) could attenuate hepatic steatosis through glucocorticoid receptor (GR) acetylation in experimental CS. To induce CS, we administered adrenocorticotropic hormone (ACTH; 40 ng/kg/day) to Sprague-Dawley rats by subcutaneous infusion with osmotic mini-pumps. We administered the HDACi, sodium valproate (VPA; 0.71% w/v), in the drinking water. Treatment with the HDACi decreased steatosis and the expression of lipogenic genes in the livers of CS rats. The enrichment of GR at the promoters of the lipogenic genes, such as acetyl-CoA carboxylase (Acc), fatty acid synthase (Fasn), and sterol regulatory element binding protein 1c (Srebp1c), was markedly decreased by VPA. Pan-HDACi and an HDAC class I-specific inhibitor, but not an HDAC class II a-specific inhibitor, attenuated dexamethasone (DEX)-induced lipogenesis in HepG2 cells. The transcriptional activity of Fasn was decreased by pretreatment with VPA. In addition, pretreatment with VPA decreased DEX-induced binding of GR to the glucocorticoid response element (GRE). Treatment with VPA increased the acetylation of GR in ACTH-infused rats and DEX-induced HepG2 cells. Taken together, these results indicate that HDAC inhibition attenuates hepatic steatosis hrough GR acetylation in experimental CS.
Acetyl-CoA Carboxylase ; Acetylation ; Adrenocorticotropic Hormone ; Animals ; Cushing Syndrome* ; Dexamethasone ; Drinking Water ; Hep G2 Cells ; Histone Deacetylase Inhibitors ; Histone Deacetylases* ; Histones* ; Hydrocortisone ; Infusions, Subcutaneous ; Lipogenesis ; Liver ; Rats* ; Rats, Sprague-Dawley ; Receptors, Glucocorticoid ; Response Elements ; Sterol Regulatory Element Binding Protein 1 ; Valproic Acid

Obesity is currently one of the most serious public health problems and it can lead to numerous metabolic diseases. Leucrose, d-glucopyranosyl-α-(1-5)-d-fructopyranose, is an isoform of sucrose and it is naturally found in pollen and honey. The aim of this study was to investigate the effect of leucrose on metabolic changes induced by a high-fat diet (HFD) that lead to obesity. C57BL/6 mice were fed a 60% HFD or a HFD with 25% (L25) or 50% (L50) of its total sucrose content replaced with leucrose for 12 weeks. Leucrose supplementation improved fasting blood glucose levels and hepatic triglyceride content. In addition, leucrose supplementation reduced mRNA levels of lipogenesis-related genes, including peroxisome proliferator-activated receptor γ, sterol regulatory element binding protein 1C, and fatty acid synthase in HFD mice. Conversely, mRNA levels of β oxidation-related genes, such as carnitine palmitoyltransferase 1A and acyl CoA oxidase, returned to control levels with leucrose supplementation. Taken together, these results demonstrated the therapeutic potential of leucrose to prevent metabolic abnormalities by mediating regulation of plasma glucose level and hepatic triglyceride accumulation.
Acyl-CoA Oxidase ; Animals ; Blood Glucose ; Carnitine O-Palmitoyltransferase ; Diet, High-Fat ; Fasting ; Honey ; Lipogenesis ; Liver ; Metabolic Diseases ; Mice ; Mice, Obese ; Negotiating ; Obesity ; Peroxisomes ; Pollen ; Public Health ; RNA, Messenger ; Sterol Regulatory Element Binding Protein 1 ; Sucrose ; Triglycerides