Sterol Regulatory Element-binding Protein Research Articles

Induction of resistance to neurotrophic tropomyosin-receptor kinase inhibitors by HMGCS2 via a mevalonate pathway.

A neurotrophic tropomyosin receptor kinase (NTRK)-tyrosine kinase inhibitor (TKI) has shown dramatic efficacy against malignant tumors harboring an NTRK fusion gene. However, almost all tumors eventually acquire resistance to NTRK-TKIs. To investigate the mechanism of resistance to NTRK-TKIs, we established cells resistant to three types of NTRK-TKIs (larotrectinib, entrectinib, and selitrectinib) using KM12 colon cancer cells with a TPM3-NTRK1 rearrangement. Overexpression of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) was observed in three resistant cells (KM12-LR, KM12-ER, and KM12-SR) by microarray analysis. Lower expression of sterol regulatory element-binding protein 2 (SREBP2) and peroxisome proliferator activated receptor α (PPARα) was found in two cells (KM12-ER and KM12-SR) in which HMGCS2 was overexpressed compared to the parental KM12 and KM12-LR cells. In resistant cells, knockdown of HMGCS2 using small interfering RNA improved the sensitivity to NTRK-TKI. Further treatment with mevalonolactone after HMGCS2 knockdown reintroduced the NTRK-TKI resistance. In addition, simvastatin and silibinin had a synergistic effect with NTRK-TKIs in resistant cells, and delayed tolerance was observed after sustained exposure to clinical concentrations of NTRK-TKI and simvastatin in KM12 cells. In xenograft mouse models, combination treatment with entrectinib and simvastatin reduced resistant tumor growth compared with entrectinib alone. These results suggest that HMGCS2 overexpression induces resistance to NTRK-TKIs via the mevalonate pathway in colon cancer cells. Statin inhibition of the mevalonate pathway may be useful for overcoming this mechanistic resistance.

Dietary betulinic acid alleviates high carbohydrate diet-induced hepatic de novo lipogenesis through AMPK signaling and improves liver health in channel catfish (Ictalurus punctatus)

A high carbohydrate diet (HCD) induced excessive hepatic de novo lipogenesis, which caused metabolic disorder and impaired the health of fish species. Betulinic acid (BA) has been applied to ameliorate fatty liver and anti-inflammatory in mammals. Here, we investigated the effects of dietary BA supplementation on HCD-induced hepatic de novo lipogenesis and liver health in channel catfish (Ictalurus punctatus). The catfish were fed with three diets: NCD (18 % carbohydrate), HCD (36 % carbohydrate), HCD+BA (36 % carbohydrate with 150 mg/kg BA). After an 8-week feeding trial, we found that dietary BA decreased hepatosomatic index (HSI) and condition factor (CF) without affecting the growth of channel catfish fed HCD. Dietary BA significantly reduced the HCD-induced excessive lipid accumulation (oil red O area, TG content, and de novo lipogenesis gene expression, P < 0.05). Moreover, we found that dietary BA prevented hepatic lipid accumulation via activating phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and inhibiting sterol regulatory element-binding protein 1 (SREBP1) (P < 0.05) in liver of channel catfish fed HCD. Besides, we also found that dietary BA significantly prevented HCD-induced liver damage, as confirmed by liver H&E staining, reduced inflammation biomarkers (ALT, AST, hydroxyproline, α-sma and tgf-1β), downregulated expression of ER stress-related genes (eif2a, bip, atf4, xbp1) (P < 0.05). Overall, the present study indicated that dietary BA inclusion attenuated hepatic de novo lipogenesis, improved liver inflammation and reduced ER stress in channel catfish fed HCD.

Nobiletin Protects Against Alcoholic Liver Disease in Mice via the BMAL1-AKT-Lipogenesis Pathway.

Alcoholic liver disease (ALD) is a global public health concern. Nobiletin, a polymethoxyflavone abundant in citrus fruits, enhances circadian rhythms and ameliorates diet-induced hepatic steatosis, but its influences on ALD are unknown. This study investigates the role of brain and muscle Arnt-like protein-1 (Bmal1), a key regulator of the circadian clock, in nobiletin-alleviated ALD. This study uses chronic ethanol feeding plus an ethanol binge to establish ALD models in Bmal1flox/flox and Bmal1 liver-specific knockout (Bmal1LKO) mice. Nobiletin mitigates ethanol-induced liver injury (alanine aminotransferase [ALT]), glucose intolerance, hepatic apoptosis, and lipid deposition (triglyceride [TG], total cholesterol [TC]) in Bmal1flox/flox mice. Nobiletin fails to modulated liver injury (ALT, aspartate aminotransferase [AST]), apoptosis, and TG accumulation in Bmal1LKO mice. The expression of lipogenic genes (acetyl-CoA carboxylase alpha [Acaca], fatty acid synthase [Fasn]) and fatty acid oxidative genes (carnitine pamitoyltransferase [Cpt1a], cytochrome P450, family 4, subfamily a, polypeptide 10 [Cyp4a10], and cytochrome P450, family4, subfamily a, polypeptide 14 [Cyp4a14]) is inhibited, andthe expression of proapoptotic genes (Bcl2 inteacting mediator of cell death [Bim]) is enhanced by ethanol in Bmal1flox/flox mice. Nobiletin antagonizes the expression of these genes in Bmal1flox/flox mice and not in Bmal1LKO mice. Nobiletin activates protein kinase B (PKB, also known as AKT)phosphorylation, increases the levels of the carbohydrate response element binding protein (ChREBP), ACC1, and FASN, and reduces the level of sterol-regulatory element binding protein 1 (SREBP1)and phosphorylation of ACC1 in a Bmal1-dependent manner. Nobiletin alleviates ALD by increasing the expression of genes involved in fatty acid oxidation by increasing AKT phosphorylation and lipogenesis in a Bmal1-dependent manner.

Research on the mechanism of sea buckthorn leaf Fu tea in the treatment of hyperlipidemia

BackgroundHyperlipidemia (HLP) presents a significant challenge to global public health. Mounting evidence suggests that statins, the recommended first-line lipid-lowering agents, have significant adverse effects. Consequently, the quest for natural and efficacious alternative therapies is steadily emerging as a research priority for HLP prevention and treatment. Consumption of tea, which is rich in diverse biologically active compounds with the capacity to regulate lipid metabolism and combat obesity, has emerged as a promising alternative therapy. Sea buckthorn leaves are rich in a multitude of biologically active substances, have a hypolipidemic effect, and can be used as a raw material for tea because of their unique flavor. There is a suggestion that combining Aspergillus cristatus with tea could modify or boost the lipid-lowering active compounds present in tea, thereby increasing its efficacy in regulating lipid metabolism. ResultsSea Buckthorn Leaf Fu Tea (SBLFT) was obtained by fermentation when sea buckthorn leaves contained 42 % moisture, inoculated with Aspergillus cristatus 0.2 mL/g, and incubated for 8 d at constant temperature. Animal experiments demonstrated that SBLFT significantly inhibited body weight gain in HLP rats and reduced lipid content and serum oxidative stress. In addition, liver tissue sections and functional indices showed that SBLFT can improve liver morphology and function abnormalities. Reverse transcription-polymerase chain reaction results indicated that the expression of Liver kinase B1 (LKB1), adenosine 5‘-monophosphate (AMP)-activated protein kinase (AMPK), acetyl CoA carboxylase 1 (ACC1), and sterol-regulatory element binding protein-1 (SREBP1c) gene related to lipid metabolism was altered. ConclusionSBLFT improved HLP, specifically via promoting the expression of LKB1 in the liver of HLP rats, activating AMPK, and inhibiting ACC1 and SREBP1c expression, resulting in the inhibition of fatty acid and triglyceride synthesis-related enzymes at the transcriptional level.

Design, synthesis, and biological evaluation of (E)-3-(3-methoxy-4-substituted phenyl)-acrylic acid derivatives: Role of compound S17 in regulating lipid accumulation via AMPK activation

Non-alcoholic fatty liver disease (NAFLD) is increasingly recognized as a global public health concern characterized by excessive lipid accumulation in the liver. Ferulic acid (FA), a common foodborne phenolic acid, has been shown to reduce lipid accumulation by activating adenosine monophosphate-activated protein kinase (AMPK) and suppressing the expression of sterol regulatory element-binding protein-1 (SREBP-1). In this study, we synthesized a new class of (E)-3-(3-methoxy-4-substituted phenyl)-acrylic acid derivatives as AMPK activators. Among these derivatives, compound S17 demonstrated a more potent inhibitory effect on lipid accumulation compared to its counterparts. Specifically, S17 notably diminished intracellular triglyceride (TG) levels and the activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), which are indicators of liver function. In addition, S17 curtailed intracellular lipid accumulation by activating the AMPK signaling pathway and down-regulating the protein expression of SREBP-1 in free fatty acid (FFA)-induced HepG2 cells. Therefore, findings from this study strongly suggest that compound S17 may serve as a promising therapeutic candidate for the treatment of NAFLD.

M6A RNA Methylation and Implications for Hepatic Lipid Metabolism.

This review presents a summary of recent progress in research on the N6-methyladenosine (m6A) modification and regulatory roles in hepatic lipid metabolism. As the most abundant internal modification of eukaryotic RNA, the m6A modification is a dynamic and reversible process of the m6A enzyme system, which includes writers, erasers, and readers. m6A methylation depressed lipid synthesis and facilitated lipolysis in liver. The depletion of m6A methyltransferase Mettl14/Mettl3 raised fatty acid synthase (FAS), stearoyl-CoA desaturase-1 (SCD1), acetyl-CoA carboxylase (ACC), and elongase of very long chain fatty acids 6 (ELOVL6) in rodent liver, causing increases in liver weight, triglyceride (TG) production, and content in hepatocytes. FTO catalyzed m6A demethylation and the suppression m6A reader YTHDC2 promoted hepatocellular TG generation and hepatic steatosis in C57BL/6 mice through sterol regulatory element-binding protein 1c (SREBP-1c) signaling pathway, which upregulated the lipogenic genes FAS, SCD1, ACC, recombinant acetyl coenzyme a carboxylase alpha, and cell death-inducing DNA fragmentation factor-like effector C (CIDEC). Furthermore, FTO overexpression did not only enhance mitochondrial fusion to impair mitochondrial function and lipid oxidation but also promoted lipid peroxidation, accompanied by excessive TG in hepatocytes and rodent liver. Elevated m6A modification potently suppressed hepatic lipid accumulation, while the shrinkage of m6A modification arose hepatic lipid deposition. These findings have highlighted the beneficial role of m6A RNA methylation in hepatic lipid metabolism, potentially protecting liver from lipid metabolic disorders.

Baicalein ameliorates lipid accumulation in HepG2 cells via the pregnane X receptor signaling pathway

The role of the pregnane X receptor (PXR) extended beyond regulating drug metabolism and transport, it also played a crucial part in lipid metabolism. Baicalein, a flavonoid derived from Scutellaria baicalensis, was demonstrated anti-inflammatory, anti-cancer, and anti-oxidative stress properties. Recent investigations reported its capacity to enhance lipid metabolism disorders. This study aimed to clarify the mechanism via which baicalein exerted its positive effects on lipid metabolism disorders by targeting PXR. The findings indicated that baicalein facilitated the nuclear translocation of PXR and controlled the expression of its target genes. In HepG2 cells with oleic acid and palmitic acid-induced lipid accumulation, baicalein treatment reduced the production of triglycerides, total cholesterol, and lipid droplets. In addition, it decreased the expression of sterol regulatory element-binding protein 1 (SREBP1), as well as lipogenic enzymes fatty acid synthase (FAS) and stearoyl-CoA desaturase-1 (SCD1). The results of computer simulation indicated that baicalein was a natural ligand of PXR. In conclusion, baicalein might potentially alleviate lipid metabolism disorders by targeting the PXR pathway.

Impact of culture medium on the interpretation of qRT-PCR data in HepG2 incubated with lactobacilli.

Recently, an increasing number of studies have investigated the mechanism of action of lactobacilli in the treatment of non-alcoholic fatty liver disease. Using four computational tools (NormFinder, geNorm, Delta Ct, and BestKeeper), six potential reference genes (RGs) were analyzed in the human liver cell line HepG2 cultivated 24 h in the presence of two strains of heat-killed lactobacilli, Limosilactobacillus reuteri E and Lactiplantibacillus plantarum KG4, respectively, in different cultivation media [Dulbecco´s Modified Eagle´s Medium (DMEM) high glucose or Roswell Park Memorial Institute (RPMI)]. The analysis revealed that the suitability of RG was similar between the two lactobacilli but quite different between the two media. The commonly used RGs, 18S rRNA and glyceraldehyde-3-phosphate dehydrogenase were the most unstable in DMEM high glucose. Normalization of the mRNA expression of the target gene encoding sterol regulatory element-binding protein 1c (SREBP-1c) to different RGs resulted in different expression profiles. This demonstrates that validation of candidate RGs under specific experimental conditions is crucial for the correct interpretation of quantitative polymerase chain reaction data. In addition, the choice of media has a profound impact on the effect of lactobacilli on lipogenesis at the gene expression level, as shown by the transcription factor SREBP-1c.

Effects of a diet supplemented with polysaccharides from Pogostemon cablin on growth performance, meat quality, and antioxidant capacity in Chongren Partridge chickens.

In this study, the Pogostemon cablin polysaccharides (PCPs) were heteropolysaccharides with molecular weights of 63.17 kDa and 8.99 kDa, and their total carbohydrate content was 76.17 ± 0.23%, uronic acid content was 19.92 ± 0.42%, and protein content was 1.24 ± 0.07%. PCP is composed of arabinose, galactose, glucose, and glucuronic acid, with a molar ratio of 0.196:0.249:0.451:0.104. In addition, we further investigated the effects of the diet supplemented with different doses of PCP on growth performance, meat quality, and anti-oxidant capacity in Chongren Partridge chickens. A total of 200 chickens were randomly allocated into 4 treatments, and fed with a basal diet of 0 (CON), 200 (LPCP), 400 (MPCP), and 800 (HPCP) mg/kg PCP for a 14-day prefeeding period and a formal experimental period of 56 days. Results showed that dietary PCP significantly increased final body weight (BW), average daily gain (ADG), and decreased feed-to-gain ratio (F/G) from days 1 to 56. Meanwhile, dietary PCP reduced yellowness (b∗) values and increased redness (a∗) values at 24 h in breast muscles (p < 0.05). Furthermore, LPCP and MPCP significantly increased the level of guanylic acid (GMP) (p < 0.05). MPCP increased the content of free amino acids (isoleucine, leucine, lysine, methionine, threonine, valine, alanine, glutamic acid, serine, cysteine), total essential amino acid (EAA), total flavor amino acid (FAA), total AA, the content of fatty acids (c14:1, c16:1, and c22:2), and monounsaturated fatty acids (MUFAs) in the breast muscle when compared to CON (p < 0.05). In addition, MPCP significantly reduced the content of malondialdehyde (MDA) and increased the transcript abundances of fatty acid desaturase 2 (FADS2), fatty acid synthase (FAS), lipoprotein lipase (LPL), and sterol regulatory element binding protein-1 (SREBP-1) in the breast muscles of the chickens (p < 0.05). In light of the aforementioned results, PCP at 400 mg/kg could be used as an effective additive because it not only promotes the growth performance of Chongren Partridge chickens but also shows a conducive role in meat quality, especially in meat flavor.

Regulatory impacts of PPARGC1A gene expression on milk production and cellular metabolism in buffalo mammary epithelial cells

The PPARGC1A gene plays a fundamental role in regulating cellular energy metabolism, including adaptive thermogenesis, mitochondrial biogenesis, adipogenesis, gluconeogenesis, and glucose/fatty acid metabolism. In a previous study, our group investigated seven SNPs in Mediterranean buffalo associated with milk production traits, and the current study builds on this research by exploring the regulatory influences of the PPARGC1A gene in buffalo mammary epithelial cells (BuMECs). Our findings revealed that knockdown of PPARGC1A gene expression significantly affected the growth of BuMECs, including proliferation, cell cycle, and apoptosis. Additionally, we observed downregulated triglyceride secretion after PPARGC1A knockdown. Furthermore, the critical genes related to milk production, including the STATS, BAD, P53, SREBF1, and XDH genes were upregulated after RNAi, while the FABP3 gene, was downregulated. Moreover, Silencing the PPARGC1A gene led to a significant downregulation of β-casein synthesis in BuMECs. Our study provides evidence of the importance of the PPARGC1A gene in regulating cell growth, lipid, and protein metabolism in the buffalo mammary gland. In light of our previous research, the current study underscores the potential of this gene for improving milk production efficiency and overall dairy productivity in buffalo populations.

Regulation of hepatic lipogenesis by asymmetric arginine methylation

Background and aimsHepatic lipogenesis is elevated in nutrient abundant conditions to convert the excess carbohydrate into triacylglycerol (TAG). Fatty acyl moiety of TAG is eventually transported into adipose tissues by very low density lipoprotein, leading to the accumulation of TAG as a preferred storage form of excess energy. Disruption of the balance between TAG clearance and synthesis leads to the accumulation of lipids in the liver, leading to the progression of non-alcoholic fatty liver disease (NAFLD) including non-alcoholic steatohepatitis. Protein arginine methyltransferase (PRMT) 6 has been linked to the various metabolic processes including hepatic gluconeogenesis, muscle atrophy and lipodystrophy in mouse models. However, the role of PRMT6 in the control of hepatic lipogenesis has not been elucidated to date. MethodsWe assessed the interaction between PRMT6 and LXR alpha by using co-immunoprecipitation assay. The specific arginine residue of LXR alpha that is methylated by PRMT6 was assessed by LC-MS/MS assay and the functional consequences of LXR alpha methylation was explored by mSREBP-1c luciferase assay. The effect of PRMT6 on hepatic lipogenesis was assessed by adenovirus-mediated ectopic expression of PRMT6 or knockdown of PRMT6 via shRNA in hepatocytes. Finally, the role of PRMT6 in hepatic lipid metabolism in vivo was explored by either ectopic expression of LXR alpha mutant that is defective in PRMT6-mediated arginine methylation or knockdown of PRMT6 in liver. ResultsWe found that promoter activity of sterol regulatory element binding protein (SREBP) 1c is robustly activated by PRMT6. Interestingly, we demonstrated that PRMT6 binds to LXR alpha, a transcription factor for SREBP-1c, via its LXXLL motif, leading to the asymmetric dimethylation of an arginine residue and activation of this protein. Indeed, ectopic expression of PRMT6 in hepatocytes led to the enhanced expression of LXR alpha target genes in the lipogenic pathway. Conversely, genetic or pharmacological inhibition of PRMT6 diminished expression of lipogenic genes and the lipid accumulation in primary hepatocytes. Mechanistically, we found that asymmetric dimethylation of LXR alpha led to the dissociation of small heterodimer partner (SHP), a transcriptional co-inhibitor of this factor, resulting in the activation of LXR alpha-mediated transcriptional process. Finally, we showed that disruption of asymmetric dimethylation of LXR alpha in the liver led to the diminished expression of genes in the lipogenesis, resulting in the reduced hepatic lipid accumulation in high fat diet-fed mice in vivo. ConclusionsWe showed that PRMT6 modulates LXR alpha activity by conferring asymmetric dimethylation of arginine 253, thus blocking SHP-mediated inhibition and promoting hepatic lipid accumulation. These results suggest that PRMT6 is critical in the control of lipid homeostasis by regulation of LXR alpha-mediated lipogenesis in the liver.

Exercise, mTOR Activation, and Potential Impacts on the Liver in Rodents.

The literature offers a consensus on the association between exercise training (ET) protocols based on the adequate parameters of intensity and frequency, and several adaptive alterations in the liver. Indeed, regular ET can reverse glucose and lipid metabolism disorders, especially from aerobic modalities, which can decrease intrahepatic fat formation. In terms of molecular mechanisms, the regulation of hepatic fat formation would be directly related to the modulation of the mechanistic target of rapamycin (mTOR), which would be stimulated by insulin signaling and Akt activation, from the following three different primary signaling pathways: (I) growth factor, (II) energy/ATP-sensitive, and (III) amino acid-sensitive signaling pathways, respectively. Hyperactivation of the Akt/mTORC1 pathway induces lipogenesis by regulating the action of sterol regulatory element binding protein-1 (SREBP-1). Exercise training interventions have been associated with multiple metabolic and tissue benefits. However, it is worth highlighting that the mTOR signaling in the liver in response to exercise interventions remains unclear. Hepatic adaptive alterations seem to be most outstanding when sustained by chronic interventions or high-intensity exercise protocols.

Integrated re-analysis of transcriptomic and proteomic datasets reveals potential mechanisms for Zika viral-based oncolytic therapy in neuroblastoma.

Paediatric neuroblastoma and brain tumours account for a third of all childhood cancer-related mortality. High-risk neuroblastoma is highly aggressive and survival is poor despite intensive multi-modal therapies with significant toxicity. Novel therapies are desperately needed. The Zika virus (ZIKV) can access the nervous system and there is growing interest in employing ZIKV as a potential therapy against paediatric nervous system tumours, including neuroblastoma. Here, we perform extensive data mining, integration and re-analysis of ZIKV infection datasets to highlight molecular mechanisms that may govern the oncolytic response in neuroblastoma cells. We collate infection data of multiple neuroblastoma cell lines by different ZIKV strains from a body of published literature to inform the susceptibility of neuroblastoma to the ZIKV oncolytic response. Integrating published transcriptomics, interaction proteomics, dependency factor and compound datasets we propose the involvement of multiple host systems during ZIKV infection. Through data mining of published literature, we observed most paediatric neuroblastoma cell lines to be highly susceptible to ZIKV infection and propose the PRVABC59 ZIKV strain to be the most promising candidate for neuroblastoma oncolytic virotherapy. ZIKV induces TNF signalling, lipid metabolism, the Unfolded Protein Response (UPR), and downregulates cell cycle and DNA replication processes. ZIKV infection is dependent on sterol regulatory element binding protein (SREBP)-regulated lipid metabolism and three protein complexes; V-ATPase, ER Membrane Protein Complex (EMC) and mammalian translocon. We propose ZIKV non-structural protein 4B (NS4B) as a likely mediator of ZIKVs interaction with IRE1-mediated UPR, lipid metabolism and mammalian translocon. Our work provides a significant understanding of ZIKV infection in neuroblastoma cells, which will facilitate the progression of ZIKV-based oncolytic virotherapy through pre-clinical research and clinical trials.

Regulatory Mechanism of Xiaozheng Tongluo Method on Hepatic Lipid Metabolism in ApoE-/- Mice: Insights from the Sterol Regulatory Element-binding Protein-2/3-hydroxy-3-methylglutaryl Coenzyme A Reductase/Low-density Lipoprotein Receptor Signaling Pathway

Abstract Objective: The objective of the study was to explore the regulatory mechanism of the Xiaozheng Tongluo method on lipid metabolism in liver tissue based on the sterol regulatory element-binding protein-2/(SREBP2)/3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR)/low-density lipoprotein receptor (LDLR) signaling pathway. Materials and Methods: C57BL/6 mice were selected as the blank group. The apolipoprotein E-deficient (ApoE-/-) mice were randomly divided into the model group, traditional Chinese medicine (TCM) group, and control group. The general condition of the mice was determined by the mouse’s state and liver weight. Liver hematoxylin and eosin staining and Oil Red O staining were used to observe the pathological changes and lipid droplet deposition of the liver. The protein expression levels of SREBP2, HMGCR, and LDLR were detected by Western blotting and polymerase chain reaction. Results: (1) The rats in the model group were in poor condition, and their liver weight increased significantly. Compared with the model group, the condition of the TCM group and the control group improved to varying degrees, and their liver weight decreased significantly. (2) Compared with the normal group, the hepatocytes in the model group were arranged in a disorderly manner, and the red-stained lipids of stem cells increased significantly. Compared with the model group, the degree of liver lesions in the control group and TCM group was reduced, and the red-stained lipid of hepatocytes was significantly reduced. (3) Compared with the blank group, the expression of SREBP2 and HMGCR protein in the model group increased significantly, and the expression of LDLR protein decreased significantly (P &lt; 0.05). Compared with the model group, the expression of SREBP2 and HMGCR protein in the TCM group decreased significantly, and the expression of LDLR protein increased significantly (P &lt; 0.05). Conclusions: The method detailed in this paper can increase the expression of SREBP2 and HMGCR protein and decrease the expression of LDLR protein, thus regulating liver cholesterol metabolism and delaying the progression of atherosclerosis.

Effects of Saponins on Lipid Metabolism: The Gut-Liver Axis Plays a Key Role.

Unhealthy lifestyles (high-fat diet, smoking, alcohol consumption, too little exercise, etc.) in the current society are prone to cause lipid metabolism disorders affecting the health of the organism and inducing the occurrence of diseases. Saponins, as biologically active substances present in plants, have lipid-lowering, inflammation-reducing, and anti-atherosclerotic effects. Saponins are thought to be involved in the regulation of lipid metabolism in the body; it suppresses the appetite and, thus, reduces energy intake by modulating pro-opiomelanocortin/Cocaine amphetamine regulated transcript (POMC/CART) neurons and neuropeptide Y/agouti-related peptide (NPY/AGRP) neurons in the hypothalamus, the appetite control center. Saponins directly activate the AMP-activated protein kinase (AMPK) signaling pathway and related transcriptional regulators such as peroxisome-proliferator-activated-receptors (PPAR), CCAAT/enhancer-binding proteins (C/EBP), and sterol-regulatory element binding proteins (SREBP) increase fatty acid oxidation and inhibit lipid synthesis. It also modulates gut-liver interactions to improve lipid metabolism by regulating gut microbes and their metabolites and derivatives-short-chain fatty acids (SCFAs), bile acids (BAs), trimethylamine (TMA), lipopolysaccharide (LPS), et al. This paper reviews the positive effects of different saponins on lipid metabolism disorders, suggesting that the gut-liver axis plays a crucial role in improving lipid metabolism processes and may be used as a therapeutic target to provide new strategies for treating lipid metabolism disorders.

Therapeutic Effect of Desmodium caudatum Extracts on Alleviating Diabetic Nephropathy Mice.

Desmodium caudatum extracts (DCE) were investigated for their potential therapeutic effects on diabetic nephropathy (DN). In our study, the high-fat diet (HFD) / streptozotocin (STZ)-induced DN model in C57BL/6 mice was treated with 100mg/kg, 200mg/kg DCE. The results showed that DCE decreased biochemical parameters and proteinuria levels. The kidney sections staining indicated that DCE treatment recovered glomerular atrophy and alleviated lipid droplets in the glomerular. Additionally, DCE inhibited lipid and glycogen accumulation down-regulated the expression of sterol regulatory element-binding protein 1 (SREBP1) and fatty acid synthase (FAS) proteins. DCE also reduced collagenous fibrous tissue and the expression of transforming growth factor-β1 (TGF-β1) and alpha-smooth muscle actin (α-SMA) through Masson's trichrome staining and immunohistochemical analysis. We found that DCE alleviated hydroxyproline content, and epithelial-mesenchymal transition (EMT). Besides, the results shown that DCE enhanced the antioxidant enzymes to mitigate fibrosis by reducing oxidative stress. In conclusion, our study provided evidence of the protective effect of DCE which down-regulated hyperglycemia, hyperlipidemia and inhibition of TGF-β1 and EMT pathway but elevated antioxidant, suggesting its therapeutic implication for DN.

The Hepatoprotective Effect of Trigonelline in Diabetic Rat through Insulin-related IRS1-GLUT2 Pathway: A Biochemical, Molecular, Histopathological, and Immunohistochemical Study

Background Diabetes significantly increases morbidity and mortality rates, causing complications such as cardiovascular disease, kidney failure, and blindness. Purpose The aim of this study was to investigate the hepatoprotective effects of trigonelline (TRIG) in diabetic rats through the antioxidative, anti-inflammatory, and insulin-related IRS1-GLUT2 pathway. Materials and Methods In this experimental investigation, sixty male Wistar rats ( n = 10/group) were randomly divided into six groups: a healthy group (HEL), healthy rats treated with 1500 and 3000 mg/kg of TRIG, a diabetic (D), and diabetic rats treated with 1500 and 3000 mg/kg of TRIG (D+ TRIG). The effects of TRIG on rats with induced diabetes were evaluated by serum biochemical parameters, such as insulin, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), free fatty acids (FFA), nitric oxide, and adiponectin levels. The activities of hepatic carbohydrate metabolic enzymes (hepatic glucokinase, glucose 6-phosphatase, glycogen, and glucose-6-phosphate dehydrogenase) were also measured. Furthermore, the expression levels of genes and proteins associated with carbohydrate/lipid metabolism, including peroxisome proliferator-activated receptor gamma (PPARg), glucose transporter 2 (GLUT2), insulin receptor substrate 1 (IRS1), sterol regulatory element-binding protein 1c (SREBP-1c) were analyzed using real-time PCR and western blotting techniques, respectively. Liver sections were examined using H&amp;E staining and immunohistochemistry targeting the p53 protein. Results The results showed that 3000 mg/kg TRIG was able to suppress TNF-α, IL-6, and FFA by inhibiting inflammatory pathways along with increasing the activity of antioxidant enzymes. TRIG treatment regulated serum levels of insulin, adiponectin, and hepatic carbohydrate metabolic enzymes as well as glycogen content by regulation of the IRS1/ GLUT2- SREBP-1c/ PPARg pathway. Conclusion These results provide evidence that TRIG has the potential to protect liver organs from oxidative damage in diabetic patients.

Puerarin Modulates Hepatic Farnesoid X Receptor and Gut Microbiota in High-Fat Diet-Induced Obese Mice.

Obesity is associated with alterations in lipid metabolism and gut microbiota dysbiosis. This study investigated the effects of puerarin, a bioactive isoflavone, on lipid metabolism disorders and gut microbiota in high-fat diet (HFD)-induced obese mice. Supplementation with puerarin reduced plasma alanine aminotransferase, liver triglyceride, liver free fatty acid (FFA), and improved gut microbiota dysbiosis in obese mice. Puerarin's beneficial metabolic effects were attenuated when farnesoid X receptor (FXR) was antagonized, suggesting FXR-mediated mechanisms. In hepatocytes, puerarin ameliorated high FFA-induced sterol regulatory element-binding protein (SREBP) 1 signaling, inflammation, and mitochondrial dysfunction in an FXR-dependent manner. In obese mice, puerarin reduced liver damage, regulated hepatic lipogenesis, decreased inflammation, improved mitochondrial function, and modulated mitophagy and ubiquitin-proteasome pathways, but was less effective in FXR knockout mice. Puerarin upregulated hepatic expression of FXR, bile salt export pump (BSEP), and downregulated cytochrome P450 7A1 (CYP7A1) and sodium taurocholate transporter (NTCP), indicating modulation of bile acid synthesis and transport. Puerarin also restored gut microbial diversity, the Firmicutes/Bacteroidetes ratio, and the abundance of Clostridium celatum and Akkermansia muciniphila. This study demonstrates that puerarin effectively ameliorates metabolic disturbances and gut microbiota dysbiosis in obese mice, predominantly through FXR-dependent pathways. These findings underscore puerarin's potential as a therapeutic agent for managing obesity and enhancing gut health, highlighting its dual role in improving metabolic functions and modulating microbial communities.

Quercetin ameliorates lipid deposition in primary hepatocytes of the chicken embryo

ABSTRACT 1. The accumulation of excessive fat plays a role in the development of non-alcoholic fatty liver disease (NAFLD) and phytogenic feed additives have the potential to ameliorate this. This study involved the isolation and culture of primary hepatocytes from chicken embryos to establish a model of hepatic steatosis induced by oleic acid/dexamethasone (OA/DEX). Lipid accumulation and cell viability were assessed using Nile Red staining, Oil Red O staining and cell count Kit −8 (CCK8) following treatment with varying concentrations of quercetin (Que). The potential mechanism by which Que exerts its effects was preliminarily investigated. 2. The results indicated that OA effectively treated lipid accumulation in hepatocytes. There was no notable variance in cell proliferation between the normal and OA/DEX groups when subjected to Que treatment at concentrations of 1000 ng/ml and 10 000 ng/ml. Triglycerides and cholesterol (low and high density) decreased with Que treatment, with the most substantial reduction observed at 10 000 ng/ml. 3. Gene expression levels decreased to levels similar to those in the control groups. Western blot data demonstrated that sterol regulatory element-binding protein 1 (SREBP-1) protein expression correlated with its mRNA expression level. Que mitigated lipid accumulation through the alpha serine/threonine protein kinase (AKT) and extracellular signal-regulated kinase (ERK) pathways. Expression levels of lipid-related genes (APOB, PPARα, CYP3A5 and SREBP-1) decreased to levels similar to the control groups. Western blot data demonstrated that the SREBP-1 protein expression correlated with its mRNA expression level. 4. Supplementation with Que ameliorated lipid accumulation through AKT and ERK signalling pathway in OA/DEX-induced high-fat hepatocytes.

Oleanolic acid inhibits cholesterol synthesis by suppressing the expression and enzymatic activity of HMGCR

ABSTRACT This study investigated the impact of Oleanolic Acid (OA) on cholesterol metabolism and. MTT assays demonstrated that OA had no cytotoxic effects on HepG2 cells at concentrations below 20 μM. Subsequent experiments focused on 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR), a key enzyme in cholesterol biosynthesis. OA significantly reduced HMGCR protein expression without affecting other enzymes. Further investigations revealed that OA reduced the protein and mRNA expression of HMGCR and its upstream regulator Sterol regulatory element binding protein-2 (SREBP-2) in HepG2 cells. OA activated Adenosine 5’-monophosphate (AMP)-activated protein kinase (AMPK), enhancing HMGCR phosphorylation and inhibiting its activity. Molecular docking experiments suggested that OA could suppress HMGCR enzymatic activity through hydrophobic interactions, reducing catalytic efficiency. Overall, OA downregulated HMGCR expression and activity, leading to decreased cholesterol synthesis. These findings highlight OA’s regulatory role in cholesterol metabolism and its potential for improving atherosclerosis (AS), supporting its application in functional food development.