Reduced Lipid Synthesis Research Articles

Liver Transcriptome Analysis Reveals the Mechanisms of Metabolic Adaptation of Xizang Sheep to Seasonal Changes.

Background/Objectives: The Xizang sheep is a unique breed of sheep in the highland regions of China that has gradually developed physiological characteristics adapted to the plate environment through long-term natural selection and artificial breeding. However, little is known about the molecular basis of metabolic adaptation to seasons in Xizang sheep. Methods: In this study, liver tissues from Xizang sheep in summer (SL) and autumn (AL) were selected for transcriptome sequencing to explore the metabolic adaptability of Xizang sheep to seasons. Results: The results showed that a total of 12,046 differentially expressed genes (DEGs) were identified, with 1123 genes significantly upregulated and 951 genes significantly downregulated in autumn. The top five pathways enriched for DEGs were Metabolic pathways, Phagosome, Valine, leucine and isoleucine degradation, Propanoate metabolism, and Fatty acid metabolism, which are involved in immune regulation, fat oxidation, and synthesis. The reduction in lipid synthesis, fatty acid oxidation, and fat breakdown metabolism promotes gluconeogenesis by inhibiting the Peroxisome proliferator-activated receptors (PPAR) and Phosphoinositide 3-kinase- Protein kinase B (PI3K-Akt) signaling pathways. Conclusions: This process helps to maintain the whole-body energy homeostasis of Xizang sheep, facilitating their adaptation to the seasonal changes in the extreme high-altitude environment. These findings provide foundational data for studying the molecular mechanisms of metabolic adaptation to seasons in ruminants.

Activation of the mTOR pathway enhances PPARγ/SREBP-mediated lipid synthesis in human meibomian gland epithelial cells

The involvement of the mechanistic targets of rapamycin (mTOR) pathway in lipid metabolism has been recently elucidated. However, its specific role in the Meibomian gland, where lipid metabolism is significant, remains not fully understood. We investigated the role of mTOR signaling system in the lipogenesis and differentiation of human meibomian gland epithelial cells (HMGECs). Treatment of HMGECs with rapamycin resulted in a reduction in lipid synthesis and the expression of PPARγ and SREBP-1, the major regulators of lipid synthesis. The phosphorylation of p70S6kinase and AKT, which are downstream signals of mTOR complexes 1 and 2, respectively, decreased following rapamycin treatment. In addition, when both mTOR complex 1 and 2 were suppressed using siRNA, there was a significant reduction in the expression of PPARγ and SREBP-1, along with a decrease in lipid synthesis in HMGECs. Our findings suggest that inhibiting the mTOR pathway diminishes the differentiation and adipogenesis of meibomian gland epithelial cells, and both mTOR complexes 1 and 2 appear to play a role in this activity.

Bushen Huoxue formula attenuates lipid accumulation evoking excessive autophagy in premature ovarian insufficiency rats and palmitic acid-challenged KGN cells by modulating lipid metabolism.

Premature ovarian insufficiency (POI) has affected about 3.7% of women of reproductive age and is a major factor contributing to infertility. Bushen Huoxue formula (BHF), a traditional Chinese medicine prescription, is clinically used to treat POI in China. This study aims to investigate the potential mechanisms of BHF in combating POI using corticosterone-induced rats and palmitic acid (PA)-challenged human ovarian granulosa cells (GCs). Initially, ultra performance liquid chromatography tandem mass spectrometry was employed to analyze the components of BHF. The pharmacodynamic parameters evaluated included body weight, ovaries index, and serum hormone in rats. Follicle numbers were observed using H&E staining. Additionally, PCNA and TUNEL staining were used to assess GCs proliferation and apoptosis, respectively. Lipid accumulation and ROS levels were examined using Oil Red O and ROS staining. Protein expressions were determined by western blot. To probe mechanisms, cell viability and E2 levels in BHF-treated, PA-stimulated GCs were determined using MTT and ELISA, respectively. Cell apoptosis and ROS levels were assessed using TUNEL and ROS staining. Proteins related to lipid metabolism and autophagy in PA-stimulated GCs were studied using agonists. Our results shown that BHF effectively normalized serum hormone levels, including follicle-stimulating hormone (FSH), anti-Müllerian hormone (AMH), estradiol (E2), and luteinizing hormone (LH). Concurrently, BHF also significantly reduced follicular atresia and promoted cell proliferation while inhibiting apoptosis in POI rats. Furthermore, BHF mitigated ovarian lipid accumulation by modulating lipid metabolism, which included reducing lipid synthesis (expression of peroxisome proliferator-activated receptor γ and CCAAT/enhancer binding protein α), increasing lipid catabolism (expression of adipose triglyceride lipase), and enhancing lipid oxidation (expression of carnitine palmitoyl transferase 1A). Mechanistically, the therapeutic effects of BHF on POI were linked with alleviation of lipid deposition-induced reactive oxygen species (ROS) accumulation and excessive autophagy, corroborating the results in PA-challenged GCs. After treatment with elesclomol (a ROS inducer) and rapamycin (an autophagy inducer) in GCs, the effects of BHF were almost counteracted under model conditions. These findings suggest that BHF alleviates the symptoms of POI by altering lipid metabolism and reducing lipid accumulation-induced ROS and autophagy, offering evidence for BHF's efficacy in treating POI clinically.

Fat body lipogenic capacity in honey bee workers is affected by age, social role and dietary protein.

All organisms need to balance processes that consume energy against those that produce energy. With an increase in biological complexity over evolutionary time, regulation of this balance has become much more complex, resulting in specialization of metabolic tasks between organelles, cells, organs and, in the case of eusocial organisms, between the individuals that comprise the 'superorganism'. Exemplifying this, nurse honey bees maintain high abdominal lipids, while foragers have very low lipid stores, likely contributing to efficient performance of their social role, and thus to colony fitness. The proximate mechanisms responsible for these metabolic differences remain poorly understood. Here, we investigated the effects of age, worker class and dietary macronutrients on the abdominal activity of fatty acid synthase (FAS), the enzyme responsible for de novo synthesis of fatty acids, as well as the effects of age on lipase activity, enzymes responsible for the breakdown of stored lipids. We found that FAS but not lipase activity declines as bees age past peak nursing age. Feeding both nurses and foragers carbohydrates increased FAS activity compared with starved bees, but, whether fed or starved, nurses had much higher FAS activity than similarly treated foragers, implicating reduced lipid synthesis as one component of foragers' low lipid stores. Finally, we used artificial diets with different amounts of protein and fat to precociously induce low, forager-like FAS activity levels in nurse-age bees deprived of protein. We speculate that reduced protein appetite and consumption during the nurse-forager transition is responsible for suppressed lipid synthesis in foragers.

Zhimu-Huangbai herb-pair ameliorates hepatic steatosis in mice by regulating IRE1α/XBP1s pathway to inhibit SREBP-1c

BackgroundCurrently, there is a lack of validated pharmacological interventions for non-alcoholic fatty liver disease (NAFLD), which is characterized by the accumulation of hepatic triglyceride. Zhimu-Huangbai (ZH) herb-pair is a traditional Chinese medicine that regulates glucose and lipid metabolism disorders. However, the precise mechanisms underlying the preventive effects of hepatic triglyceride induced by high-fat diet (HFD) remain elusive. PurposeThe study aimed to examine the impact of ZH herb-pair on NAFLD in mice and explore the underlying mechanisms, particularly its effects on endoplasmic reticulum (ER) stress and lipid metabolism. MethodsNAFLD was induced in mice using HFD, and the treated mice were orally administered ZH, metformin (Glucophage) or lovastatin. The lipid metabolism factors, ER stress markers, and the unfolded protein response (UPR) branch factors were measured using immunohistochemistry, western blotting or qRT-PCR. Co-Immunoprecipitation (CoIP) was performed to reveal the connection between SCAP and SREBP-1c. Tunicamycin (TM) and plasmid delivery were used to induce acute ER stress or crease XBP1 gain function models. The main compounds in ZH binding to IRE1α protein were studied by molecular docking and cellular thermal shift assay (CETSA). ResultsTreatment with ZH significantly ameliorated hepatic steatosis and reduced lipid synthesis process mainly inhibiting the expression of mature active form of SREBP-1c through relieving ER stress. The expression of IRE1α and XBP1s was inhibited after treatment with ZH. In addition, ZH improved the fatty liver phenotype caused by XBP1 overexpression via decreasing srebp1c transcription. In vitro experimental results suggested that the main compounds in ZH decreased cellular TG contents. Mechanistically, ZH targeted IRE1α and inhibited XBP1s mRNA expression to relieve ER stress and inhibit SREBP-1c production. ConclusionsZH herb-pair can protect against NAFLD by reducing the expression of SREBP-1c, in part, via regulating IRE1α/XBP1s pathway.

MiR-33 deletion in hepatocytes attenuates MASLD-MASH-HCC progression.

The complexity of the mechanisms underlying metabolic dysfunction-associated steatotic liver disease (MASLD) progression remains a significant challenge for the development of effective therapeutics. miRNAs have shown great promise as regulators of biological processes and as therapeutic targets for complex diseases. Here, we study the role of hepatic miR-33, an important regulator of lipid metabolism, during the progression of MASLD and the development of hepatocellular carcinoma (HCC). We report that miR-33 was elevated in the livers of humans and mice with MASLD and that its deletion in hepatocytes (miR-33 HKO) improved multiple aspects of the disease, including steatosis and inflammation, limiting the progression to metabolic dysfunction-associated steatotic hepatitis (MASH), fibrosis, and HCC. Mechanistically, hepatic miR-33 deletion reduced lipid synthesis and promoted mitochondrial fatty acid oxidation, reducing lipid burden. Additionally, absence of miR-33 altered the expression of several known miR-33 target genes involved in metabolism and resulted in improved mitochondrial function and reduced oxidative stress. The reduction in lipid accumulation and liver injury resulted in decreased YAP/TAZ pathway activation, which may be involved in the reduced HCC progression in HKO livers. Together, these results suggest suppressing hepatic miR-33 may be an effective therapeutic approach to temper the development of MASLD, MASH, and HCC in obesity.

Pioglitazone alleviates lacrimal gland impairments induced by high-fat diet by suppressing M1 polarization

A high-fat diet (HFD) contributes to the pathogenesis of various inflammatory and metabolic diseases. Previous research confirms that under HFD conditions, the extraorbital lacrimal glands (ELGs) can be impaired, with significant infiltration of pro-inflammatory macrophages (Mps). However, the relationship between HFD and Mps polarization in the ELGs remains unexplored. We first identified and validated the differential expression of PPAR-γ in murine ELGs fed ND and HFD through RNA sequencing. Tear secretion was measured using the Schirmer test. Lipid droplet deposition within the ELGs was observed through Oil Red O staining and transmission electron microscopy. Mps phenotypes were determined through quantitative RT-PCR, immunofluorescence, and flow cytometric analysis. An in vitro high-fat culture system for Mps was established using palmitic acid (PA), with supernatants collected for co-culture with lacrimal gland acinar cells. Gene expression was determined through ELISA, immunofluorescence, immunohistochemistry, quantitative RT-PCR, and Western blot analysis. Pioglitazone reduced M1-predominant infiltration induced by HFD by increasing PPAR-γ levels in ELGs, thereby alleviating lipid deposition and enhancing tear secretion. In vitro tests indicated that PPAR-γ agonist shifted Mps from M1-predominant to M2-predominant phenotype in PA-induced Mps, reducing lipid synthesis in LGACs and promoting lipid catabolism, thus alleviating lipid metabolic disorders within ELGs. Conversely, the PPAR-γ antagonist induced opposite effects. In summary, the lacrimal gland is highly sensitive to high-fat and lipid metabolic disorders. Downregulation of PPAR-γ expression in ELGs induces Mps polarization toward predominantly M1 phenotype, leading to lipid metabolic disorder and inflammatory responses via the NF-κb/ERK/JNK/P38 pathway.

Role of gut-liver axis and glucagon-like peptide-1 receptor agonists in the treatment of metabolic dysfunction-associated fatty liver disease.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a hepatic manifestation of the metabolic syndrome. It is one of the most common liver diseases worldwide and shows increasing prevalence rates in most countries. MAFLD is a progressive disease with the most severe cases presenting as advanced fibrosis or cirrhosis with an increased risk of hepatocellular carcinoma. Gut microbiota play a significant role in the pathogenesis and progression of MAFLD by disrupting the gut-liver axis. The mechanisms involved in maintaining gut-liver axis homeostasis are complex. One critical aspect involves preserving an appropriate intestinal barrier permeability and levels of intestinal lumen metabolites to ensure gut-liver axis functionality. An increase in intestinal barrier permeability induces metabolic endotoxemia that leads to steatohepatitis. Moreover, alterations in the absorption of various metabolites can affect liver metabolism and induce liver steatosis and fibrosis. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a class of drugs developed for the treatment of type 2 diabetes mellitus. They are also commonly used to combat obesity and have been proven to be effective in reversing hepatic steatosis. The mechanisms reported to be involved in this effect include an improved regulation of glycemia, reduced lipid synthesis, β-oxidation of free fatty acids, and induction of autophagy in hepatic cells. Recently, multiple peptide receptor agonists have been introduced and are expected to increase the effectiveness of the treatment. A modulation of gut microbiota has also been observed with the use of these drugs that may contribute to the amelioration of MAFLD. This review presents the current understanding of the role of the gut-liver axis in the development of MAFLD and use of members of the GLP-1 RA family as pleiotropic agents in the treatment of MAFLD.

Single cell transcriptome profiling of infrapatellar fat pad highlights the role of interstitial inflammatory fibroblasts in osteoarthritis

ObjectivesOsteoarthritis (OA) is a whole-joint disease in which the role of the infrapatellar fat pad (IFP) in its pathogenesis is unclear. Our study explored the cellular heterogeneity of IFP to understand OA and identify therapeutic targets. MethodsSingle-cell and single-nuclei RNA sequencing were used to analyze 10 IFP samples, comprising 5 from OA patients and 5 from healthy controls. Analyses included differential gene expression, enrichment, pseudotime trajectory, and cellular communication, along with comparative studies with visceral and subcutaneous fats. Key subcluster and pathways were validated using multiplex immunohistochemistry. ResultsThe scRNA-seq performed on the IFPs of the OA and control group profiled the gene expressions of over 49,674 cells belonging to 11 major cell types. We discovered that adipose stem and progenitor cells (ASPCs), contributing to the formation of both adipocytes and synovial-lining fibroblasts (SLF). Interstitial inflammatory fibroblasts (iiFBs) were a subcluster of ASPCs that exhibit notable pro-inflammatory and proliferative characteristics. We identified four adipocyte subtypes, with one subtype showing a reduced lipid synthesis ability. Furthermore, iiFBs modulated the activities of macrophages and T cells in the IFP. Compared to subcutaneous and visceral adipose tissues, iiFBs represented a distinctive subpopulation of ASPCs in IFP that regulated cartilage proliferation through the MK pathway. ConclusionThis study presents a comprehensive single-cell transcriptomic atlas of IFP, uncovering its complex cellular landscape and potential impact on OA progression. Our findings highlight the role of iiFBs in OA, especially through MK pathway, opening new avenues for understanding OA pathogenesis and developing novel targeted therapies.

Sodium butyrate alleviates free fatty acid-induced steatosis in primary chicken hepatocytes via the AMPK/PPARα pathway

Fatty liver hemorrhagic syndrome (FLHS) is a prevalent metabolic disorder observed in egg-laying hens, characterized by fatty deposits and cellular steatosis in the liver. Our preliminary investigations have revealed a marked decrease in the concentration of butyric acid in the FLHS strain of laying hens. It has been established that sodium butyrate (NaB) protects against metabolic disorders. However, the underlying mechanism by which butyrate modulates hepato-lipid metabolism to a great extent remains unexplored. In this study, we constructed an isolated in vitro model of chicken primary hepatocytes to induce hepatic steatosis by free fatty acids (FFA). Our results demonstrate that treatment with NaB effectively mitigated FFA-induced hepatic steatosis in chicken hepatocytes by inhibiting lipid accumulation, downregulating the mRNA expression of lipo-synthesis-related genes (sterol regulatory element binding transcription factor 1 (SREBF1), acetyl-CoA carboxylase 1(ACC1), fatty acid synthase (FASN), stearoyl-CoA desaturase 1 (SCD1), liver X receptor α (LXRα), 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR)) (P < 0.05), and upregulating the mRNA and protein expression of AMP-activated protein kinase α1 (AMPKα1), peroxisome proliferator-activated receptor α (PPARα), and carnitine palmitoyl-transferase 1A (CPT1A) (P < 0.05). Moreover, AMPK and PPARα inhibitors (Compound C (Comp C) and GW6471, respectively) reversed the protective effects of NaB against FFA-induced hepatic steatosis by blocking the AMPK/PPARα pathway, leading to lipid droplet accumulation and triglyceride (TG) contents in chicken primary hepatocytes. With these findings, NaB can alleviate hepatocyte lipoatrophy injury by activating the AMPK/PPARα pathway, promoting fatty acid oxidation, and reducing lipid synthesis in chicken hepatocytes, potentially being able to provide new ideas for the treatment of FLHS.

Alisol B regulates AMPK/mTOR/SREBPs via directly targeting VDAC1 to alleviate hyperlipidemia

BackgroundThe occurrence of hyperlipidemia is significantly influenced by lipid synthesis, which is regulated by sterol regulatory element binding proteins (SREBPs), thus the development of drugs that inhibit lipid synthesis has become a popular treatment strategy for hyperlipidemia. Alisol B (ALB), a triterpenoid compound extracted from Alisma, has been reported to ameliorate no-nalcoholic steatohepatitis (NASH) and slow obesity. However, the effect of ALB on hyperlipidemia and mechanism are unclear. PurposeTo examine the therapeutic impact of ALB on hyperlipidemia whether it inhibits SREBPs to reduce lipid synthesis. Study DesignHepG2, HL7702 cells, and C57BL/6J mice were used to explore the effect of ALB on hyperlipidemia and the molecular mechanism in vivo and in vitro. MethodsHyperlipidemia models were established using western diet (WD)-fed mice in vivo and oleic acid (OA)-induced hepatocytes in vitro. Western blot, real-time PCR and other biological methods verified that ALB regulated AMPK/mTOR/SREBPs to inhibit lipid synthesis. Cellular thermal shift assay (CETSA), molecular dynamics (MD), and ultrafiltration-LC/MS analysis were used to evaluate the binding of ALB to voltage-dependent anion channel protein-1 (VDAC1). ResultsALB decreased TC, TG, LDL-c, and increased HDL-c in blood, thereby ameliorating liver damage. Gene set enrichment analysis (GSEA) indicated that ALB inhibited the biosynthesis of cholesterol and fatty acids. Consistently, ALB inhibited the protein expression of n-SREBPs and downstream genes. Mechanistically, the impact of ALB on SREBPs was dependent on the regulation of AMPK/mTOR, thereby impeding the transportation of SREBPs from endoplasmic reticulum (ER) to golgi apparatus (GA). Further investigations indicated that the activation of AMPK by ALB was independent on classical upstream CAMKK2 and LKB1. Instead, ALB resulted in a decrease in ATP levels and an increase in the ratios of ADP/ATP and AMP/ATP. CETSA, MD, and ultrafiltration-LC/MS analysis indicated that ALB interacted with VDAC1. Molecular docking revealed that ALB directly bound to VDAC1 by forming hydrogen bonds at the amino acid sites S196 and H184 in the ATP-binding region. Importantly, the thermal stabilization of ALB on VDAC1 was compromised when VDAC1 was mutated at S196 and H184, suggesting that these amino acids played a crucial role in the interaction. ConclusionOur findings reveal that VDAC1 serves as the target of ALB, leading to the inhibition of lipid synthesis, presents potential target and candidate drugs for hyperlipidemia.

Long-term drinking of green tea combined with exercise improves hepatic steatosis and obesity in male mice induced by high-fat diet.

Dietary habits and exercise play an important role in the well-being of human health. Currently, how long of drinking tea combined with exercise could efficiently ameliorate hepatic steatosis and obesity still needs to be investigated. Here, short-term and long-term green tea drinking combined with exercise were studied to improve hepatic steatosis and obesity in high-fat diet-induced (HF) mice. Our results showed that Yunkang 10 green tea (GT) combined with exercise (Ex) exhibited synergistic prevention effects on ameliorating hepatic steatosis and obesity. Especially, 22-week intervention with GT or Ex improved all symptoms of obesity, which indicated that long-term intervention exhibited profound preventive effects than the short term. Moreover, the combined intervention of 22 weeks inhibited the activation of NF-κB pathway and the expression of proinflammatory cytokines, which suggests that tea combined exercise may improve liver steatosis mainly by inhibiting inflammation. The key molecules for regulating lipid and glucose metabolism SCD1 were obviously downregulated, and GLU2 and PPARγ were significantly upregulated by GT and exercise in the liver of high-fat diet-induced mice. This study demonstrated that long-term intervention with GT and exercise effectively relieved hepatic steatosis and obesity complications by ameliorating hepatic inflammation, reducing lipid synthesis, and accelerating glucose transport.

Virgin Camellia Seed Oil Improves Glycolipid Metabolism in the Kidney of High Fat-Fed Rats through AMPK-SREBP Pathway

Camellia seed oil (CO) is used as edible oil in southern China because of its excellent fatty acid composition and abundant bioactive compounds. Chronic kidney disease (CKD) is one of the most common chronic degenerative diseases in China, and active compounds in vegetable oil, like virgin olive oil, have been demonstrated to be efficacious in the management of CKD. In this study, virgin CO was refined using a standard process. The refining had minimal impact on the fatty acid composition, but significantly reduced the presence of bioactive compounds like polyphenols in CO. Sprague-Dawley (SD) rats fed with high fat diet (Group G) were treated with either virgin (Group Z) or refined CO (Group R). The oral administration of CO alleviated lipid accumulation and decreased body and kidney weight gain. Furthermore, treatment with virgin CO increased the renal ATP content. The renal expression levels of AMPK and key enzymes involved in fatty acid oxidation (CPT-1 and ACOX1) and glycolysis (HK, PFK, PK and GAPDH) were up-regulated in Group Z, thereby enhancing the ATP production. Virgin CO treatment downregulated the expression level of SREBP2 and its downstream target genes, such as ACC, FAS, and HMGCR, which reduced lipid synthesis. These findings indicate that virgin CO improves glycolipid metabolism and restores energy homeostasis in the kidneys of rats fed with a high-fat diet by modulating the AMPK–SREBP-signaling pathway, suggesting the potential of active compounds in virgin CO for managing the renal failure associated with glycolipid dysmetabolism.

Radix Saposhnikoviae enhancing Huangqi Chifeng Decoction improves lipid metabolism in AS mice

Ethnopharmacological relevanceHuangqi Chifeng decoction (HQCF) combined with parsnips is a classic Chinese traditional medicine formula that has certain advantages in the clinical treatment of cardiovascular and cerebrovascular diseases. At present, there is an absence of research on the regulatory effect and mechanism of this formula on atherosclerosis (AS). The synergistic effect of Radix Saposhnikoviae (RS) in HQCF is also unclear. Aim of the studyThis study was designed to investigate the role of RS, which is designed as a guide drug for HQCF, in improving the lipid metabolism of AS. Materials and methodsIn this study, we studied the effect of HQCF on ApoE−/− mice before and after RS compatibility. Hematoxylin and eosin (HE) staining and oil red staining were used to evaluate atherosclerotic lesions and lipid accumulation in the aorta and liver, respectively. The expression of adenosine monophosphate-activated protein kinase (AMPK) and pAMPK in the aorta was measured by immunofluorescence, and AMPK and sterol regulatory element binding protein-1 (SREBP-1),fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC) in liver tissue were measured by Western blot analysis. Metabolomics was used to compare the changes in serum and liver metabolites of ApoE−/− mice before and after RS combination. ResultsCompared with the control group, the serum lipid levels of ApoE−/− mice increased, the aortic intima thickened with plaque formation, and liver tissue pathological changes and lipid deposition occurred. Both (HQCFT without RS)HQCS and HQCF can improve the pathological condition of tissue and regulate the blood lipid level. It was noted that HQCF could promote the phosphorylation of AMPK to activate it, inhibit the expression of SREBP-1c and FAS, reduce lipid synthesis, and inhibit ACC to promote the oxidative decomposition of fatty acids. Serum and liver metabolome results showed that HQCS and HQCF treated AS mainly by regulating glycerophospholipid metabolism, sphingolipid metabolism and the arachidonic acid metabolism pathway. Importantly, HQCF showed better efficacy in regulating lipid metabolism than the HQCS group. ConclusionHQCF decoction reduces atherosclerotic lesions in the aorta and lipid accumulation in the liver, which may regulate lipid transport and metabolic function by activating the AMPK pathway. These effects can be attributed to the guidance and synergism of RS.

Auraptene Enhances AMP-Activated Protein Kinase Phosphorylation and Thereby Inhibits the Proliferation, Migration and Expression of Androgen Receptors and Prostate-Specific Antigens in Prostate Cancer Cells.

Citrus hassaku extract reportedly activates AMPK. Because this extract contains an abundance of auraptene, we investigated whether pure auraptene activates AMPK and inhibits proliferation using prostate cancer cell lines. Indeed, auraptene inhibited the proliferation and migration of LNCaP cells and induced phosphorylation of AMPK or its downstream ACC in LNCaP, PC3, and HEK-293 cells, but not in DU145 cells not expressing LKB1. In addition, the mTOR-S6K pathway, located downstream from activated AMPK, was also markedly suppressed by auraptene treatment. Importantly, it was shown that auraptene reduced androgen receptor (AR) and prostate-specific antigen (PSA) expressions at both the protein and the mRNA level. This auraptene-induced downregulation of PSA was partially but significantly reversed by treatment with AMPK siRNA or the AMPK inhibitor compound C, suggesting AMPK activation to, at least partially, be causative. Finally, in DU145 cells lacking the LKB1 gene, exogenously induced LKB1 expression restored AMPK phosphorylation by auraptene, indicating the essential role of LKB1. In summary, auraptene is a potent AMPK activator that acts by elevating the AMP/ATP ratio, thereby potentially suppressing prostate cancer progression, via at least three molecular mechanisms, including suppression of the mTOR-S6K pathway, reduced lipid synthesis, and AR downregulation caused by AMPK activation.

Diosgenin alleviates NAFLD induced by a high-fat diet in rats via mTOR/SREBP-1c/HSP60/MCAD/SCAD signaling pathway

This study aims to observe the effects of diosgenin on the expression of mammalian target of rapamycin(mTOR), sterol regulatory element-binding protein-1c(SREBP-1c), heat shock protein 60(HSP60), medium-chain acyl-CoA dehydrogenase(MCAD), and short-chain acyl-CoA dehydrogenase(SCAD) in the liver tissue of the rat model of non-alcoholic fatty liver disease(NAFLD) and explore the mechanism of diosgenin in alleviating NAFLD. Forty male SD rats were randomized into five groups: a control group, a model group, low-(150 mg·kg~(-1)·d~(-1)) and high-dose(300 mg·kg~(-1)·d~(-1)) diosgenin groups, and a simvastatin(4 mg·kg~(-1)·d~(-1)) group. The rats in the control group were fed with a normal diet, while those in the other four groups were fed with a high-fat diet. After feeding for 8 weeks, the body weight of rats in the high-fat diet groups increased significantly. After that, the rats were administrated with the corresponding dose of diosgenin or simvastatin by gavage every day for 8 weeks. The levels of triglyceride(TG), total cholesterol(TC), alanine transaminase(ALT), and aspartate transaminase(AST) in the serum were determined by the biochemical method. The levels of TG and TC in the liver were measured by the enzyme method. Oil-red O staining was employed to detect the lipid accumulation, and hematoxylin-eosin(HE) staining to detect the pathological changes in the liver tissue. The mRNA and protein levels of mTOR, SREBP-1c, HSP60, MCAD, and SCAD in the liver tissue of rats were determined by real-time fluorescence quantitative polymerase chain reaction(RT-qPCR) and Western blot, respectively. Compared with the control group, the model group showed increased body weight, food uptake, liver index, TG, TC, ALT, and AST levels in the serum, TG and TC levels in the liver, lipid deposition in the liver, obvious hepatic steatosis, up-regulated mRNA and protein expression levels of mTOR and SREBP-1c, and down-regulated mRNA and protein expression levels of HSP60, MCAD, and SCAD. Compared with the model group, the rats in each treatment group showed obviously decreased body weight, food uptake, liver index, TG, TC, ALT, and AST levels in the serum, TG and TC levels in the liver, lessened lipid deposition in the liver, ameliorated hepatic steatosis, down-regulated mRNA and protein le-vels of mTOR and SREBP-1c, and up-regulated mRNA and protein levels of HSP60, MCAD, and SCAD. The high-dose diosgenin outperformed the low-dose diosgenin and simvastatin. Diosgenin may prevent and treat NAFLD by inhibiting the expression of mTOR and SREBP-1c and promoting the expression of HSP60, MCAD, and SCAD to reduce lipid synthesis, improving mitochondrial function, and promoting fatty acid β oxidation in the liver.

Chlorogenic acid enhances PPARγ-mediated lipogenesis through preventing Lipin 1 nuclear translocation in Staphylococcus aureus-exposed bovine mammary epithelial cells

Chlorogenic acid (CGA) as one of the most ubiquitously dietary polyphenolic compounds, has been reported to have various antimicrobial effects and exhibit strong anti-inflammatory ability. Staphylococcus aureus is a gram-positive bacterium that can induce mastitis. However, the mechanism through which S. aureus infection affects lipid synthesis and whether CGA have protective effect on S. aureus reduced lipid synthesis is not fully understood. In this study, the internalization of S. aureus reduced intracellular lipid droplet formation, decreased the levels of intracellular triacylglycerol, total cholesterol and 7 types of fatty acid and downregulated the expression of lipogenic genes FAS, ACC, and DGAT1 in bovine mammary epithelial cells (BMECs). In addition, we found that S. aureus intracellular infection attenuated mTORC1 activation resulting in Lipin 1 nuclear localization. Remarkablely, S. aureus infection-mediated repression of lipid synthesis related to the mTORC1 signaling and Lipin 1 nuclear localization can be alleviated by CGA. Thus, our findings provide a novel mechanism by which lipid synthesis is regulated under S. aureus infection and the protective effects of CGA on lipid synthesis in BMECs.

Puerarin Prevents Bisphenol S Induced Lipid Accumulation by Reducing Liver Lipid Synthesis and Promoting Lipid Metabolism in C57BL/6J Mice.

Bisphenol S (BPS) is an environmental pollutant that can accumulate in the human body and cause harm. Puerarin (PUE) is a flavonoid with anti-inflammatory and antioxidant effects. In this study, we used 50 mg/kg/d BPS as a poison and PUE as an intervention for model mice for 42 d. BPS exposure significantly increased the levels of the impairment of the mice's liver function, T-CHO, TG, LDL-C, ALT, and AST in the BPS group were significantly increased (p < 0.05). Additionally, BPS exposure caused inflammatory cell infiltration in the mice liver tissue and enhanced oxidative stress response, the level of MDA was significantly increased (p < 0.05). The expression of CD36 and pparγ was stimulated after BPS exposure. Moreover, the expression of cpt1a and cpt1b, which promote fatty acid oxidation, was downregulated. After PUE intervention, the levels of genes and proteins involved in lipid synthesis (PPARγ, SREBP1C, and FASN) and metabolism (Cpt1a, Cpt1b, and PPARα) in mice returned to those of the control group, or much higher than those in the BPS group. Therefore, we hypothesized that BPS causes lipid accumulation in the liver by promoting lipid synthesis and reducing lipid metabolism, whereas PUE reduces lipid synthesis and promotes lipid metabolism. Conclusively, our results imply that long-term exposure to BPS in mice affects liver lipid metabolism and that PUE intervention could maintain the liver function of mice at normal metabolic levels.

Melanoma cells induce dedifferentiation and metabolic changes in adipocytes present in the tumor niche

BackgroundOne of the factors that affect the progression of melanoma is the tumor microenvironment, which consists of cellular elements, extracellular matrix, acidification, and a hypoxic state. Adipocytes are one of the types of cell present in the niche and are localized in the deepest layer of the skin. However, the relationship between fat cells and melanoma remains unclear.MethodsWe assessed the influence of melanoma cells on adipocytes using an indirect coculture system. We estimated the level of cancer-associated adipocyte (CAA) markers through quantitative PCR analysis. The fibroblastic phenotype of CAAs was confirmed by cell staining and western blotting analysis. The lipid content was estimated by lipid detection in CAAs using LipidSpot and by quantitative analysis using Oil Red O. The expression of proteins involved in lipid synthesis, delipidation, and metabolic processes were assessed through quantitative PCR or western blotting analysis. Lactate secretion was established using a Lactate-Glo™ assay. Proteins secreted by CAAs were identified in cytokine and angiogenesis arrays. The proliferation of melanoma cells cocultured with CAAs was assessed using an XTT proliferation assay. Statistical analysis was performed using a one-way ANOVA followed by Tukey’s test in GraphPad Prism 7 software.ResultsObtained CAAs were identified by decreased levels of leptin, adiponectin, resistin, and FABP4. Adipocytes cocultured with melanoma presented fibroblastic features, such as a similar proteolytic pattern to that of 3T3L1 fibroblasts and increased levels of vimentin and TGFβRIII. Melanoma cells led to a reduction of lipid content in CAAs, possibly by downregulation of lipid synthesis pathways (lower FADS, SC4MOL, FASN) or enhancement of lipolysis (higher level of phosphorylation of ERK and STAT3). Adipocytes cocultured with melanoma cells secreted higher IL6 and SerpinE1 levels and produced less CCL2, CXCL1, and angiogenic molecules. CAAs also showed metabolic changes comprising the increased secretion of lactate and enhanced production of glucose, lactate, and ion transporters. In addition, changes in adipocytes observed following melanoma coculture resulted in a higher proliferation rate of cancer cells.ConclusionsMelanoma cells led to decreased lipid content in adipocytes, which might be related to enhanced delipidation or reduction of lipid synthesis. Fibroblast-like CAAs showed metabolic changes that may be the reason for accelerated proliferation of melanoma cells.

Modulation of the Microbiome-Fat-Liver Axis by Lactic Acid Bacteria: A Potential Alleviated Role in High-Fat-Diet-Induced Obese Mice.

The major characteristics of obesity are abnormal lipid metabolism, chronic inflammation, and imbalanced gut microbiota. It has been reported that lactic acid bacteria (LAB) possess potential for alleviating obesity, considering which the strain-specific functions and diverse mechanisms and the roles and mechanisms of various LAB are worthy of investigation. This study aimed to validate and investigate the alleviating effects and underlying mechanisms of three LAB strains, Lactiplantibacillus plantarum NCUH001046 (LP), Limosilactobacillus reuteri NCUH064003, and Limosilactobacillus fermentum NCUH003068 (LF), in high-fat-diet-induced obese mice. The findings demonstrated that the three strains, particularly LP, suppressed body weight gain and fat deposition; ameliorated lipid disorders, liver and adipocyte morphology, and chronic low-grade inflammation; and reduced lipid synthesis via activating the adenosine 5'-monophosphate-activated protein kinase (AMPK) signaling pathway. In addition, LP and LF decreased the enrichment of bacteria positively correlated with obesity, like Mucispirillum, Olsenella, and Streptococcus, but facilitated the growth of beneficial bacteria negatively correlated with obesity, like Roseburia, Coprococcus, and Bacteroides, along with increasing the short-chain fatty acid levels. It is deduced that the underlying alleviating mechanism of LP was to modulate the hepatic AMPK signaling pathway and gut microbiota by the microbiome-fat-liver axis to alleviate obesity development. In conclusion, as a diet supplement, LP has promising potential in obesity prevention and treatment.