Expression Of SREBF1 Research Articles

NAT10 promotes liver lipogenesis in mouse through N4-acetylcytidine modification of Srebf1 and Scap mRNA.

Metabolic dysfunction associated steatotic liver disease (MASLD), closely linked to excessive lipogenesis, induces chronic liver disease. MASLD often cause other metabolic diseases, such as cardiovascular disease, diabetes and obesity. However, the mechanism of N-acetyltransferase 10 (NAT10)-mediated N4-acetylcytidine (ac4C) mRNA modification in lipogenesis of MASLD has not been fully elucidated. This study investigated the role of NAT10 in lipogenesis targeting mRNA ac4C modification. The expression of NAT10 in mouse liver was assessed after a 12-week high-fat diet. In addition, the expression of NAT10 also was detected after AML12 hepatocytes cells were treated with 150 µmol/L palmitic acid (PA). The ac4C mRNA modification was performed by dot blotting. Oil red O staining and the mRNA expression of Srebf1, Acaca and Fasn were used to assess lipogenesis in AML12 cells with NAT10 overexpression or knockdown. acRIP-PCR and NAT10 RIP-PCR were used to verify the Srebf1 and Scap mRNA ac4C modification by NAT10. Furthermore, the liver lipogenesis was evaluated by AAV-mediated target knockdown of NAT10 in mouse liver and treating a specific inhibitor, Remodelin. This study revealed that NAT10 is significantly upregulated in liver lipogenesis after a 12-week high-fat diet. NAT10 and ac4C mRNA modification were also drastically increased in AML12 cells after treated with 150 µmol/L PA. Silencing of NAT10 notably inhibited the lipogenesis in AML12 cells and AAV-mediated target knockdown of NAT10 in mouse liver. The acRIP-PCR and NAT10-RIP-PCR revealed that NAT10 ac4C modified Srebf1 and Scap mRNA, the critical modulator of liver lipogenesis, to regulate liver lipogenesis. Besides, Remodelin strongly inhibited liver lipogenesis, including liver TG, serum ALT, AST, TG and TC level and glucose metabolism. NAT10 mediates ac4C modification of Srebf1 and Scap mRNA, thereby affecting lipogenesis in the liver. This study provided a new target for the treatment of MASLD.

Elucidating hydroxysafflor yellow A's multi-target mechanisms against alcoholic liver disease through integrative pharmacology

BackgroundAlcoholic liver disease (ALD) significantly contributes to global liver-related morbidity and mortality. Natural products play a crucial role in the prevention and treatment of ALD. Hydroxysafflor yellow A (HSYA), a unique and primary component of Safflower (Carthamus tinctorius l.), exhibits diverse pharmacological activities. However, the impact and mechanism of HSYA on ALD have not been fully elucidated. PurposeThe purpose of this study was to employ an integrative pharmacology approach to assess the multi-targeted mechanism of HSYA against ALD. MethodsNetwork pharmacology and molecular docking techniques were used to analyze the potential therapeutic signaling pathways and targets of HSYA against ALD. An ALD model in zebrafish larvae was established. Larvae were pretreated with HSYA and then exposed to ethanol. Liver injury was measured by fluorescence expression analysis in the liver-specific transgenic zebrafish line Tg (fabp10a:DsRed) and liver tissue H&E staining. Liver steatosis was determined by whole-mount oil red O staining and TG level. Additionally, an ethanol-induced hepatocyte injury model was established in vitro to observe hepatocyte damage (cell viability, ALT level), lipid accumulation (oil red O staining, TC and TG), and oxidative stress (ROS, MDA, GPx and SOD) in HepG2 cells treated with or without HSYA. Finally, qRT-PCR combined with network pharmacology and molecular docking was employed to validate the effects of HSYA on targets. ResultsHSYA exhibited a significant, dose-dependent improvement in ethanol-induced liver injury in zebrafish larvae and HepG2 cells. Network pharmacology analysis revealed that HSYA may exert pharmacological effects against ALD through 341 potential targets. These targets are involved in various signaling pathways, including lipid metabolism and atherosclerosis, PI3K-Akt signaling pathway, MAPK signaling pathway, and ALD itself. Molecular docking studies displayed that HSYA had a strong binding affinity toward the domains of IL1B, IL6, TNF, PPARA, PPARG, HMGCR and ADH5. qRT-PCR assays demonstrated that HSYA effectively reversed the ethanol-induced aberrant gene expression of SREBF1, FASN, ACACA, CPT1A, PPARA, IL1B, IL6, TNFα, ADH5, and ALDH2 in vivo and in vitro. ConclusionThis study offers a comprehensive investigation into the anti-ALD mechanisms of HSYA using an integrative pharmacology approach. The potential targets of HSYA may be implicated in enhancing ethanol catabolism, reducing lipid accumulation, mitigating oxidative stress, and inhibiting inflammatory response.

Pea Albumin Extracted from Pea (Pisum sativum L.) Seeds Ameliorates High-Fat-Diet-Induced Non-Alcoholic Fatty Liver Disease by Regulating Lipogenesis and Lipolysis Pathways.

Non-alcoholic fatty liver disease (NAFLD) is now recognized as the most prevalent liver disease globally. Pea albumin (PA) has demonstrated positive impacts on reducing obesity and improving glucose metabolism. In this research, a mouse model of NAFLD induced by a high-fat diet (HFD) was employed to examine the impact of PA on NAFLD and explore its potential mechanisms. The findings revealed that mice subjected to a HFD developed pronounced fatty liver alterations. The intervention with PA significantly lowered serum TC by 26.81%, TG by 43.55%, and LDL-C by 57.79%. It also elevated HDL-C levels by 1.2 fold and reduced serum ALT by 37.94% and AST by 31.21% in mice fed a HFD. These changes contributed to the reduction in hepatic steatosis and lipid accumulation. Additionally, PA improved insulin resistance and inhibited hepatic oxidative stress and inflammatory responses. Mechanistic studies revealed that PA alleviated lipid accumulation in HFD-induced NAFLD by activating the phosphorylation of AMPKα and ACC, inhibiting the expression of SREBF1 and FASN to reduce hepatic lipogenesis, and increasing the expression of ATGL, PPARα, and PPARγ to promote lipolysis and fatty acid oxidation. These results indicate that PA could serve as a dietary supplement for alleviating NAFLD, offering a theoretical foundation for the rational intake of PA in NAFLD intervention.

Identification of proteins related to SIS3 by iTRAQ and PRM-based comparative proteomic analysis in cisplatin-induced acute kidney injury.

Cisplatin is a commonly used nephrotoxic drug and can cause acute kidney injury (AKI). In the present study, isobaric tags for relative and absolute quantification (iTRAQ) and parallel reaction monitoring (PRM)-based comparative proteomics were used to analyze differentially expressed proteins (DEPs) to determine the key molecular mechanism in mice with cisplatin-induced AKI in the presence or absence of SIS3, a specific p-smad3 inhibitor, intervention. The cisplatin-induced AKI mouse model was established and treated with SIS3. We used iTRAQ to search for DEPs, PRM to verify key DEPs and combined Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) for bioinformatics analysis. We then assessed lipid deposition, malondialdehyde (MDA) and reactive oxygen species (ROS) and detected the expression of SREBF1, SCD1, CPT1A, PPARα and NDRG1 in vitro. Proteomic analysis showed that the identified DEPs were mainly enriched in energy metabolism pathways, especially in lipid metabolism. When SIS3 was applied to inhibit the phosphorylation of Smad3, the expression of NDRG1 and fatty acid oxidation key proteins CPT1A and PPARα increased, the expression of lipid synthesis related proteins SREBF1 and SCD1 decreased and the production of lipid droplets, MDA and ROS decreased. SIS3 alleviates oxidative stress, reduces lipid accumulation and promotes fatty acid oxidation through NDRG1 in cisplatin-induced AKI. Our study provides a new candidate protein for elucidating the molecular mechanisms of fatty acid metabolism disorders in cisplatin-induced acute kidney injury.

Expression of components involved in cholesterol homeostasis maintenance during experimental autoimmune encephalomyelitis in rat spinal cord.

Dysregulations in cholesterol homeostasis contribute to the pathogenesis of multiple sclerosis (MS) and its best described animal model, experimental autoimmune encephalomyelitis (EAE). Cholesterol is an important component of myelin, which is necessary for signal transmission between neurons. Demyelination leads to the formation of oxysterols, degradation products of cholesterol that are ligands for nuclear liver X receptors (LXRs). Genes regulated by LXRs are involved in cholesterol efflux, absorption, transport, and excretion, which we investigated in this study. In this study, we detected changes in gene expression of Srebf1, Ldlr, Soat1, Abca1, Lrp1, and Npc1, all of which are important in the regulation of cholesterol homeostasis, during the course of EAE in male and female rats. In particular, differential expression of Srebf1, Ldlr, and Soat1 was observed in the spinal cord of male and female rats during EAE. Moreover, these genes are altered during EAE. In contrast, the expression of Abca1 and Lrp1 was significantly affected only by sex. In male animals, the expression of Npc1 is conspicuously reduced in EAE pathology. Thus, our study confirms the involvement of enzymes of cholesterol metabolism in the pathophysiology of EAE, with sex and disease progression affecting the expression of these genes. These findings may improve the understanding of neurodegenerative diseases associated with impaired lipid metabolism in the brain, such as MS/EAE.

Corydalis saxicola Bunting total alkaloids improve NAFLD by suppressing de novo lipogenesis through the AMPK-SREBP1 axis

Ethnopharmacological relevanceAlong with the gradually increasing incidence, nonalcoholic fatty liver disease (NAFLD) has already been influencing the health of more and more people in the world. Corydalis saxicola Bunting (CSB), a valuable folk medicine, is the dried whole grass of a perennial herb, Yanhuanglian (Papaveraceae), which has significant effects on various hepatitis, liver fibrosis, cirrhosis and other liver diseases. Corydalis saxicola Bunting total alkaloids (CSBTA), a mixture of alkaloids extracted from CSB, exhibit widely-accepted hepatoprotective effects. Aim of the studyThis study aimed to explore the therapeutic potential of CSBTA on NAFLD and the underlying mechanism. Materials and methodsA mice model was established by high fat and high cholesterol diet (HFHCD) to study the benefits of CSBTA on the progression of NAFLD. The efficacy of CSBTA on NAFLD was revealed systematically via RNA-sequencing analysis. Further efficacy and molecular mechanism study were explored in mouse primary hepatocytes and HepG2 cells stimulated with high energy with or without pharmacological inhibition or gene silencing. ResultsCSBTA effectively improved the major hallmarks of NAFLD including liver lipid accumulation, liver injury, inflammation and fibrosis in HFHCD-fed mice. RNA sequencing and targeted qPCR analysis jointly evidenced CSBTA significantly suppressed the expression of Srebf1, Acc1 and Fasn which are the genes responsible for fatty acid biosynthesis. Moreover, stable isotope tracer test denoted CSBTA reduced lipid accumulation via interrupting fatty acid biosynthesis in hepatocytes or the liver. Mechanistically, CSBTA could impede SREBP1 maturation via AMPK activation, thereby reducing DNL-derived lipid accumulation in hepatocytes. ConclusionsCSBTA protected against hepatic steatosis and other hallmarks of NAFLD induced by HFHCD via suppressing DNL, through modulating the AMPK-SREBP1 axis. CSBTA may therefore have a therapeutic potential for NAFLD treatment.

DEX-Induced SREBF1 Promotes BMSCs Differentiation into Adipocytes to Attract and Protect Residual T-Cell Acute Lymphoblastic Leukemia Cells After Chemotherapy.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignant blood disorder with a high rate of relapse. Patients relapse as a result of minimal residual disease (MRD), which originates from residual T-ALL cells in the bone marrow microenvironment (BMM). In the present study, it is observed that adipocytes increase dramatically in the BMM of T-ALL patients after exposure to chemotherapeutic drugs. Then, it is proved that adipocytes attract T-ALL cells by releasing CXCL13 and support leukemia cell survival by activating the Notch1 signaling pathway via DLL1 and Notch1 binding. Furthermore, it is verified that dexamethasone (DEX) induces adipogenic differentiation by enhancing the expression of SREBF1 in bone marrow mesenchymal stromal cells (BMSCs), and an SREBF1 inhibitor significantly decreases the adipogenic potential of BMSCs and the subsequent ability of adipocytes to support T-ALL cells in vitro and in vivo. These findings confirm that the differentiation of BMSCs to adipocytes induced by DEX contributes to MRD in T-ALL and provides an auxiliary clinical treatment to reduce the recurrence rate.

Gypenosides ameliorate high-fat diet-induced nonalcoholic fatty liver disease in mice by regulating lipid metabolism.

Gypenosides (GP), extracted from the traditional Chinese herb Gynostemma pentaphyllum (Thunb.) Makino, have been used to treat metabolic disorders, including lipid metabolism disorders and diabetes. Although recent studies have confirmed their beneficial effects in nonalcoholic fatty liver disease (NAFLD), the underlying therapeutic mechanism remains unclear. In this study, we explored the protective mechanism of GP against NAFLD in mice and provided new insights into the prevention and treatment of NAFLD. Male C57BL6/J mice were divided into three experimental groups: normal diet, high-fat diet (HFD), and GP groups. The mice were fed an HFD for 16 weeks to establish an NAFLD model and then treated with GP for 22 weeks. The transcriptome and proteome of the mice livers were profiled using RNA sequencing and high-resolution mass spectrometry, respectively. The results showed that GP decreased serum lipid levels, liver index, and liver fat accumulation in mice. Principal component and heatmap analyses indicated that GP significantly modulated the changes in the expression of genes associated with HFD-induced NAFLD. The 164 differentially expressed genes recovered using GP were enriched in fatty acid and steroid metabolism pathways. Further results showed that GP reduced fatty acid synthesis by downregulating the expression of Srebf1, Fasn, Acss2, Acly, Acaca, Fads1, and Elovl6; modulated glycerolipid metabolism by inducing the expression of Mgll; promoted fatty acid transportation and degradation by inducing the expression of Slc27a1, Cpt1a, and Ehhadh; and reduced hepatic cholesterol synthesis by downregulating the expression of Tm7sf2, Ebp, Sc5d, Lss, Fdft1, Cyp51, Nsdhl, Pmvk, Mvd, Fdps, and Dhcr7. The proteomic data further indicated that GP decreased the protein expression levels of ACACA, ACLY, ACSS2, TM7SF2, EBP, FDFT1, NSDHL, PMVK, MVD, FDPS, and DHCR7 and increased those of MGLL, SLC27A1, and EHHADH. In conclusion, GP can regulate the key genes involved in hepatic lipid metabolism in NAFLD mice, providing initial evidence for the mechanisms underlying the therapeutic effect of GP in NAFLD.

Selegiline ameliorated dyslipidemia and hepatic steatosis in high-fat diet mice.

Certain monoamine oxidase (MAO) inhibitors exhibit beneficial effects, such as reducing adiposity and metabolic disorders; however, their effects on hepatic lipid metabolism have not been revealed. This study aimed to investigate the effects of a selective MAO-B inhibitor, selegiline, on dyslipidemia and hepatic steatosis in mice induced by a high-fat diet (HFD). Administration of selegiline (0.6mg/kg body weight) by intraperitoneal injection was found to reduce HFD-induced body weight gain and increases in liver and adiposity coefficients, blood lipids and fatty acid levels. Furthermore, selegiline dramatically reduced the total triglyceride (TG) and cholesterol (TC) levels and lipid accumulation in the livers of HFD-fed mice and palmitic acid (PA)-treated AML-12 hepatocytes. In vivo and in vitro results indicated that selegiline protects against HFD- and PA-induced hepatic inflammation by reducing the expression of proinflammatory cytokines, namely IL-6, TNF-α, IL-1β, and IL-1α. Additionally, selegiline exhibited antioxidative effects on HFD and PA exposure in mouse liver and AML-12 cells by decreasing the levels of reactive oxygen species (ROS) and malonaldehyde (MDA) and increasing superoxide dismutase (SOD) activity. Further study showed that selegiline administration mitigated the expression of Srebf-1, Fasn, and Acaca and downregulated the expression of Cpt-1 and Pparα in HFD-fed mouse livers and PA-treated AML-12 cells. In conclusion, our findings suggest that selegiline exerts protective effects against HFD-induced dyslipidemia and hepatic steatosis, which may be related to an improved inflammatory response, oxidative stress, and hepatic lipid metabolism.

Bacillus coagulans XY2 ameliorates copper-induced toxicity by bioadsorption, gut microbiota and lipid metabolism regulation

Excessive copper pollutes the environment and endangers human health, attracting plenty of global attention. In this study, a novel strain named Bacillus coagulans XY2 was discovered to have a great copper tolerance and adsorption capacity. B. coagulans XY2 might maintain copper homeostasis through multisystem synergies of copper resistance, sulfur metabolism, Fe-S cluster assembly, and siderophore transport. In mice, by promoting the expression of SREBF-1 and SREBF-2 and their downstream genes, B. coagulans XY2 significantly inhibited the copper-induced decrease in weight growth rate, ameliorated dyslipidemia, restored total cholesterol and triglyceride contents both in serum and liver. Furthermore, B. coagulans XY2 recovered the diversity of gut microbiota and suppressed the copper-induced reduction in the ratio of Firmicutes to Bacteroidota. Serum metabolomics analysis showed that the alleviating effect of B. coagulans XY2 on copper toxicity was mainly related to lipid metabolism. For the first time, we demonstrated mechanisms of copper toxicity mitigation by B. coagulans XY2, which was related to self-adsorption, host copper excretion promotion, and lipid metabolism regulation. Moreover, working model of B. coagulans XY2 on copper homeostasis was predicted by whole-genome analysis. Our study provides a new solution for harmfulness caused by copper both in human health and the environment.

The Expression of SREBF1 Inducing By Dexamethasone Promotes Bone Marrow Mesenchymal Stromal Cells Differentiate to Adipocytes to Attract and Protect the Residual T-Cell Acute Lymphoblastic Leukemia Cells

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive blood malignant disorder with high rate of relapse. The patients relapse as a result of minimal residual disease (MRD), which is originated from residual T-ALL cells in the bone marrow microenvironment (BMM). In the present study, we observed that adipocytes increased dramatically in BMM of T-ALL patients after being exposed to chemotherapeutic drugs. Then, we proved adipocytes attracted T-ALL cells by releasing CXCL13 and supported leukemia survival by activating Notch1 signaling pathway via DLL1 and Notch1 binding. Furthermore, we verified that DEX induced adipogenic differentiation by enhancing the expression of SREBF1 in BMSCs, and SREBF1 inhibitor significantly decreased adipogenic potential of BMSCs and the following ability of adipocytes to support T-ALL cells in vitro and in vivo. These findings confirmed that differentiation of BMSCs to adipocytes induced by DEX contributed to MRD of T-ALL and provided an auxiliary clinical treatment to reduce the recurrence rate of it.

Prepartum dietary energy intake alters hepatic expression of genes related to peroxisome proliferator-activated receptor and inflammation in peripartal dairy cows.

We determined the effect of prepartum plane of energy intake on liver function and metabolism pre- and postpartum by combining in vivo and in vitro data with mRNA expression data. A subset of multiparous prepartal Holsteins (n = 18) from a previously conducted experiment consumed 1 of 3 amounts of dietary energy intake, relative to their requirements. A diet formulated to allow consumption of ≥150% of net energy requirements during the far-off dry period and the close-up dry period was fed for ad libitum intake (150E) or in restricted amounts so that cows consumed 80% of requirements for energy (80E). A second diet was formulated to include wheat straw (26.1% of dry matter) to limit energy intake to 100% of NRC (2001) requirements for energy when fed ad libitum during the far-off period (100E). In the close-up period, 100E was fed the 150E diet for ad libitum intake. Expression of mRNA for genes related to fatty acid oxidation (PPARA, CPT1A, ACOX1) was greater for 100E cows than 150E cows on d 14 postpartum. These expression patterns were related to in vitro data for conversion of palmitate to CO2, acid-soluble products, and esterified products by liver slices. Abundance of mRNA for PC displayed a sharp peak for all groups on d 1 postpartum, but serum glucose did not reflect this peak. The mRNA expression of SREBF1 was greater for 150E and 100E cows prepartum compared with 80E, and was positively related to rate of palmitate esterification postpartum. Expression of NR1H3 (LXRA) mRNA was greater for 100E cows on d 14 postpartum compared with 150E cows, which corresponded to expression of PPARA. An inflammatory response occurred in the liver around the time of parturition for 150E cows, as expression of IL1B was elevated both pre- and postpartum compared with 100E cows. The spike in IL1B expression for 150E cows on d 14 postpartum corresponded to the peak concentration of total lipids in liver tissue for all groups in this experiment. Overconsumption of energy prepartum was detrimental to the expression of important genes related to PPAR and liver function, especially postpartum. Furthermore, results provide evidence for inflammation related to accumulation of lipids in liver and overnutrition prepartum.

Performance and muscle lipogenesis of calves born to Nellore cows with different residual feed intake classification.

This study aimed to evaluate relationships among maternal residual feed intake (RFI) with growth performance and expression of genes involved in lipid metabolism in offspring of Nellore cattle. Fifty-three cows classified as negative or positive RFI by genomic prediction were exposed to fixed-time artificial insemination (FTAI) protocols at 2 and 3 years of age using semen from the same bull. In the first year, cows gestated under grazing conditions and nursed their calves in the feedlot. In the second year, the opposite occurred. Cows were weighed every 28 days during pregnancy and calves were weighed at birth and every 28 days until weaning. Ultrasound images were collected from the carcass of cows and calves. Muscle gene expression was evaluated in calves at birth and weaning. Data were analyzed by year considering the fixed effects of RFI class and FTAI protocol for variables measured in cows, and RFI class, FTAI protocol and sex for variables measured in calves. There was no effect of maternal RFI on calves performance in the first year. Lower expression of FABP4 gene and trend towards lower expression of SREBF1 and LPL genes were detected in samples collected after birth from calves born to negative RFI cows, indicating that adipogenesis was reduced during the fetal and neonatal period. In the second year, negative RFI cows had greater subcutaneous fat thickness than positive RFI cows, and their calves tended to be heavier at birth and to have less rump fat thickness at weaning. No significant differences in expression of genes studied were detected between cow RFI classes. Nellore cows classified as negative RFI consume less feed and produce calves whose growth potential is similar to that of calves produced by positive RFI cows.

Puerarin ameliorates nonalcoholic fatty liver in rats by regulating hepatic lipid accumulation, oxidative stress, and inflammation.

Nonalcoholic fatty liver disease (NAFLD) has become one of the public health problems globally. The occurrence of NAFLD is usually accompanied by a series of chronic metabolic diseases, with a prevalence rate is 25.24% among adults worldwide. Therefore, NAFLD seriously affects the quality of life in patients and causes a large economic burden. It has been reported that puerarin has the function of lowering the serum lipids, but due to the complexity of NAFLD, the specific mechanism of action has not been clarified. The aim of this study was to evaluate the preventive or ameliorating effects of two doses of puerarin (0.11% and 0.22% in diet) on high-fat and high-fructose diet (HFFD)-induced NAFLD in rats. The rats were fed with HFFD-mixed puerarin for 20 weeks. The results showed that puerarin ameliorated the levels of lipids in the serum and liver. Further exploration of the mechanism found that puerarin ameliorated hepatic lipid accumulation in NAFLD rats by reducing the expression of Srebf1, Chrebp, Acaca, Scd1, Fasn, Acacb, Cd36, Fatp5, Degs1, Plin2, and Apob100 and upregulating the expression of Mttp, Cpt1a, and Pnpla2. At the same time, after administration of puerarin, the levels of antioxidant markers (superoxide dismutase, glutathione peroxidase, and catalase) were significantly increased in the serum and liver, and the contents of serum and hepatic inflammatory factors (interleukin-18, interleukins-1β, and tumor necrosis factor α) were clearly decreased. In addition, puerarin could ameliorate the liver function. Overall, puerarin ameliorated HFFD-induced NAFLD by modulating liver lipid accumulation, liver function, oxidative stress, and inflammation.

The effect of bile salt diet supplementation on genes related to fat metabolism in yellow-feathered broilers.

Background and Aim:As a new feed additive, bile acid (BA) can promote the absorption and transport of lipids and fat-soluble vitamins. In recent years, BAs have been widely used in animal feed to promote fat absorption. Therefore, this study aimed to investigate the effect of bile salt supplementation in the diet of yellow-feathered broilers on messenger RNA (mRNA) expression of sterol regulatory element-binding protein 1 (SREBF1), fatty acid synthase (FAS), acetyl-coenzyme A carboxylase (ACC), and fatty acid transport protein 4 (FATP4).Materials and Methods:Four hundred and twenty commercial male chicks were randomly divided into seven groups (with four replicates per group and 15 chickens per replicate). They were fed diets supplemented with bile salts at 0, 1.5, 2.5, 3.5, 4.5, 5.5 mg/kg, and 2 mg/kg tylosin for 30 days. Changes in SREBF1, fatty acid transporter 4, FAS, and acetyl-CoA carboxylase genes in intestinal mucosa and liver of yellow-feathered broilers were determined using a quantitative fluorescence polymerase chain reaction.Results:mRNA expression of SREBF1, FAS, ACC, and FATP4 in the small intestine decreased in chicks fed diets supplemented with 3.5 and 4.5 mg/kg bile salts (p<0.05) compared with the control group on 7 days and 14 d. The mRNA expressions of SREBF1, FAS, ACC, and FATP4 in liver tissue decreased in chicks fed diets supplemented with 4.5 and 5.5 mg/kg bile salts (p<0.05) compared to the control group on 7 days. The mRNA expression of SREBF1, FAS, ACC, and FATP4 in the liver at 14 days and the small intestine on 21 days also decreased in chicks fed diets supplemented with 4.5 mg/kg bile salts (p<0.05) compared to the control group. When contrasted with the control group on day 21, the mRNA expression of SRWBF1, FAS, ACC, and FATP4 detected in the liver was lower in chicks fed diets supplemented with bile salts (p<0.05).Conclusion:The dietary supplementation of bile salts at 4.5 mg/kg effectively regulates the expression of fat metabolism genes, such as SREBF1, FAS, ACC, and FATP4 mRNA. At this concentration, bile salts promote fat catabolism, inhibit fat synthesis, and play an essential role in improving the fat deposition of broilers.

PPARγ/LXRα axis mediated phenotypic plasticity of lung fibroblasts in silica-induced experimental silicosis

Silicosis is a disease mainly caused by pulmonary interstitial fibrosis caused by long-term inhalation of dust with excessively high content of free SiO2. Transdifferentiation of lung fibroblasts into myofibroblasts is an important cellular basis for silicosis, but the key transcription factors (TFs) involved in this process are still unclear. In order to explore the biological regulation of transcription factor PPARγ/LXRα in silica-induced pulmonary fibrosis, this study explored the molecular mechanism of PPARγ/LXRα involved in regulating transcription factors related to SiO2-induced lung injury at the cellular level and in animal models. ChIP-qPCR detected that PPARγ directly regulated the transcriptional activity of the LXRα gene promoter, while the PPARγ agonist RSG increased the expression of LXRα. In addition, we demonstrated in the cell model that upregulation of LXRα can inhibit silica-mediated fibroblast transdifferentiation, accompanied by an increase in the expression of SREBF1, PLTP and ABCA1. The results of LXRα silencing experiment matched those of overexpression experiment. These studies explored the role of LXRα in plasticity and phenotypic transformation between lung fibroblasts and myofibroblasts. Therefore, inhibiting or reversing the transdifferentiation of lung fibroblasts to myofibroblasts by intervening PPARγ/LXRα may provide a new therapeutic target for the treatment of silicosis.

Effect of vitamin A injection at birth on intramuscular fat development and meat quality in beef cattle

This study aimed to evaluate intramuscular fat and expression of genes in the muscle of Montana × Nellore treated with vitamin A at birth. We hypothesized that an injection of vitamin A after birth would increase marbling by increasing the expression of angiogenic, adipogenic, and lipogenic genes. Animals treated with vitamin A had greater marbling in the longissimus muscle (P = 0.05). The vitamin A treatment increased the expression of VEGFA gene at 40 days of age and at weaning and increased the expression of ZNF423 at weaning and at harvesting (P ≤ 0.03). The expression of WNT was higher (P = 0.01) at 40 days of age and at weaning in the animals treated with vitamin A. Vitamin A also increased the expression of SREBF1 at 40 days of age and at weaning (P ≤ 0.05). Therefore, the administration of vitamin A to cattle at birth could be a way to increase carcass marbling without affecting the performance of the animals.

Biological Mechanism(s) Underpinning the Association between Antipsychotic Drugs and Weight Gain.

Weight gain and consequent metabolic alterations are common side-effects of many antipsychotic drugs. Interestingly, several studies have suggested that improvement in symptoms and adverse metabolic effects are correlated. We used next generation sequencing data from NT-2 (human neuronal) cells treated with aripiprazole, amisulpride, risperidone, quetiapine, clozapine, or vehicle control, and compared with the Pillinger P-score (ranked from 0 to 1, indicating greater increase in weight gain and related metabolic parameters) to identify the genes most associated with the drugs’ propensity to cause weight gain. The top 500 genes ranked for their correlation with the drugs’ propensity to cause weight gain were subjected to pathway analysis using DAVID (NIH). We further investigated transcription factors (TFs) that are more likely to regulate the genes involved in these processes using the prediction tool of key TFs from TRRUST. The results suggest an enrichment for genes involved in lipid biosynthesis and metabolism, which are of interest for mechanisms underpinning weight-gain. The list of genes involved in the lipid pathways that correlated with weight gain was enriched for genes transcriptionally regulated by SREBF1 and SREBF2. Furthermore, quetiapine significantly increased the expression of SREBF1 and SREBF2 in NT-2 cells. Our results suggest that the effects of these antipsychotic drugs on lipid metabolism may be mediated, at least in part, via regulation of SREBF1/SREBF2 expression, with evidence of a direct effect of quetiapine on the expression of SREBF1/2. The effects of antipsychotic drugs on lipid metabolism may influence white matter structure (therapeutic effect) and the risk of weight gain, lipid disturbances, and, consequently, metabolic syndrome (adverse effects). Understanding the different molecular effects of these drugs could inform a personalized medicine approach in treating patients with schizophrenia.

Hepatic GH Receptor Signaling Directly Suppresses Hepatic Steatosis and De Novo Lipogenesis, Independent of Changes in Plasma IGF1 and Insulin

A reduction in GH, as well as IGF1, is associated with non-alcoholic fatty liver disease (NAFLD). However, the relative contribution of changes in circulating GH and IGF1, to hepatic triglyceride accumulation (steatosis), remains to be clearly defined. To study the direct actions of GH on hepatocyte metabolism, we have utilized a mouse model of adult-onset, hepatocyte-specific, GHR knockdown (aHepGHRkd; 10–12 week-old, GHRfl/fl male mice, treated with AAV8-TBGp-Cre). In this and previous reports, we have observed that aHepGHRkd male mice rapidly develop steatosis (after 7 days) associated with enhanced de novo lipogenesis (DNL; measured by deuterated H2O labeling, 10h after 0800h food removal), and low ketone levels, suggestive of reduced hepatic β-oxidation. Of note, aHepGHRkd also reduces plasma IGF1 levels to >80% of GHR-intact controls (GHRfl/fl mice treated with AAV8-TBGp-Null), leading to a rise in GH, due to loss of IGF1 negative feedback to the pituitary/hypothalamus. This reciprocal shift in IGF1/GH is associated with an increase in insulin levels. Therefore, it is possible that the steatosis that develops in aHepGHRkd mice is the consequence of systemic insulin resistance supplying excess substrates (glucose and NEFA) for hepatic lipogenesis. However, inconsistent with this theory is the fact that glucose and NEFA levels are not altered after aHepGHRkd. To tease out the indirect (perhaps driven by high insulin levels) vs. direct effects of GH on hepatocyte lipid accumulation, male aHepGHRkd mice were injected with a vector expressing rat IGF1 (AAV8-TBGp-rIGF1). Reconstitution of hepatocyte IGF1 in aHepGHRkd mice, raised plasma IGF1 and normalized GH, insulin and ketone levels, but hepatic steatosis and DNL remained greater than that of GHR-intact controls, indicating GH directly suppresses hepatic fat accumulation. RNAseq analysis of livers from aHepGHRkd mice showed expression of genes related to carbohydrate metabolism (Gck, Khk) and fatty acid synthesis (Fasn, Srebf1, Usf1), processing (Scd1) and uptake (Cd36) were increased, while genes related to gluconeogenesis (Pck1, Fbp1, G6pc) were reduced. Remarkably, IGF1 reconstitution had no major impact on the hepatic transcriptome of aHepGHRkd mice, with the exception of reducing the expression of Srebf1, consistent with the reduction in circulating insulin levels. Interestingly, carbohydrate-responsive element-binding protein (CHREBP) levels, but not mRNA levels, were greater in aHepGHRkd mice with or without IGF1 reconstitution, consistent with upregulation of CHREBP target genes (Khk and Fasn among others). Taken together, these results suggest GH directly regulates steatosis, at least in part, by suppressing carbohydrate-driven DNL, where additional studies are underway to test this hypothesis.

Berberine regulates lipid metabolism via miR-192 in porcine oocytes matured in vitro.

BackgroundThe berberine (Ber) is an isoquinoline alkaloid compound extracted from Rhizoma coptidis and has the effect that reduces adipose. MicroRNA‐192 (miR‐192) is related to fat metabolism. However, the relevant mechanism of berberine on lipid metabolism during in vitro maturation (IVM) of porcine oocytes remains unclear.ObjectivesIn this study, we investigated the molecular mechanism by which berberine promotes the IVM and lipid metabolism of porcine oocytes via miR‐192.MethodsBer was added to IVM medium of porcine oocytes. MiR‐192 agomir, miR‐192 antagomir and negative control fragment were microinjected into the cytoplasm of oocytes without Ber. Rates of oocyte IVM and embryonic development in each group were observed. The content of lipid droplets in IVM oocytes in each group was analyzed by Nile red staining. Expression levels of miR‐192 and FABP3, SREBF1 and PPARG, were detected by qPCR and western blotting. The target genes of miR‐192 were determined by luciferase reporter assays.Results and ConclusionsWe found that Ber significantly increased the rate of oocytes IVM and blastocyst development, and decreased the area and numbers of lipid droplets in IVM oocytes. Ber significantly increased the expression of miR‐192 in IVM oocytes, and significantly decreased the expression of SREBF1 and PPARG, which were target genes of miR‐192. This study indicates that Ber promotes lipid metabolism in porcine oocytes by activating the expression of miR‐192 and down‐regulating SREBF1 and PPARG, thus, improving IVM of porcine oocytes.