Sterol Regulatory Element-binding Transcription Factor-1c Research Articles

Analyzing the impact of acupuncture in conjunction with a Quantum lipid-lowering device on hyperlipidemic rats: insights into adenosine monophosphate-activated protein kinase signaling, blood lipids, and gut microbiota.

We explored the impact of acupuncture (ACUP) in conjunction with a quantum lipid-lowering device (Quantum) on the blood lipids and gut microbiota in hyperlipidemic rats, focusing on the adenosine monophosphate- (AMP)-activated protein kinase (AMPK) signaling pathway. Fifty Sprague-Dawley rats were randomly allocated into five groups: Normal, Model, Acup + Quantum, Acup, and Quantum. Hyperlipidemic models were established in all groups except Normal. The Model group did not receive any intervention after modeling. The Acup + Quantum group received both treatments, the Acup group received only acupuncture, and the Quantum group received only the quantum lipid-lowering device. We used ELISA to measure serum lipid and liver enzyme levels, hematoxylin and eosin (HE) staining for liver pathology, Western blot for protein expression, and 16S rRNA sequencing to analyze intestinal microbiota diversity in rats. Elisa results showed that compared with the model group, Acup + Quantum group could reduce the levels of total cholesterol (TC), triglycerides (TG), low-density lipoprotein-cholesterol (LDL-C), aspartate transaminase (AST) and aspartate transaminase (ALT) in rats with hyperlipidemia (P<0.01), and increase the level of high-density lipoprotein-cholesterol (HDL-C) (P<0.01). HE staining results showed that compared with the model group, the hepatocytes of rats in the Acup + Quantum group looked round and full, the liver plates were arranged regularly and neatly, and there was no obvious abnormality in the liver sinusoids. Western blot results showed that compared with the model group, the Acup + Quantum group inhibited AMPK activation, increased P-AMPK/AMPK protein expression (P<0.05), and decreased phospho-acetyl-CoA carboxylases (P-ACC/ACC), Sterol regulatory element-binding transcription factor-1C (SREBP-1C), and FAS protein expression (P<0.05; P<0.01; P<0.01), which resulted in lipid-lowering effect. The results of intestinal flora showed that Acup + Quantum group improved the intestinal microbial microenvironment of hyperlipidemic rats by regulating the structure of intestinal microflora, increasing the abundance of Firmicutes flora, and decreasing the abundance of harmful bacteria, such as Bacteroidetes and Proteobacteria. Acupuncture combined with quantum lipid-lowering device can improve the blood lipid and liver function levels and regulate the intestinal microbial microenvironment of hyperlipidemic rats. This therapeutic outcome is likely achieved through the activation of the AMPK pathway and the beneficial modulation of the intestinal microbiota of rats.

The Protective Effects of Cinnamyl Alcohol Against Hepatic Steatosis, Oxidative and Inflammatory Stress in Nonalcoholic Fatty Liver Disease Induced by Childhood Obesity

ABSTRACT Background Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive intracellular lipid accumulation, oxidative stress, and inflammation. Cinnamyl alcohol (CA), one of the cinnamon extracts, has been shown to exhibit anti-oxidative and anti-inflammatory activities. We proposed that CA was beneficial to NAFLD. Methods Serum cytokines and components of the lipid metabolism were determined in children with NAFLD against age-matched comparisons. A NAFLD mouse model was established by high fat and high carbohydrate (HFHC) diet in male C57BL/6 mouse pups, followed by administration of CA. The effects of CA on lipid metabolism, oxidative stress, and inflammation in hepatic tissues were assessed. Results Abnormal lipid metabolism and inflammatory responses were observed in the children with NAFLD as compared with the controls. CA reduced the weight of obese mice without affecting food intake as well as alleviating liver injury caused by HFHC feeding. CA was found to mitigate dyslipidemia and reduce hepatic steatosis in HFHC-fed mice by down-regulating genes related to lipogenesis, including peroxisome proliferator-activated receptor gamma (PPARγ), sterol regulatory element-binding transcription factor-1c (SREBP-1c), and acetyl-CoA carboxylase 1 (ACC1). Additionally, CA treatment reversed HFHC-induced oxidative stress and inflammation, evidenced by the decreased liver reactive oxygen species (ROS), hepatic inflammatory cytokine levels, and F4/80-positive macrophage infiltration in HFHC diet mice. CA reduced the protein levels of pyrin domain-containing protein 3 (NLRP3), adapter protein apoptosis-associated speck-like protein (ASC), and caspase-1 in the liver tissues significantly. Conclusion CA alleviates HFHC-induced NAFLD in mice, which is associated with the amelioration in lipid metabolism, oxidative stress, and inflammation.

Galbanic acid of Ferula assa-foetida L, as a regulator of the AMPK pathway in reduction of lipid accumulation in HepG2 cells

Introduction: Hepatic fat accumulation is a complication of non-alcoholic fatty liver disease (NAFLD). An AMP-activated protein kinase (AMPK) reduces the synthesis of fatty acids by inhibiting sterol regulatory element-binding transcription factor 1-c (SREBP1-C) and acetyl COA carboxylase (ACC). Objectives: We aimed to investigate the impress of galbanic acid (Gal) from the Ferula plant on AMPK and its inhibitory effect on lipogenic enzymes in HepG2 cells. Materials and Methods: In an applied-fundamental study, HepG2 cells were treated for 24 hours with Gal in palmitate (Pal). Resveratrol (RSV) was conducted as a positive control. Fatty acid synthase (FAS) and SREBP1-C gene expression were evaluated by reverse transcription polymerase chain reaction (RT-PCR). FAS, phospho-acetyl-CoA carboxylase (P-ACC), P-AMPK, AMPK, SREBP-1c, and ACC protein levels were measured by western blotting. Lipid accumulation was investigated qualitatively and semi-quantitatively with oil red. Results: The semi-quantitative results of oil revealed a substantial reduction (P&lt;0.004) in lipid accumulation for treatment with Gal. The significant increase in the protein level of P-AMPK (P&lt;0.001) and P-ACC (P=0.054) and significant decrease in FAS (P&lt;0.003), SREBP-1c (P&lt;0.001) and ACC (P&lt;0.011) due to the effect galbanic acid was observed. FAS gene expression decreased significantly (P&lt;0.009), while the decrease in SREBP-1c gene expression was not significant (P=0.303). Conclusion: These findings direct that galbanic acid can be a new regulator of AMPK. Hence, the present study may introduce galbanic acid as a new plan to positively regulate the AMPK pathway, which leads to the regulation of various cellular processes.

Effects of propylene glycol used at different doses in Akkaraman lambs rations on metabolism-related parameters and liver gene and protein expression during different feeding periods.

This study aimed to investigate the metabolic effects of propylene glycol (PG) over 60, 90, and 120 days in lambs. Seventy-two weaned male lambs were allocated into three groups: control (Con), PG1.5 (1.5 mL/kg live weight0.75 ), and PG3 (3mL/kg live weight0.75 ). Blood samples were collected at the beginning and slaughter days. Biochemical parameters (glucose, triglycerides, ALT, AST, LDH, BUN, and insulin) and gene and protein levels of peroxisome proliferator activated receptor gamma (PPARγ), diacylglycerol o-acyltransferase 1 (DGAT1), carbohydrate responsive element binding protein (ChREBP), and sterol regulatory element binding transcription factor 1c (SREBP-1c) in the liver were determined. Glucose in PG1.5 was increased on Day 60, while significant differences were observed in biochemical parameters except for insulin on the 60, 90, and 120 days. Biochemical parameters such as ALT, AST, LDH, and BUN increased over time, while triglycerides decreased. DGAT1 gene and protein levels were lower, while SREBP-1c and PPARγ were higher in PG groups on Day 60. While SREBP-1c was lower in PG1.5, ChREBP was higher in PG3 on Day 90. PPARγ, DGAT1, and ChREBP were upregulated in PG3 on Day 120. Positive correlations were found between proteins. The long-term use of PG in lambs did not have detrimental effects on metabolism. The study provides valuable insights into the molecular mechanisms underlying the metabolic effects of PG in lambs, shedding light on its potential applications in lamb production.

Maternal pyrimidine nucleoside supplementation regulates fatty acid, amino acid and glucose metabolism of neonatal piglets.

Pyrimidine nucleosides (PN) are abundant in mammalian milk and mainly involved in glycogen deposition and lipid metabolism. To investigate the effects of maternal supplementation with pyrimidine nucleoside on glucose, fatty acids (FAs), and amino acids (AAs) metabolism in neonatal piglets. Forty pregnant sows were randomly assigned into the control (CON) group (fed a basal diet, n = 20) or the PN group (fed a basal diet supplemented with PN at 150 g/t, n = 20). Litter size, born alive and birth litter weight were recorded. The serum and placenta of sows, and jejunum and liver of neonatal piglets were sampled. The results indicated that supplementing sow diets with PN decreased birth mortality and increased the birth weight of piglets (P < 0.05). In addition, neonates from sows supplemented with PN had higher glucose levels in serum and liver compared with the CON group (P < 0.05). Moreover, maternal PN supplementation regulated the ratio of saturated FAs and polyunsaturated FAs, and AAs content in serum and liver of piglets (P < 0.05). Furthermore, an up-regulation of mRNA expression of genes related to glucose and AA transport were observed in the neonatal jejunum from the PN group (P < 0.05). Additionally, hepatic protein expressions of phosphorylated hormone-sensitive lipase (P-HSL), HSL, sterol regulatory element-binding transcription factor 1c (SREBP-1c), and phosphorylated protein kinase B (P-AKT) was higher in the piglets from the PN group than the CON group (P < 0.05). Together, maternal PN supplementation may regulate nutrient metabolism of neonatal piglets by modulating the gene expression of glucose and AA transporters in placenta and jejunum, and the gene and protein expression of key enzymes related to lipid metabolism in liver of neonatal piglets, which may improve the reproductive performance of sows.

Effects of Bile Acid Modulation by Dietary Fat, Cholecystectomy, and Bile Acid Sequestrant on Energy, Glucose, and Lipid Metabolism and Gut Microbiota in Mice.

Bile acid metabolism, involved with the digestion and absorption of nutrients in the gut, is linked to the gut microbiota community, greatly impacting the host’s metabolism. We examined the hypothesis that the modulation of bile acid metabolism by dietary fat contents, gallbladder removal (GBX; cholecystectomy), and bile acid sequestrant (BAS; cholestyramine) treatment could alter energy, glucose, and lipid metabolism through the changes in the gut microbiota. Mice were randomly assigned to the following six groups: (1) Sham GBX surgery (Sham) + low fat/high carbohydrate diet (LFD), (2) Sham + high fat diet (HFD), (3) Sham + HFD + BAS, (4) GBX + LFD, (5) GBX + HFD, and (6) GBX + HFD + BAS. BAS groups received 2% cholestyramine. After an 8-week intervention, energy, glucose, and lipid metabolism, and the gut microbiota community were measured. HFD groups exhibited higher body weight gain than LFD, and GBX increased the weight gain comped to Sham groups regardless of BAS in HFD (p < 0.05). Homeostatic model assessment for insulin resistance (HOMA-IR) was higher in HFD than LFD, and GBX increased it regardless of BAS. Serum lipid profiles were worsened in GBX + HFD compared to Sham + LFD, whereas BAS alleviated them, except for serum HDL cholesterol. Hepatic tumor-necrosis-factor-α (TNF-α) mRNA expression and lipid peroxide contents increased with GBX and BAS treatment compared to Sham and no BAS treatment (p < 0.05). Hepatic mRNA expression of sterol regulatory element-binding transcription factor 1c (SREBP1c) and peroxisome proliferator-activated receptor gamma (PPAR-γ) exhibited the same trend as that of tumor necrosis factor-α (TNF-α). The α-diversity of gut bacteria decreased in GBX + HFD and increased in GBX + HFD + BAS. Akkermentia, Dehalobacterium, SMB53, and Megamonas were high in the Sham + LFD, and Veillonella and Streptococcus were rich in the Sham + HFD, while Oscillospira and Olsenella were high in Sham + HFD + BAS (p < 0.05). GBX + LFD increased Lactobacillus and Sutterella while GBX + HFD + BAS elevated Clostridium, Alistipes, Blautia, Eubacterium, and Coprobacillus (p < 0.05). In conclusion, the modulation of bile acid metabolism influences energy, glucose, and lipid metabolisms, and it might be linked to changes in the gut microbiota by bile acid metabolism modulation.

3T3-L1 세포에서 김치유산균 Weissella koreensis DB1 추출물의 지방분화 억제효과

Weissella koreensis (W. koreensis) DB1 with high-ornithine-producing capacity was isolated from kimchi and shows the anti-adipogenic activity via its production of ornithine. This study was carried out the effects of W. koreensis DB1 cell extracts on the inhibition of adipogenesis in 3T3-L1 cells. MTT results showed that 0-0.75 μg/mL W. koreensis DB1 cell extracts had no significant effect on cell vability. The cell extracts of W. koreensis DB1 at non-cytotoxic concentrations significantly suppressed the differentiated 3T3-L1 cells by decreasing triglyceride level and intracellular lipid accumulation compared to that associated with the untreated control group. The major transcriptional factors involved in adipocyte differentiation, such as peroxisome proliferator-activated receptorγ (PPARγ), CCAAT/enhancer-binding proteinα (C/EBPα), and sterol regulatory element-binding transcription factor-1c (SREBP-1c), were down-regulated by the cell extracts of W. koreensis DB1 treatments compared with the untreated control group. Furthermore, the expressions of lipogenesis-related enzymes including acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) genes were also decreased by the cell extracts of W. koreensis DB1 treatment. Accordingly, these results indicate that the cell extracts of W. koreensis DB1 treatment inhibited the adipogenesis and lipogenesis of 3T3-L1 cells, suggesting a protective role in adipocyte differentiation.

Dysregulated SREBP1c/miR-153 signaling induced by hypertriglyceridemia worsens acute pancreatitis and delays tissue repair

Severe acute pancreatitis (AP) is a life-threatening disease with up to 30% mortality. Therefore, prevention of AP aggravation and promotion of pancreatic regeneration are critical during the course and treatment of AP. Hypertriglyceridemia (HTG) is an established aggravating factor for AP that hinders pancreatic regeneration; however, its exact mechanism remains unclear. Using miRNA sequencing and further verification, we found that miRNA-153 (miR-153) was upregulated in the pancreas of HTG animal models and in the plasma of patients with HTG-AP. Increased miR-153 aggravated HTG-AP and delayed pancreatic repair via targeting TRAF3. Furthermore, miR-153 was transcriptionally suppressed by sterol regulatory element-binding transcription factor 1c (SREBP1c), which was suppressed by lipoprotein lipase malfunction-induced HTG. Overexpressing SREBP1c suppressed miR-153 expression, alleviated the severity of AP, and facilitated tissue regeneration in vivo. Finally, therapeutic administration of insulin also protected against HTG-AP via upregulating SREBP1c. Collectively, our results not only provide evidence that HTG leads to the development of more severe AP and hinders pancreatic regeneration via inducing persistent dysregulation of SREBP1c/miR-153 signaling, but also demonstrate that SREBP1c activators, including insulin, might be used to treat HTG-AP in patients.

The effects of multispecies probiotic formulations on growth performance, hepatic metabolism, intestinal integrity and fecal microbiota in growing-finishing pigs

Probiotics have received attention as alternatives to antibiotics due to their relative biosafety. Despite the health-promoting effects of multispecies probiotic formulation (MPF) in weaning pigs were well-documented, the health-promoting potential of MPF in growing-finishing pigs remain limited. Therefore, we conducted a six-week experiment to investigate the beneficial effects of MPF supplementation (the formulations containing Lactobacillus plantarum CJLP243, L. fermentum LF21, L. salivarius E4101, Leuconostoc paramesenteroides KJP421, Bacillus subtilis CJMPB957 and B. licheniformis CJMPB283) on intestinal environments and hepatic lipid metabolism in growing-finishing pigs. The results showed that the growth performance of MPF group was improved compared to control group during the experimental period without affecting feed intake. The dietary MPF supplementation also significantly increased the jejunal mRNA expression levels of zonula occludens-1 (ZO-1) and decreased that of interleukin-12 (IL-12). Dietary MPF supplementation was found to not only reduce the hepatic triglyceride concentration but down-regulate hepatic mRNA expression levels of lipid metabolism-related markers, such as as sterol regulatory element-binding transcription factor 1c (SREBP-1c), CCAAT/enhancer binding protein α (CEBPα), acetyl coA carboxylase (ACC) and carnitine palmitoyl transferase 1β (CPT1β). Nonetheless, MPF supplementation also had the capability to modulate gut microbiota populations, including Clostridiaceae, Lachnospiraceae, and Turicibacter. Collectively, our results suggest that dietary MPF inclusion could be a promising approach to promote the growth performance and the overall health of growing-finishing pigs via modulation of gut microbiota.

Genistin: A Novel Potent Anti-Adipogenic and Anti-Lipogenic Agent.

Soy isoflavones are popular ingredients with anti-adipogenic and anti-lipogenic properties. The anti-adipogenic and anti-lipogenic properties of genistein are well-known, but those of genistin and glycitein remain unknown, and those of daidzein are characterized by contrasting data. Therefore, the purpose of our study was to investigate the effects of daidzein, glycitein, genistein, and genistin on adipogenesis and lipogenesis in 3T3-L1 cells. Proliferation of 3T3-L1 preadipocytes was unaffected by genistin and glycitein, but it was affected by 50 and 100 µM genistein and 100 µM daidzein for 48 h. Among the four isoflavones, only 50 and 100 µM genistin and genistein markedly suppressed lipid accumulation during adipogenesis in 3T3-L1 cells through a similar signaling pathway in a dose-dependent manner. Genistin and genistein suppress adipocyte-specific proteins and genes, such as peroxisome proliferator-activated receptor γ (PPARγ), CCAAT-enhancer-binding protein α (C/EBPα), and adipocyte binding protein 2 (aP2)/fatty acid-binding protein 4 (FABP4), and lipogenic enzymes such as ATP citrate lyase (ACL), acetyl-CoA carboxylase 1 (ACC1), and fatty acid synthase (FAS). Both isoflavones also activate AMP-activated protein kinase α (AMPKα), an essential factor in adipocyte differentiation, and inhibited sterol regulatory element-binding transcription factor 1c (SREBP-1c). These results indicate that genistin is a potent anti-adipogenic and anti-lipogenic agent.

Black Ginseng and Ginsenoside Rb1 Promote Browning by Inducing UCP1 Expression in 3T3-L1 and Primary White Adipocytes.

In this study, we investigated the effects of black ginseng (BG) and ginsenoside Rb1, which induced browning effects in 3T3-L1 and primary white adipocytes (PWATs) isolated from C57BL/6 mice. BG and Rb1 suppressed the expressions of CCAAT/enhancer-binding protein alpha (C/EBPα) and sterol regulatory element-binding transcription factor-1c (SREBP-1c), whereas the expression level of peroxisome proliferator-activated receptor gamma (PPARγ) was increased. Furthermore, BG and Rb1 enhanced the protein expressions of the brown-adipocyte-specific markers PR domain containing 16 (PRDM16), peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), and uncoupling protein 1 (UCP1). These results were further supported by immunofluorescence images of mitochondrial biogenesis. In addition, BG and Rb1 induced expressions of brown-adipocyte-specific marker proteins by AMP-activated protein kinase (AMPK) activation. BG and Rb1 exert antiobesity effects by inducing browning in 3T3-L1 cells and PWATs through AMPK-mediated pathway activation. We suggest that BG and Rb1 act as potential functional antiobesity food agents.

Regulatory effect of Grifola frondosa extract rich in polysaccharides and organic acids on glycolipid metabolism and gut microbiota in rats

The present study investigated the composition of water extract of Grifola frondosa (GFWE) and its regulatory effects on glycolipid metabolism and gut microbiota in rats. Structural characteristics of GFWE were detected by high performance liquid chromatography and ultra-high-performance liquid chromatography with mass spectrometry. The hypoglycemic and hypolipidemic activities of GFWE were obtained by inhibition of weight gain, recovery of serum glucose and lipid, and reverse of liver tissue damage. GFWE has up-regulated the relative mRNA and protein expression levels of adenine monophosphate activated protein kinase-α, peroxisome proliferator-activated receptors-α, and glucokinase, while down-regulated sterol regulatory element-binding transcription factor-1c and acetyl CoA carboxylase. Moreover, GFWE increased the abundances of caecal bacteria Oscillibacter and Barnesiella, which showed a significant negative correlation with serum glucose and lipid parameters. And GFWE enhanced the levels of total bile acids and short-chain fatty acids in the cecum. These results indicated that GFWE could be provided as a potential candidate to regulate glycolipid metabolism and gut microbiota.

Role and mechanisms of action of microRNA‑21 as regards the regulation of the WNT/β‑catenin signaling pathway in the pathogenesis of non‑alcoholic fatty liver disease.

The aim of the present study was to investigate the role of microRNA-21 (miR-21) in regulating the classical WNT/β-catenin signaling pathway by targeting low-density lipoprotein-related receptor 6 (LRP6) in non-alcoholic fatty liver disease (NAFLD). For this purpose, we established a NAFLD model by feeding C57BL/6J mice a methionine-choline-deficient diet. Antagomir-21 was then injected via the tail vein, and the expression levels of WNT/β-catenin signaling pathway-related proteins, such as LRP6, glycogen synthase kinase-3β (GSK3β), p-β-catenin, β-catenin and the downstream protein, peroxisome proliferator-activated receptor γ (PPAR-γ), and lipid metabolism-related genes, including sterol regulatory element-binding transcription factor 1c (SREBP1c), fatty acid synthase (FAS), carnitine palmitoyl transferase 1α (CPT1α) and adenosine 5-monophosphate (AMP)-activated protein kinase α (AMPKα), were detected. The results revealed that in the NAFLD model, LRP6 expression was negatively associated with miR-21 expression. After antago-nizing the expression of miR-21, the protein level of LRP6 was increased. In addition, the WNT/β-catenin signaling pathway was activated, and lipid accumulation and inflammation were alleviated in the liver. However, the expression of PPAR-γ was not inhibited following the upregulation of the WNT signaling pathway. Taken together, the results of this study demonstrate that the inhibition of miR-21 expression can alleviate NAFLD by targeting LRP6 to activate the WNT/β-catenin signaling pathway.

Effect of divergence in residual feed intake on expression of lipid metabolism-related genes in the liver of meat-type ducks1

Lipid metabolism is considered one of the important factors affecting residual feed intake (RFI). However, the relationship between RFI and expression of lipid metabolism-related genes is unknown in meat-type ducks. To address this issue, a total of 1,000 male meat-type ducks with similar body weight were randomly selected to measure body weight gain and feed intake from 21 to 42 d of age to estimate RFI. The 8 greatest- (high RFI [HRFI]) and lowest- (low RFI [LRFI]) ranking birds were then selected for the present study. Relative expressions of key genes, namely sirtuin 1 (Sirt1), forkhead box O1 (Foxo1), peroxisome proliferator-activated receptor gamma (PPARγ), sterol regulatory element-binding transcription factor 1c (SREBP-1c), fas cell surface death receptor (FAS), acetyl-CoA carboxylase alpha (ACC), carnitine palmitoyltransferase 1A (CPT1A), and acyl-CoA oxidase 1 (ACOX1), were then determined in the HRFI and LRFI ducks by quantitative PCR. The results showed that RFI, feed conversion ratio (FCR), and average daily feed intake (ADFI) were significantly lower (P < 0.05) in LRFI ducks than in HRFI ducks. In addition, expression of Sirt1, Foxo1, CPT1A, and ACOX1 were significantly higher in LRFI ducks than in HRFI ducks (P < 0.05), whereas PPARγ and FAS expression levels were significantly lower in LRFI ducks than in HRFI ducks (P < 0.01). Correlation analysis showed that Sirt1, CPT1A, and ACOX1 expressions were significantly negatively correlated with FCR (r = -0.81 to -0.93; P < 0.01), whereas PPARγ and FAS expressions were significantly positively correlated with FCR (r = 0.74 to 0.87; P < 0.01). PPARγ expression was significantly positively correlated with RFI (r = 0.83; P < 0.01), whereas CPT1A and ACOX1 expressions were significantly negatively correlated with RFI (r = -0.84 to -0.89; P < 0.01). Sirt1 mRNA expression was positively correlated with Foxo1, CPT1A, and ACOX1 mRNA expression (r = 0.78 to 0.92; P < 0.01). Association of Foxo1 with CPT1A and ACOX1 was positive (r = 0.88 to 0.96; P < 0.01). These results suggest that genes related to fatty acid oxidation are upregulated in the liver of ducks with high feed efficiency, while genes associated with lipid synthesis are downregulated. Furthermore, the inclusion of lipid metabolism-related genes in future breeding programs might be beneficial for selecting ducks with greater feed efficiency phenotype.

Abstract 1829: HSF1 suppresses AMPK to promote lipogenesis, cholesterol biosynthesis and protein lipidation

Abstract AMP-activated protein kinase (AMPK), a key cellular metabolic sensor, suppresses anabolic pathways, including lipogenesis and cholesterol biosynthesis, thereby maintaining energy homeostasis. Heat shock factor 1 (HSF1) is the master regulator of the evolutionarily conserved proteotoxic stress response (PSR), thereby preserving proteostasis in the face of environmental insults. In contrast to its beneficial role in enhancing survival under proteotoxic stress, it has been demonstrated that HSF1 acts as a potent pro-oncogenic factor. Our previous study has shown that metabolic stressors, via AMPK activation, inactivate HSF1 and disrupt proteostasis to suppress tumor growth. Interestingly, our new study now reveals that HSF1, in reciprocal, also suppresses AMPK activation. HSF1 does so independently of its canonical transcriptional action. Furthermore, Hsf1 deficiency promotes the interactions between AMPK and LKB1, a key upstream kinase activating AMPK. Congruent with the suppression of lipogenesis by AMPK, Hsf1 deficiency depletes cellular lipid content and reduces body fat mass in mice. Importantly, these defects can be largely rescued by either pharmacological or genetic inhibition of AMPK. At the molecular level, Hsf1 deficiency leads to inactivation of acetyl-CoA Carboxylase (ACC) and sterol regulatory element-binding transcription factor 1c (SREBP1c), both of which are key players in de novo lipogenesis. In addition to impaired lipogenesis, Hsf1-deficient cells and mice display reduced cholesterol levels. Of particular interest, this defect leads to impaired cholesteroylation of sonic hedgehog (SHH), the best known signaling molecule undergoing this covalent modification. In consequence, SHH secreted by HSF1-deficient cells are less potent in activating its downstream signaling cascade, indicated by reduced DNA binding of GLI1, a transcription factor responding to activation of SHH signaling. Conversely, HSF1 overexpression increases the lipid content, cholesterol levels and the amount of cholesteroylated SHH proteins in xenografted melanomas. Taken together, our results reveal that HSF1, through AMPK suppression, promotes lipogenesis, cholesterol biosynthesis and protein lipidation, thereby supporting malignant growth. Citation Format: Kuo-Hui Su, Chengkai Dai. HSF1 suppresses AMPK to promote lipogenesis, cholesterol biosynthesis and protein lipidation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1829.

A Regulatory Role of Apoptosis Antagonizing Transcription Factor in the Pathogenesis of Nonalcoholic Fatty Liver Disease and Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is increasing as a cause of liver-related mortality largely because of the growing burden of nonalcoholic steatohepatitis (NASH). The mechanisms of HCC development in nonalcoholic fatty liver disease (NAFLD) are incompletely understood. We initially identified apoptosis antagonizing transcription factor (AATF) to be associated with HCC in a mouse model of NASH that develops HCC without the addition of specific carcinogens. AATF, also called che-1, is a transcriptional factor that is highly conserved among eukaryotes. AATF is known to be a central mediator of the cellular responses as it promotes cell proliferation and survival by inducing cell cycle arrest, autophagy, DNA repair, and inhibition of apoptosis. However, the role of AATF in NASH and HCC remains unknown. Here, we provide evidence for AATF as a contributory factor for HCC in NAFLD. AATF overexpression was further verified in human NASH and HCC and multiple human HCC cell lines. Tumor necrosis factor-α (TNFα), known to be increased in NASH, induced AATF expression. Promoter analysis of AATF revealed a sterol regulatory element binding transcription factor 1-c (SREBP-1c) binding site; inhibition of SREBP-1 by using specific inhibitors as well as small interfering RNA decreased TNFα-induced AATF expression. AATF interacted with signal transducer and activator of transcription 3 to increase monocyte chemoattractant protein-1 expression. AATF knockdown decreased cell proliferation, migration, invasion, colony formation, and anchorage-dependent growth in HCC cell lines. Xenograft of QGY-7703 HCC cells with AATF stably knocked down into nonobese diabetic scid gamma mice demonstrated reduced tumorigenesis and metastases. Conclusion: AATF drives NAFLD and hepatocarcinogenesis, offering a potential target for therapeutic intervention.

Effect of Breed on Transcriptional and Protein Expression of Lipogenic Enzymes in Tail and Subcutaneous Adipose Tissue from Two Grazing Breeds of Lambs.

Simple SummaryAn experiment to determine the effect of sheep breed on subcutaneous fatty acid composition was carried out at the Butalcura Research Station, Chiloé, Chile. To this end, two breeds of lambs were challenged to graze a typical, naturalized pasture of the Chiloé Archipelago, Chile, from 60 d to 120 d after birth. The animals were sacrificed to collect samples from subcutaneous fat (SCF) from the back, and tail fat (TF) to determine the effect of breed on transcriptional expression of lipogenic enzymes and fatty acid profile in these two fat depots. The results showed that although mRNA expression of enzymes was similar in both breeds, there were differences in certain protein levels in the SCF, partially related with the fatty acid profiles, thus affecting the selection of lamb breed either for human consumption or experimental purposes.This experiment was carried out to determine the effect of breed on mRNA and protein expression levels of lipogenic enzymes acetyl-CoA carboxylase α (ACC), fatty acid synthase (FAS), stearoyl-CoA desaturase 1 (SCD1) plus sterol regulatory element binding transcription factor 1c (SREBP1c) in the subcutaneous fat (SCF) from the back of the animal, and tail fat (TF) of both Chilota and Suffolk Down lambs grazing Calafatal. Eight Chilota and six Suffolk Down 2-month-old male lambs were allocated to graze a “Calafatal”, a typical secondary succession of Chiloé Archipelago, Chile. After 62 d, lambs were slaughtered according to Chile’s meat industry standards. Fatty acid profile, RT-qPCR, and Western blot analyses from SCF and TF samples were performed. Although the mRNA expression levels of ACC, FAS, SCD1 and SREBP1c in SCF did not differ significantly between breeds (p > 0.05), a trend to higher mRNA expression of FAS and SREBP1c in TF from Chilota lambs was observed (p = 0.06). On the other hand, FAS levels in SCF were higher in Chilota than in Suffolk Down lambs (p < 0.02), although Suffolk Down showed higher fat contents and saturated fatty acid (SFA) proportions than Chilota lambs (p < 0.01). The FAS protein expression in TF was similar in both breeds (p > 0.05). Although the fat content was higher in Suffolk Down than in Chilota lambs (p < 0.01), the SFA proportions were similar in both breeds. Finally, it can be concluded that although mRNA expression of enzymes was similar in both breeds, there were differences in some protein levels in the SCF, partially related with the fatty acid profiles, thus affecting the selection of lamb breed either for human consumption or experimental purposes.

Regulatory Efficacy of Spirulina platensis Protease Hydrolyzate on Lipid Metabolism and Gut Microbiota in High-Fat Diet-Fed Rats.

Lipid metabolism disorder (LMD) is a public health issue. Spirulina platensis is a widely used natural weight-reducing agent and Spirulina platensis is a kind of protein source. In the present study, we aimed to evaluate the effect of Spirulina platensis protease hydrolyzate (SPPH) on the lipid metabolism and gut microbiota in high-fat diet (HFD)-fed rats. Our study showed that SPPH decreased the levels of triglyceride (TG), total cholesterol (TC), low-density-lipoprotein cholesterol (LDL-c), alanine transaminase (ALT), and aspartate transaminase (AST), but increased the level of high-density-lipoprotein cholesterol (HDL-c) in serum and liver. Moreover, SPPH had a hypolipidemic effect as indicated by the down-regulation of sterol regulatory element-binding transcription factor-1c (SREBP-1c), acetyl CoA carboxylase (ACC), SREBP-1c, and peroxisome proliferator-activated receptor-γ (PPARγ) and the up-regulation of adenosine 5’-monophosphate (AMP)-activated protein kinase (AMPK) and peroxisome proliferator-activated receptorα (PPARα) at the mRNA level in liver. SPPH treatment enriched the abundance of beneficial bacteria. In conclusion, our study showed that SPPH might be produce glucose metabolic benefits in rats with diet-induced LMD. The mechanisms underlying the beneficial effects of SPPH on the metabolism remain to be further investigated. Collectively, the above-mentioned findings illustrate that Spirulina platensis peptides have the potential to ameliorate lipid metabolic disorders, and our data provides evidence that SPPH might be used as an adjuvant therapy and functional food in obese and diabetic individuals.

Effect of Marine Microalga Chlorella pyrenoidosa Ethanol Extract on Lipid Metabolism and Gut Microbiota Composition in High-Fat Diet-Fed Rats.

Effects of marine microalga Chlorella pyrenoidosa 55% ethanol extract (CPE55) on lipid metabolism, gut microbiota and regulation mechanism in high fat diet-fed induced hyperlipidaemia rats were investigated. Structure characterizations of major compounds in CPE55 were determined by ultra-performance liquid chromatography-quadrupole/time of flight mass spectrometry (UPLC-Q-TOF-MS/MS). The compositions of gut microbiota in rats were analyzed by high-throughput next-generation 16S rRNA gene sequencing. Oral administration with CPE55 markedly alleviated dyslipidemia through improving adverse blood lipid profile and inhibiting hepatic lipid accumulation and steatosis. CPE55 has downregulated the gene expression levels of acetyl CoA carboxylase, sterol regulatory element-binding transcription factor-1c, and 3-hydroxy-3-methyl glutaryl coenzyme A reductase and upregulated adenosine 5′-monophosphate-activated protein kinase-α. It has also improved the abundance of bacteria Alistipes, Prevotella, Alloprevotella, and Ruminococcus1 and decreased the abundances of Turicibacter and Lachnospira. Turicibacter and Lachnospira were both positive correlations of metabolic phenotypes. The findings above illustrated that CPE55 might be developed as food ingredients to ameliorate lipid metabolic disorders and hyperlipidaemia.

Pistachio Consumption Prevents and Improves Lipid Dysmetabolism by Reducing the Lipid Metabolizing Gene Expression in Diet-Induced Obese Mice.

Pistachios contain beneficial substances such as unsaturated fatty acids, phytosterols, and polyphenols. In the present study, we investigated if pistachio consumption is able to prevent or to revert hyperglycemia, dyslipidemia, hepatic steatosis, and adipose tissue morphological alterations caused by high fat diet (HFD) in the mouse. Moreover, the impact of pistachio intake on the mRNA expression of peroxisome proliferator-activated receptor γ (PPAR-γ), fatty acid transport proteins (FAT-P), fatty acid synthase (FAS), stearoyl-CoA desaturase (SCD1), and sterol regulatory element-binding transcription factor-1c (SREBP-1c) in liver and adipose tissue was also analyzed. No change in body weight, food intake, and hyperglycemia was observed between mice consuming pistachios (HFD-P) and HFD mice. Pistachio intake was able to prevent but not to reverse HFD-induced hypertriglyceridemia. Cholesterol plasma levels, steatosis grading, body fat mass, and adipocyte size were significantly lower in HFD-P group compared to HFD in both prevention and reversal protocol. Pistachio-diet was able to prevent HFD-induced overexpression of PPAR-γ, FAS, and SCD1 in the liver and SREBP-1c, PPAR-γ, and FAT-P in adipose tissue. Similarly, HFD-P significantly ameliorated the expression levels of FAT-P and SCD1 in the liver and SREBP-1c, FAS, and SCD1 in adipose tissue of obese mice. The present study shows that pistachio consumption is able to prevent and to ameliorate obesity-related dysfunctions by positively modulating the expression of genes linked to lipid metabolism.