Sterol Regulatory Element-binding Protein-1c Research Articles

Antiobesity Effects of Lactobacillus paracasei Subsp. paracasei, L. casei 431 on High-Fat Diet-Induced Obese Rats.

Obesity is currently regarded as a global concern, and the key objectives of the global health strategy include its prevention and control. Probiotic supplementation can help achieve these objectives. This study aimed to assess whether a probiotic strain Lactobacillus paracasei ssp. paracasei, Lactobacillus casei 431 (henceforth, L. casei 431) possesses antiobesogenic properties. High-fat diet-induced obese Sprague-Dawley rats were treated with L. casei 431 for 10 weeks, and the outcomes were compared with those of rats treated with the antiobesity medication orlistat. Body weights, epididymal fat, and tissues from mice were assessed. Furthermore, serological and histological analyses were performed. Epididymal fat accumulation was significantly reduced in groups administered L. casei 431 and orlistat. Furthermore, L. casei 431 and orlistat treatments lowered serum alanine transaminase, aspartate aminotransferase, and triglyceride (TG) levels. Hematoxylin and eosin staining of the liver and epididymal adipose tissues showed that the L. casei 431-treated groups exhibited reduced lipid buildup and adipocyte size. Furthermore, sterol regulatory element-binding protein 1c, adipose TG lipase, and lipoprotein lipase messenger RNA (mRNA) levels were upregulated, leading to lipid oxidation and degradation, in L. casei 431-supplemented groups. Furthermore, carnitine palmitoyltransferase 1, a major factor in lipolysis, was consistently upregulated at the protein level after L. casei 431 administration. Collectively, these results demonstrate the potential of L. casei 431 in alleviating obesity in rats through optimizing lipid metabolism and some related biomarkers.

Patulin alleviates hepatic lipid accumulation by regulating lipogenesis and mitochondrial respiration

AimsThe aim of this study is to evaluate the effects of patulin on hepatic lipid metabolism and mitochondrial oxidative function and elucidate the underlying molecular mechanisms. Main methodsThe effects of patulin on hepatic lipid accumulation were evaluated in free fatty acid-treated AML12 or HepG2 cells through oil red O staining, triglyceride assay, real-time polymerase chain reaction, and western blotting. Alteration of mitochondrial oxidative capacity by patulin treatment was determined using Seahorse analysis to measure the oxygen consumption rate. Key findingsThe increased amounts of lipid droplets induced by free fatty acids were significantly reduced by patulin treatment. Patulin markedly activated the CaMKII/AMP-activated protein kinase (AMPK)/proliferator-activated receptor-γ coactivator (PGC)-1α signaling pathway in hepatocytes, reduced the expression of sterol regulatory element binding protein 1c (SREBP-1c) and lipogenic genes, and increased the expression of genes related to mitochondrial fatty acid oxidation. In addition, patulin treatment enhanced the mitochondrial consumption rate and increased the expression of mitochondrial oxidative phosphorylation proteins in HepG2 hepatocytes. The effects of patulin on anti-lipid accumulation; SREBP-1c, PGC-1α, and carnitine palmitoyltransferase 1 expression; and mitochondrial oxidative capacity were significantly prevented by compound C, an AMPK inhibitor. SignificancePatulin is a potent inducer of the AMPK pathway, and AMPK-mediated mitochondrial activation is required for the efficacy of patulin to inhibit hepatic lipid accumulation. This study is the first to report that patulin is a promising bioactive compound that prevents the development and worsening of fatty liver diseases, including non-alcoholic fatty liver disease, by improving mitochondrial quality and lipid metabolism.

AdipoRon alleviates fatty acid–induced lipid accumulation and mitochondrial dysfunction in bovine hepatocytes by promoting autophagy

During the transition period in dairy cows, high circulating concentrations of nonesterified fatty acids (NEFA) increase hepatic lipid deposits and are considered a major pathological factor for liver damage. We investigated whether AdipoRon, a synthetic small-molecule agonist of adiponectin receptors 1 and 2 shown to prevent liver lipid accumulation in nonruminants, could alleviate NEFA-induced lipid accumulation and mitochondrial dysfunction. Bovine hepatocytes were isolated from 5 healthy Holstein female newborn calves (1 d of age, 30-40 kg, fasting), and independently isolated hepatocytes from at least 3 different calves were used for each subsequent experiment. The composition and concentration of NEFA used in this study were selected according to hematological criteria of dairy cows with fatty liver or ketosis. First, hepatocytes were cultured with various concentrations of NEFA (0, 0.6, 1.2, or 2.4 mM) for 12 h. In a second experiment, hepatocytes were treated with AdipoRon at different concentrations (0, 5, 25, or 50 μM for 12 h) and times (25 μM for 0, 6, 12, or 24 h) with or without NEFA (1.2 mM) treatment. In the last experiment, hepatocytes were treated with AdipoRon (25 μM), NEFA (1.2 mM), or both for 12 h after treatment with or without the autophagy inhibitor chloroquine. Hepatocytes treated with NEFA had increased protein abundance of sterol regulatory element-binding protein 1c (SREBP-1c) and mRNA abundance of acetyl-CoA carboxylase 1 (ACACA), and decreased protein abundance of peroxisome proliferator-activated receptor α (PPARA), proliferator-activated receptor gamma coactivator-1 α (PGC-1α), mitofusin 2 (MFN2), cytochrome c oxidase subunit IV (COX IV), and mRNA abundance of carnitine palmitoyltransferase 1A (CPT1A), along with lower ATP concentrations. AdipoRon treatment reversed these effects, suggesting this compound had a positive effect on lipid metabolism and mitochondrial dysfunction during the NEFA challenge. In addition, upregulated expression of microtubule-associated protein 1 light chain 3-II (LC3-II, encoded by MAP1LC3) and downregulated expression of sequestosome-1 (SQSTM1, also called p62) indicated that AdipoRon enhanced autophagic activity in hepatocytes. The fact that chloroquine impeded the beneficial effects of AdipoRon on lipid accumulation and mitochondrial dysfunction suggested a direct role for autophagy during NEFA challenge. Our results suggest that autophagy is an important cellular mechanism to prevent NEFA-induced lipid accumulation and mitochondrial dysfunction in bovine hepatocytes, which is consistent with other studies. Overall, AdipoRon may represent a promising therapeutic agent to maintain hepatic lipid homeostasis and mitochondrial function in dairy cows during the transition period.

Diosgenin attenuates nonalcoholic hepatic steatosis through the hepatic FXR-SHP-SREBP1C/PPARα/CD36 pathway

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide and has no approved treatment. The hepatic farnesoid X receptor (FXR) is one of the most promising therapeutic targets for NAFLD. Diosgenin (DG), a natural compound extracted from Chinese herbal medicine, is very effective in preventing metabolic diseases. Our research aims to determine the effects and molecular mechanisms of DG on NAFLD in vivo and in vitro. The effect of DG on hepatic steatosis was evaluated in Sprague‒Dawley (SD) rats induced by a high-fat diet (HFD) and in HepG2 cells exposed to free fatty acids (FFAs, sodium oleate:sodium palmitate = 2:1). DG treatment efficiently managed hepatic lipid deposition in vivo and in vitro. Mechanistically, DG upregulated the expression of FXR and small heterodimer partner (SHP) and downregulated the expression of genes involved in hepatic de novo lipogenesis (DNL), including sterol regulatory element-binding protein 1C (SREBP1C), acetyl-CoA carboxylase 1 (ACC1), and fatty acid synthase (FASN). Moreover, DG promoted the expression of peroxisome proliferator-activated receptor alpha (PPARα), which is related to fatty acid oxidation. In addition, DG inhibited the expression of the CD36 molecule (CD36) related to fatty acid uptake. However, hepatic FXR silencing weakened the regulatory effects of DG on these genes. Collectively, our data show that DG has a good effect on alleviating nonalcoholic hepatic steatosis via the hepatic FXR-SHP-SREBP1C/PPARα/CD36 pathway. DG promises to be a novel candidate FXR activator that can be utilized to treat NAFLD.

Effect of Roselle Flower Extract (Hibiscus sabdariffa Linn.) on Reducing Steatosis and Steatohepatitis in Vitamin B12 Deficiency Rat Model.

Background and Objectives: Non-alcoholic Fatty Liver Disease (NAFLD) can occur as a result of micronutrient deficiencies. Hibiscus sabdarifa, a plant used in traditional medicine, contains ingredients that can help prevent this process. This study looked at the potency of Hibiscus sabdariffa Ethanol Extract (HSE) to prevent homocysteine-induced liver damage in animals that were deficient in vitamin B12. Materials and Methods: A comparative study of the effects of roselle extract is presented in an experimental design. Thirty Sprague-Dawley rats were divided into six groups using randomization. To demonstrate the absence of liver damage in the experimental animals under normal conditions, a control group was fed a normal diet without HSE. For the induction of liver damage in the experimental animals, the vitamin B12-restricted group was administered a vitamin B12-restricted diet. To test the effect of HSE on liver damage, the treatment group was given HSE along with a vitamin B12-restricted diet. Each group was given two treatment periods of eight and sixteen weeks. These results were compared with the results of the parameter examination between the vitamin B12 restriction group, with and without HSE, using an ANOVA statistic. The data were analyzed with licensed SPSS 20.0 software. Results: HSE significantly increased the blood levels of vitamin B12 while lowering homocysteine levels. The administration of HSE reduced liver damage based on the activity of liver function enzymes in the plasma due to a limitation of vitamin B12. HSE decreased Sterol Regulatory Element-Binding Protein-1c (SREBP1c) and Nuclear Factor Kappa B (NFkB) protein expressions in the liver tissue, but did not decrease Glucose-Regulated Protein 78 (GRP78) protein expression. Significantly, the levels of Tumor Necrosis Factor alpha (TNF-a) and IL-6 in the liver tissue were lower, while the levels of IL-10 and Nuclear factor-erythroid-2 Related Factor 2 (NRF2) were higher with HSE administration. HSE produced a better histopathological profile of the Hematoxylin and Eosin (H&E)-Masson tricrome for inflammation, fat and fibrosis in the liver. Conclusions: In this study, HSE was found to slow the development of liver damage in experimental animals that were given a vitamin B12-deficient diet.

Vitamin D3 alleviates nonalcoholic fatty liver disease in rats by inhibiting hepatic oxidative stress and inflammation via the SREBP-1-c/ PPARα-NF-κB/IR-S2 signaling pathway.

Introduction: Nonalcoholic fatty liver disease (NAFLD) is a chronic disease characterized by fat deposits in liver cells, which can lead to hepatitis and fibrosis. This study attempted to explore the protective effect of vitamin D3 (VitD) against NAFLD. Methods: Adult male albino rats were randomized into four separate groups: the negative control group was fed a standard rat chow; the positive group received a high-fat diet (20%) and 25% fructose water (NAFLD); the VitD control group was intramuscularly treated with VitD (1,000 IU/kg BW) 3days per week for 10 weeks; and the NAFLD group was treated with VitD therapy. Biochemical and hepatic histological analyses were performed. Hepatic oxidative stress and inflammatory conditions were also studied. Hepatic expression of sterol regulatory element-binding protein 1-c (SREBP-1-c), peroxisome proliferator-activated receptor alpha (PPAR-α), and insulin receptor substrate-2 was analyzed by quantitative real-time polymerase chain reaction. Results and discussion: The NAFLD rats exhibited elevated terminal body weight, hepatic injury markers, dyslipidemia, glucose intolerance, and insulin resistance. Moreover, the NAFLD rats had increased SREBP-1-c expression and reduced PPAR-α and IRS-2 expressions. Histological analysis showed hepatic steatosis and inflammation in the NAFLD group. In contrast, VitD administration improved the serum biochemical parameters and hepatic redox status in NAFLD rats. Also, VitD treatment ameliorated hepatic inflammation and steatosis in the NAFLD group by decreasing the expression of SREBP-1-c and increasing the expression of PPAR-α. Overall, these results suggest that VitD could have a protective effect against NAFLD and its associated complication.

Green Tea and Java Pepper Mixture Prevents Obesity by Increasing Energy Expenditure and Modulating Hepatic AMPK/MicroRNA-34a/370 Pathway in High-Fat Diet-Fed Rats.

This study was performed to evaluate the anti-obesity effects of green tea and java pepper mixture (GJ) on energy expenditure and understand the regulatory mechanisms of AMP-activated protein kinase (AMPK), microRNA (miR)-34a, and miR-370 pathways in the liver. Sprague-Dawley rats were divided into four groups depending on the following diets given for 14 weeks: normal chow diet (NR), 45% high-fat diet (HF), HF + 0.1% GJ (GJL), and HF + 0.2% GJ (GJH). The results revealed that GJ supplementation reduced body weight and hepatic fat accumulation, improved serum lipids, and increased energy expenditure. In the GJ-supplemented groups, the mRNA levels of genes related to fatty acid syntheses, such as a cluster of differentiation 36 (CD36), sterol regulatory element binding protein-1c (SREBP-1c), fatty acid synthase (FAS), and stearoyl-CoA desaturase 1 (SCD1) were downregulated, and mRNA levels of peroxisome proliferator-activated receptor alpha (PPARα), carnitine/palmitoyl-transferase 1 (CPT1), and uncoupling protein 2 (UCP2), which participate in fatty acid oxidation, were upregulated in the liver. GJ increased the AMPK activity and decreased the miR-34a and miR-370 expression. Therefore, GJ prevented obesity by increasing energy expenditure and regulating hepatic fatty acid synthesis and oxidation, suggesting that GJ is partially regulated through AMPK, miR-34a, and miR-370 pathways in the liver.

Principal component analysis of adipose tissue gene expression of lipogenic and adipogenic factors in obesity

ObjectiveA better understanding of mechanisms regulating lipogenesis and adipogenesis is needed to overcome the obesity pandemic. We aimed to study the relationship of the transcript levels of peroxisome proliferator activator receptor γ (PPARγ), CCAAT/enhancer-binding protein alpha (C/EBP-α), liver X receptor (LXR), sterol regulatory element-binding protein-1c (SREBP-1c), fatty acid synthase (FAS), and acetyl-CoA carboxylase (ACC) in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) from obese and normal-weight women with a variety of anthropometric indices, metabolic and biochemical parameters, and insulin resistance.MethodsReal‐time PCR was done to evaluate the transcript levels of the above‐mentioned genes in VAT and SAT from all participants.ResultsUsing principal component analysis (PCA) results, two significant principal components were identified for adipogenic and lipogenic genes in SAT (SPC1 and SPC2) and VAT (VPC1 and VPC2). SPC1 was characterized by relatively high transcript levels of SREBP1c, PPARγ, FAS, and ACC. However, the second pattern (SPC2) was associated with C/EBPα and LXR α mRNA expression. VPC1 was characterized by transcript levels of SREBP1c, FAS, and ACC. However, the VPC2 was characterized by transcript levels of C/EBPα, LXR α, and PPARγ. Pearson’s correlation analysis showed that unlike SPC2, which disclosed an inverse correlation with body mass index, waist and hip circumference, waist to height ratio, visceral adiposity index, HOMA-IR, conicity index, lipid accumulation product, and weight-adjusted waist index, the VPC1 was positively correlated with above-mentioned obesity indices.ConclusionThis study provided valuable data on multiple patterns for adipogenic and lipogenic genes in adipose tissues in association with a variety of anthropometric indices in obese subjects predicting adipose tissue dysfunction and lipid accumulation.

MiR-363-3p/PTEN is involved in the regulation of lipid metabolism by genistein in HepG2 cells via ERβ

BackgroundGenistein (GEN) is one of the most well-known phytoestrogens identified in various legumes. Although increasing evidence shows GEN has a potential use in phytotherapy to regulate lipid metabolism, its therapeutic mechanisms have not yet been completely elucidated, especially epigenetic alterations of miRNAs to alleviate lipid accumulation in the liver remains unknown. PurposeTo clarify how GEN modulates the miRNA profile in HepG2 cells and investigate molecular mechanisms of the modulated miRNA on regulating hepatic lipid metabolism. MethodsThe miRNA microarray was performed to compare the miRNAs expression patterns, followed by determining principal miRNA and its target gene associated with hepatic lipid metabolism modulated by GEN. miR-363-3p mimics (mi) and phosphatase and tensin homolog (PTEN)-siRNA were transfected into HepG2 cells and GEN was further treated with the cells for 24 h ResultsGEN induced downregulation of miR-363-3p and upregulation of PTEN, which was a target mRNA of miR-363-3p. The miR-363-3p mi led to an upregulation of sterol-regulatory element-binding protein-1c (SREBP-1c) and its downstream lipid synthesis-related factors in HepG2 cells. In addition, the inhibition of PTEN led to an increase of lipogenesis, which was associated with the AKT/mTOR signal regulation. However, GEN treatment could abrogate the lipogenic effects of miR-363-3p mi or PTEN siRNA. The modulation was associated with estrogen receptor β (ERβ). ConclusionWe discerned a new mechanism that GEN regulated hepatic lipid metabolism by inhibiting miR-363-3p, which could be mediated via ERβ and by targeting PTEN in HepG2 cells. Additionally, GEN reduced hepatic lipid accumulation by regulating PTEN-AKT/mTOR signal. It implicated a protective role of GEN by elucidating its epigenetic modification of the miRNA modulated by ERβ on improving hepatic lipid metabolism and provided novel evidence of the mechanism on targeting miR-363-3p/PTEN in treating hepatic lipid disorders.

Quantitative analysis and hepatoprotective mechanism of Cistanche deserticola Y. C. Ma against alcohol-induced liver injury in mice

Cistanche deserticola Y. C. Ma (CD), known as “desert ginseng”, has been found to have hepatoprotective effect. This research aimed to investigate the quality control and its alleviating effect on alcoholic liver injury in mice. In this study, for the first time, a sensitive and efficient ultra-high-performance liquid chromatography with quadrupole ion-trap mass spectrometry (UPLC-Q-TRAP/MS) method was developed to rapidly characterize nine representative phenylethanoid glycosides (PhGs) in the CD extract within 14 min, offering a reference for the quality control standard of this plant. In addition, we found that the CD extract significantly inhibited the weight loss, decreased the liver index, and attenuated excessive lipid deposition, inflammatory and oxidative stress in the mice liver. With the help of the high-throughput lipidomics technique, we discovered that CD markedly reversed 17 lipid metabolites and their involved linoleic acid, arachidonic acid and glycerophospholipid metabolic pathways. As these metabolites are mainly associated with lipid metabolism and liver damage, we further used molecular biological tests to found that CD could regulate the upstream genes and proteins of the lipid metabolism pathway, including adenosine 5′-monophosphate-activated protein kinase (AMPK), sterol regulatory element binding protein-1c (SREBP-1c), fatty acid synthase (FAS), and peroxidase proliferators activate receptors α (PPARα). In conclusion, this study elucidates the modulatory effects of CD on lipid metabolism disorders in alcoholic fatty liver from holistic system and provides a reference for further research and development of CD as a therapeutic agent.

HM-chromanone suppresses lipid accumulation by modulating AMPK/SREBP-1c pathway in ob/ob mice

This study investigated whether HM-chromanone, a bioactive compound isolated from Portulaca oleracea L., inhibits lipid accumulation in adipose tissue and liver of C57BL/6J ob/ob mice. C57BL/6J mice were used for the normal group and C57BL/6J ob/ob mice were randomly divided into three groups: ob/ob, metformin and HM-chromanone. In the HM-chromanone group, body and liver weight, fat mass and fat size were significantly lower than that in the ob/ob group. The HM-chromanone group also showed lower serum lipid levels and hepatic lipid accumulation compared with the ob/ob group. HM-chromanone administration significantly activated adenosine monophosphate-activated protein kinase (AMPK) and inhibited sterol regulatory element binding protein-1c (SREBP-1c), peroxisome proliferator-activated receptor γ (PPARγ), CCAAT/enhancer binding protein α (C/EBPα), fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC) in adipose tissue and liver. These results suggest that HM-chromanone potentially suppresses lipid accumulation by modulating AMPK/SREBP-1c pathway in adipose tissue and liver of ob/ob mice.

Quinoa and Chia Modulate AMPK/PPAR-ɣ Signaling in High-Fat Diet–Induced Obesity Rat Model

Obesity is one of the principal reasons behind a wide range of metabolic diseases and dramatic health complications. Recent studies shed the light on chia (Salvia hispanica L., Lamiaceae) and quinoa (Chenopodium quinoa Willd., Amaranthaceae) seeds and identified them as products of utmost health benefits. The present study was designed to explore the molecular mechanisms of the hydroalcoholic extract of those seeds in weight management. Rats were divided randomly into two main groups: control and treated. The control groups received regular chow diet, high-fat diet, and green tea. The treated groups received high-fat diet and chia or quinoa extracts. Results revealed that the seeds showed hepatoprotective effects and anti-inflammatory and antioxidant activities, and modulated leptin, adiponectin, serum lipid, and glycemic profiles. Effects are further consolidated by normal hepatic tissue architecture upon histopathological examination. Moreover, modulation of peroxisome proliferator-activated receptors-γ transcriptional activity via activation of 5′AMP-activated protein kinase and suppression of nuclear expression of sterol regulatory element-binding protein-1c in obese rats as compared to green tea were demonstrated. Characterization of the major secondary bioactive metabolites was done using HPLC/PDA/ESI-MS/MS. Our study advocates evidence-based study on nutrition and health claims on the use of chia and quinoa extracts as nutraceutical supplements for promoting weight wellness and alleviating its related metabolic disorders.

Healthy regulation of Tibetan Brassica rapa L. polysaccharides on alleviating hyperlipidemia: A rodent study

Hyperlipidemia is a common metabolic disorder, which can lead to obesity, hypertension, diabetes, atherosclerosis and other diseases. Studies have shown that polysaccharides absorbed by the intestinal tract can regulate blood lipids and facilitate the growth of intestinal flora. This article aims to investigate whether Tibetan turnip polysaccharide (TTP) plays a protective role in blood lipid and intestinal health via hepatic and intestinal axes. Here we show that TTP helps to reduce the size of adipocytes and the accumulation of liver fat, playing a dose-dependent effect on ADPN levels, suggesting an effect on lipid metabolism regulation. Meantime, TTP intervention results in the downregulation of intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and serum inflammatory factors (interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α)), implying that TTP suppresses the progression of inflammation in the body. The expression of key enzymes associated with cholesterol and triglyceride synthesis, such as 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), cholesterol 7α-hydroxylase (CYP7A1), peroxisome proliferator-activated receptors γ (PPARγ), acetyl-CoA carboxylase (ACC), fatty acid synthetase (FAS) and sterol-regulatory element binding proteins-1c (SREBP-1c), can be modulated by TTP. Furthermore, TTP also alleviates the damage to intestinal tissues caused by high-fat diet, restores the integrity of the intestinal barrier, improves the composition and abundance of the intestinal flora and increases the levels of SCFAs. This study provides a theoretical basis for the regulation of body rhythm by functional foods and potential intervention in patients with hyperlipidemia.

Resveratrol protects against postmenopausal atherosclerosis progression through reducing PCSK9 expression via the regulation of the ERα-mediated signaling pathway

Elevated circulating proprotein convertase subtilisin/kexin 9 (PCSK9) levels are an important contributor to postmenopausal atherosclerosis (AS). We have previously reported that resveratrol (RSV), as a phytoestrogen, reduces hepatocyte steatosis and PCSK9 expression in L02 cells. This study aimed to investigate how RSV reduces PCSK9 expression to inhibit postmenopausal AS progression. Here, we found that treatment of Ovx/ApoE −/− mice with RSV significantly reduced dyslipidemia, plasma PCSK9 concentration and aortic plaque area. In addition, RSV significantly inhibited liver fat accumulation and improved the hepatocyte ultrastructure. Further studies showed that RSV upregulated estrogen receptor α (ERα) expression, while reduced the liver X receptor α (LXRα) expression and sterol regulatory-element-binding protein-1c (SREBP-1c) transcriptional activity. In vitro, RSV inhibited insulin-induced elevated intracellular/extracellular PCSK9 levels, enhanced receptor-mediated uptake of low-density lipoproteins in HepG2 cells. Furthermore, RSV attenuated the activity of the SRE-dependent PCSK9 promoter. However, these effects can be partially reversed by the antiestrogen ICI 182,780. Attenuation of these changes with ERα inhibition suggest that RSV may prevent the progression of postmenopausal AS by reducing PCSK9 expression in hepatocytes through ERα-mediated signaling.

CM3-SII polysaccharide obtained from Cordyceps militaris ameliorates hyperlipidemia in heterozygous LDLR-deficient hamsters by modulating gut microbiota and NPC1L1 and PPARα levels

Accumulating evidence has demonstrated that polysaccharides derived from edible fungi have lipid-lowering effects in mice. However, the lipid metabolism mechanisms in mice and humans are different. We have previously elucidated the structural characteristics of the alkali-extracted polysaccharide CM3-SII obtained from Cordyceps militaris. This study aimed to investigate whether CM3-SII could ameliorate hyperlipidemia in a heterozygous low-density lipoprotein receptor (LDLR)-deficient hamster model of hyperlipidemia. Our data demonstrated that CM3-SII significantly decreased total plasma cholesterol, non-high-density lipoprotein cholesterol, and triglyceride levels in heterozygous LDLR-deficient hamsters. Unlike ezetimibe, CM3-SII could enhance the concentration of plasma apolipoprotein A1 and the expression of liver X receptor α/ATP-binding cassette transporter G8 mRNA pathway and suppress the expression of Niemann-Pick C1-like 1, which help to reduce cholesterol levels further. Moreover, the results of molecular docking analysis demonstrated that CM3-SII could directly bind to Niemann-Pick C1-like 1 with high affinity. The triglyceride-lowering mechanisms of CM3-SII were related to its downregulation of sterol regulatory element-binding protein 1c and upregulation of peroxisome proliferator-activated receptor α. Importantly, CM3-SII increased the abundance of Actinobacteria and Faecalibaculum and the ratio of Bacteroidetes/Firmicutes. Thus, CM3-SII attenuated hyperlipidemia by modulating the expression of multiple molecules involved in lipid metabolism and the gut microbiota.

Uncarboxylated Osteocalcin Decreases SCD1 by Activating AMPK to Alleviate Hepatocyte Lipid Accumulation

Uncarboxylated osteocalcin (GluOC), a small-molecule protein specifically synthesized and secreted by osteoblasts, is important in the regulation of energy metabolism. In our previous study, GluOC was shown to be effective in ameliorating dyslipidemia and hepatic steatosis in KKAy mice. However, the underlying mechanism of GluOC action on hepatocytes has not been well validated. In this study, oleic acid/palmitic acid (OA/PA)-induced HepG2 and NCTC 1469 cells were used as non-alcoholic fatty liver disease (NAFLD) cell models, and triacylglycerol (TG) levels were measured by oil red O staining, Nile Red staining, and ELISA. The fatty acid synthesis-related protein expression was detected by real-time quantitative polymerase chain reaction, Western blotting, and immunofluorescence. The results show that GluOC reduced triglyceride levels, and decreased the expression of sterol regulatory element-binding protein-1c (SREBP-1c) and stearyl-coenzyme A desaturase 1 (SCD1). si-SCD1 mimicked the lipid accumulation-reducing effect of GluOC, while overexpression of SCD1 attenuated the effect of GluOC. In addition, GluOC activated AMP-activated protein kinase (AMPK) phosphorylation to affect lipid metabolism in hepatocytes. Overall, the results of this study suggest that GluOC decreases SCD1 by activating AMPK to alleviate hepatocyte lipid accumulation, which provides a new target for improving NAFLD in further research.

Regulation of NOX/p38 MAPK/PPARα pathways and miR-155 expression by boswellic acids reduces hepatic injury in experimentally-induced alcoholic liver disease mouse model: novel mechanistic insight

Alcoholic liver disease (ALD) refers to hepatic ailments induced by excessive alcohol intake. The pathogenesis of ALD comprises a complex interplay between various mechanistic pathways, among which inflammation and oxidative stress are key players. Boswellic acids (BAs), found in Boswellia serrata, have shown hepatoprotective effects owing to their antioxidant and anti-inflammatory activities, nevertheless, their therapeutic potential against ALD has not been previously investigated. Hence, this study was performed to depict the possible protective effect of BAs and detect their underlying mechanism of action in an experimentally-induced ALD mouse model. Male BALB/c mice were equally categorized into six groups: control, BAs-treated, ALD, and ALD that received BAs at three-dose levels (125, 250, and 500 mg/kg) by oral gavage for 14 days. Results showed that the high dose of BAs had the most protective impact against ALD according to histopathology examination, blood alcohol concentration (BAC), and liver function enzymes. Mechanistic investigations revealed that BAs (500 mg/kg) caused a significant decrease in cytochrome P450 2E1(CYP2E1), nicotine adenine dinucleotide phosphate oxidase (NOX) 1/2/4, p38 mitogen-activated protein kinase (MAPK), and sterol regulatory element-binding protein-1c (SREBP-1c) levels, and the expression of miR-155, yet increased peroxisome proliferator-activated receptor alpha (PPARα) levels. This led to an improvement in lipid profile and reduced hepatic inflammation, oxidative stress, and apoptosis indices. In summary, our study concludes that BAs can protect against ethanol-induced hepatic injury, via modulating NOX/p38 MAPK/PPARα pathways and miR-155 expression.

Comparative transcriptomic analysis of mammary gland tissues reveals the critical role of GPR110 in palmitic acid-stimulated milk protein and fat synthesis.

The G protein-coupled receptors (GPCR) sensing nutritional signals (amino acids, fatty acids, glucose, etc.) are not fully understood. In this research, we used transcriptome sequencing to analyse differentially expressed genes (DEG) in mouse mammary gland tissues at puberty, lactation and involution stages, in which eight GPCR were selected out and verified by qRT-PCR assay. It was further identified the role of GPR110-mediating nutrients including palmitic acid (PA) and methionine (Met) to improve milk synthesis using mouse mammary epithelial cell line HC11. PA but not Met affected GPR110 expression in a dose-dependent manner. GPR110 knockdown decreased milk protein and fat synthesis and cell proliferation and blocked the stimulation of PA on mechanistic target of rapamycin (mTOR) phosphorylation and sterol-regulatory element binding protein 1c (SREBP-1c) expression. In summary, these experimental results disclose DEG related to lactation and reveal that GPR110 mediates PA to activate the mTOR and SREBP-1c pathways to promote milk protein and fat synthesis.

Subcritical water extraction of Gracilaria chorda abbreviates lipid accumulation and obesity-induced inflammation

Obesity-induced inflammation is crucial in the pathogenesis of insulin resistance and type 2 diabetes. In this study, we investigated the effects of the Gracilaria chorda (GC) on lipid accumulation and obesity-induced inflammatory changes or glucose homeostasis in cell models (3T3-L1 adipocytes and RAW 264.7 macrophages). Samples of GC were extracted using solvents (water, methanol, and ethanol) and subcritical water (SW) at different temperatures (90, 150, and 210°C). The total phenolic content of GCSW extract at 210°C (GCSW210) showed the highest content compared to others, and GCSW210 highly inhibited lipid accumulation and significantly reduced gene expressions of peroxisome proliferatoractivated receptor-γ, CCAAT/enhancer-binding protein-α, sterol regulatory element-binding protein-1c, and fatty acid synthase in 3T3-L1 adipocytes. In addition, GCSW210 effectively downregulated the pro-inflammatory cytokine regulator pathways in RAW 264.7 macrophages, including mitogen-activated protein kinase, signal transducers and activators of transcription and nuclear factor-κB. In co-culture of 3T3-L1 adipocytes and RAW 264.7 macrophages, GCSW210 significantly reduced nitric oxide production and interleukin-6 levels, and improved glucose uptake with dose-dependent manner. These findings suggest that GCSW210 improves glucose metabolism by attenuating obesity-induced inflammation in adipocytes, which may be used as a possible treatment option for managing obesity and associated metabolic disorders.

Mulberry leaf extract reduces abdominal fat deposition via adenosine-activated protein kinase/sterol regulatory element binding protein-1c/acetyl-CoA carboxylase signaling pathway in female Arbor Acre broilers

This experiment was carried out to investigate the mechanism of action of mulberry leaf extract (MLE) in reducing abdominal fat accumulation in female broilers. A total of 192 one-day-old female Arbor Acres (AA) broilers were divided into 4 diet groups, with each group consisting of 8 replicates with 6 birds per replicate. The diets contained a basal diet and 3 test diets with supplementation of 400, 800, or 1,200 MLE mg/kg, respectively. The trial had 2 phases that lasted from 1 to 21 d and from 22 to 56 d, respectively. The growth performance, abdominal fat deposition, fatty acid composition, serum biochemistry and mRNA expression of genes related to fat metabolism in liver were determined. The results showed that, 1) dietary supplementation with MLE had no significant impact on broilers final body weight, average daily gain (ADG), or feed to gain ration (F/G) (P > 0.05), but linearly reduced abdominal fat accumulation in both experimental phases (P < 0.05); 2) the total contents of monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA), such as palmitoleic acid, oleic acid, and eicosadienoic acid, were increased quadratically as a result of dietary supplements of 400, 800, and 1,200 mg/kg MLE (P < 0.01), while the total contents of saturated fatty acids (SFA), such as teracosanoic acid were decreased (P < 0.01); 3) the addition of 800 or 1,200 MLE mg/kg to the diet linearly reduced total cholesterol (TC) in the serum and liver (P < 0.05). Adenosine-activated protein kinase (AMPK) mRNA expression in the liver was quadratically increased by the addition of 800 or 1,200 MLE mg/kg to the diet (P < 0.05), and the mRNA expression of sterol regulatory element binding protein-1c (SREBP-1c), acetyl-CoA carboxylase (ACC), and acetyl-CoA carboxylate), fatty acid synthase (FAS) were linearly decreased (P < 0.05). In conclusion, MLE can be employed as a viable fat loss feed supplement in fast-growing broiler diets since it reduces abdominal fat deposition in female AA broilers via the AMPK/SREBP-1c/ACC signaling pathway. MLE can also be utilized to modify the fatty acid profile in female broilers (AA) at varied inclusion levels.