High-fat Diet-induced Fatty Liver Research Articles

Protective effects of Gymnaster koraiensis extract on high fat diet-induced fatty liver in mice

Obesity produces non-alcoholic liver disease, with relationship of the beginning of abnormal lipid metabolism. Recent studies show that abnormal cholesterol metabolism has a specific role in the pathological cause of non-alcoholic fatty liver disease (NAFLD). Gymnaster koraiensis (GK), a worthy perennial Korean wild plant has specific polyacetylene compounds. Many researches have presented that GK has many pharmacological properties, such as oxidation prevention, liver protection, and inflammation prevention. However, the conservative effect of GK on non-alcoholic fatty liver has not been researched so far. Male C57/BL6J mice were randomly separated to normal feeding (ND) (fed a ND for 12 weeks) and high fat feeding (HF) groups. Mice in the HF group were administered a high fat feeding (60% kcal high fat diet) and administered GK extract (125, 250, or 500 mg/kg/day), silymarin (200 mg/kg/day), or no treatment for 12 weeks. Each treatment group contained eight mice. The administration with GK decreased serum levels of triglycerides, total cholesterol, LDL-cholesterol, alanine aminotransferase and aspartate aminotransferase, while decreased body weight, body fat and liver weight. Alterations in liver histology, as assessed by H&E and Oil-red O staining, showed that the GK treatment decreased amass of lipids and NAFLD activity scores in liver. These results present that GK extract may be potential therapeutic agent for NAFLD by preventing increases of serum lipids and increases of body weight and fat, while decreasing lipid accumulation and increase of liver weight in high fat diet-triggered fatty liver.

Prolyl endopeptidase gene disruption attenuates high fat diet-induced nonalcoholic fatty liver disease in mice by improving hepatic steatosis and inflammation.

BackgroundProlyl endopeptidase (PREP) is a serine endopeptidase that regulates inflammatory responses. PREP inhibitors can reduce hepatocyte lipid accumulation and may participate in the progression of nonalcoholic fatty liver disease (NAFLD). We investigated whether disruption of PREP regulates hepatic steatosis and inflammation in mice with NAFLD.MethodsWild-type and PREP gene disrupted mice were randomly divided into low-fat diet wild-type (LFD-WT), high-fat diet wild-type (HFD-WT), low-fat diet PREP disruption (LFD-PREPgt), and high-fat diet PREP disruption (HFD-PREPgt) groups. Animals were euthanized at the endpoint of 32 weeks. The NAFLD activity score and number of inflammatory cells were determined by hematoxylin-eosin staining and immunohistochemical staining of liver tissue. The expression levels of inflammation- and lipid metabolism-associated genes in the liver and serum were detected by quantitative reverse transcription PCR, mass spectrometry, or enzyme-linked immunosorbent assay.ResultsThe body weight and epididymal fat tissue index of the HFD-PREPgt mice were significantly decreased compared with that of the HFD-WT mice. Moreover, the NAFLD activity score and liver function were attenuated in the HFD-PREPgt mice. Fat accumulation and the level of expression of mRNAs associated with lipid metabolism and proinflammatory responses were improved in the HFD-PREPgt mice. The number of CD68-positive cells in liver tissue and the serum levels of inflammation-associated factors were significantly decreased in the HFD-PREPgt mice compared with those in the HFD-WT mice. Further mechanistic investigations indicated that the protective effect of PREP disruption on liver inflammation was associated with the suppressed production of matrix metalloproteinases (MMPs) and proline-glycine-proline (PGP) and the inhibition of neutrophil infiltration.ConclusionsLoss of PREP lowers the severity of hepatic steatosis and inflammatory responses in a high-fat diet-induced nonalcoholic steatohepatitis model. PREP inhibition may protect against NAFLD.

DHA Protects Against Hepatic Steatosis by Activating Sirt1 in a High Fat Diet-Induced Nonalcoholic Fatty Liver Disease Mouse Model.

AimDocosahexaenoic acid (DHA; C22; n-3) shows beneficial effects on Non-alcoholic fatty liver disease (NAFLD). Deacetylase Sirtuin1 (Sirt1) was reported to increase energy metabolism and decrease lipogenesis. Here, we investigated whether DHA plays a role in protecting against hepatic steatosis via Sirt1.Main MethodsBoth in vivo and in vitro hepatic steatosis models were used: diet-induced obesity (DIO) model (middle-aged C57BL/6 mice fed a high-fat diet (HFD)) and palmitic acid (PA)-induced lipid accumulation cell model (HepG2 cells).Key FindingsIn DIO mice, treatment with DHA (gavage supplementation) for 8 weeks not only inhibited the lipid accumulation, but also increased fatty acids (FA) oxidation and induced triglyceride export in liver. These changes were accompanied by attenuation of inflammation. Moreover, DHA reversed the HFD-induced reduction of Sirt1 in liver. Interestingly, the beneficial effects of DHA were reversed by lentivirus-mediated Sirt1 knockdown, accompanied with increased expression of markers of lipogenesis, inflammation and reduced FA oxidation. In HepG2 cells, DHA prevented the accumulation of PA-induced lipid droplets, the decrease of FA oxidation and the reduction of Sirt1 level. Inhibition of Sirt1 by sirtinol partially reversed the beneficial effects of DHA on PA-treated cells.SignificanceDHA alleviated hepatic steatosis and reduced inflammation of liver in obese middle-aged mice by mechanisms involving Sirt1 activation.

Sodium fluorocitrate having inhibitory effect on fatty acid uptake ameliorates high fat diet-induced non-alcoholic fatty liver disease in C57BL/6J mice

Non-alcoholic fatty liver disease (NAFLD) is excessive fat build-up in the liver without alcohol consumption and includes hepatic inflammation and damage. Excessive influx of fatty acids to liver from circulation is thought to be a pathogenic cause for the development of NAFLD. Thus, inhibition of fatty acid intake into hepatocyte would be a maneuver for protection from high fat diet (HFD)-induced NAFLD. This study was initiated to determine whether sodium fluorocitrate (SFC) as a fatty acid uptake inhibitor could prevent palmitate-induced lipotoxicity in hepatocytes and protect the mice from HFD-induced NAFLD. SFC significantly inhibited the cellular uptake of palmitate in HepG2 hepatocytes, and thus prevented palmitate-induced fat accumulation and death in these cells. Single treatment with SFC reduced fasting-induced hepatic steatosis in C57BL/6J mice. Concurrent treatment with SFC for 15 weeks in HFD-fed C57BL/6J mice prevented HFD-induced fat accumulation and stress/inflammatory signal activation in the liver. SFC restored HFD-induced increased levels of serum alanine aminotransferase and aspartate aminotransferases as hepatic injury markers in these mice. SFC treatment also improved HFD-induced hepatic insulin resistance, and thus ameliorated HFD-induced hyperglycemia. In conclusion, inhibition of fatty acid mobilization into liver through SFC treatment can be a strategy to protect from HFD-induced NAFLD.

Controlling Obesity and Metabolic Diseases by Hydrodynamic Delivery of a Fusion Gene of Exendin-4 and \u03b11 Antitrypsin

Obesity and associated metabolic comorbidities represent a growing public health problem. In this study, we demonstrate the use of a newly created fusion gene of exendin-4 and α1-antitrypsin to control obesity and obesity-associated metabolic disorders including insulin resistance, fatty liver and hyperglycemia. The fusion gene encodes a protein with exendin-4 peptide placed at the N-terminus of human α-1 antitrypsin, and is named EAT. Hydrodynamic transfer of the EAT gene to mice prevents high-fat diet-induced obesity, insulin resistance and fatty liver development. In diet-induced obese mice, expression of EAT gene induces weight loss, improves glucose homeostasis, and attenuates hepatic steatosis. In ob/ob mice, EAT gene transfer suppresses body weight gain, maintains metabolic homeostasis, and completely blocks fatty liver development. Six-month overexpression of the EAT fusion gene in healthy mice does not lead to any detectable toxicity. Mechanistic study reveals that the resulting metabolic benefits are achieved by a reduced food take and down-regulation of transcription of pivotal genes responsible for lipogenesis and lipid droplet formation in the liver and chronic inflammation in visceral fat. These results validate the feasibility of gene therapy in preventing and restoring metabolic homeostasis under diverse pathologic conditions, and provide evidence in support of a new strategy to control obesity and related metabolic diseases.

Freeze-dried Si-Ni-San powder can ameliorate high fat diet-induced non-alcoholic fatty liver disease.

BACKGROUNDNon-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease worldwide. However, to date, there is no ideal therapy for this disease.AIMTo study the effects of Si-Ni-San freeze-dried powder on high fat diet-induced NAFLD in mice.METHODSTwenty-four male C57BL/6 mice were randomized into three groups of eight. The control group (CON) was allowed ad libitum access to a normal chow diet. The high fat diet group (FAT) and Si-Ni-San group (SNS) were allowed ad libitum access to a high fat diet. The SNS group was intragastrically administered Si-Ni-San freeze-dried powder (5.0 g/kg) once daily, and the CON and FAT groups were intragastrically administered distilled water. After 12 wk, body weight, liver index, visceral fat index, serum alanine aminotransferase (ALT), portal lipopoly-saccharide (LPS), liver tumor necrosis factor (TNF)-α and liver triglycerides were measured. Intestinal microbiota were analyzed using a 16S r DNA sequencing technique.RESULTSCompared with the FAT group, the SNS group exhibited decreased body weight, liver index, visceral fat index, serum ALT, portal LPS, liver TNF-α and liver triglycerides (P < 0.05). Intestinal microbiota analysis showed that the SNS group had different bacterial composition and function compared with the FAT group. In particular, Oscillospira genus was a bacterial biomarker of SNS group samples.CONCLUSIONThe beneficial effects of Si-Ni-San freeze-dried powder on high fat diet-induced NAFLD in mice may be associated with its anti-inflammatory and changing intestinal microbiota effects.

The hepatic-targeted, resveratrol loaded nanoparticles for relief of high fat diet-induced nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is the early stage of many metabolic syndromes. The intervention of NAFLD can prevent its further development into severe metabolic syndromes. Given the inefficiency and side effects of chemical drugs for treating NAFLD, the hepatic-targeted nanocarriers loaded with bioactive compounds may offer a more effective and acceptable strategy for eliminating NAFLD. Here we developed hepatic-targeted oxidized starch-lysozyme (OSL) nanocarriers to specifically deliver resveratrol (Res) to liver tissue in order to maximize its therapeutic efficiency. The hepatic targeting was achieved using covalently conjugated galactose (Gal), which is recognized by the asialoglycoprotein receptors specifically expressed in hepatocytes. In steatotic HepG2 cell model, treatment with hepatic-targeted Gal-OSL/Res nanocarriers enhanced the cellular Res uptake and anti-lipogenesis capabilities, and effectively decreased triglyceride accumulation by modulating AMP-activated protein kinase (AMPK)/silent information regulation 2 homolog 1(SIRT1)/fatty acid synthase (FAS)/sterol regulatory element-binding protein-1c (SREBP1c) signaling pathway. In mice, Gal-OSL increased Res delivery into liver tissues and increased their hepatic effective concentration in liver. Most importantly, Gal-OSL/Res nanocarriers effectively reversed NAFLD and recovered hepatic insulin sensitivity of NAFLD mice to the healthy state. Furthermore, Gal-OSL/Res efficiently ameliorated lipid deposition and insulin resistance by modulating AMPK/SIRT1/FAS/SREBP1c signaling pathway and downregulated insulin receptor substrate-1 (IRS-1) phosphorylation at serine 307 in liver. These findings suggested that the hepatic-targeted Gal-OSL nanocarriers delivering Res could potentially serve as a safe and promising platform for NAFLD and other liver related diseases.

Preventive Effects of Total Flavonoid C-Glycosides from Abrus mollis on Nonalcoholic Fatty Liver Disease through Activating the PPARα Signaling Pathway.

Abrus pulchellus subsp. mollis (Hance) Verdc. (Leguminosae) is a well-known edible plant usually added to soups and beverages. In this study, vicenin-2 (1: ), isoschaftoside (2: ), schaftoside (3: ), and their enrichment fraction, total flavonoid C-glycosides, derived from the extracts of A.mollis, were firstly found to prevent nonalcoholic fatty liver disease both in vitro and in vivo. In the in vitro study, total flavonoid C-glycosides decreased the lipid accumulation in oleic acid-treated HepG2 cells. The mechanisms of total flavonoid C-glycosides are involved in the regulation of peroxisome proliferator-activated receptor α and its downstream, and the reduction of proinflammatory cytokines. In high-fat diet-induced fatty liver rats, total flavonoid C-glycosides decreased the levels of glutamic-oxalacetic transaminease and glutamic-pyruvic transaminase, and decreased the lipid accumulation both in the liver and blood without affecting food intake. In addition, total flavonoid C-glycosides also increased the activities of the antioxidant enzyme system in vivo. In conclusion, total flavonoid C-glycosides are active components of A.mollis on nonalcoholic fatty liver disease, and can be used in functional food and supplements for nonalcoholic fatty liver disease prevention and treatment.

Attenuation of high-fat diet-induced fatty liver through PPARα activation by stevioside

Abstract This study aimed to investigate the effect of stevioside on fatty liver. Rats with hyperlipidemic fatty liver were treated with 75–150 mg/kg stevioside for 6 weeks. After oral administration of stevioside, the levels of serum and hepatic lipids and degree of hepatic steatosis were decreased. Stevioside treatment increased the expressions of hepatic peroxisome proliferator-activated receptor (PPAR)α and carnitine palmitoyltransferase-1A proteins and decreased the expressions of hepatic sterol regulatory element-binding protein-1c, fatty acid synthase and diacylglycerol acyltransferase proteins. Following treatment of oleic acid-stimulated hepatocytes with 100–400 μM stevioside, the intracellular lipids were also decreased. In the hepatocytes of PPARα gene silence, the lipid-lowering effect of stevioside was abolished, and its regulatory effects on PPARα-mediated target proteins were reversed. These findings demonstrated that stevioside was effective in treating fatty liver, and its mechanisms were associated with the increment of hepatic PPARα expression and subsequent modulation of its target gene expressions.

SUN-095 Attenuation of Inflammation by a Novel Small Molecule Prevents High Fat Diet-Induced Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of both metabolic and inflammatory diseases, and it has become pervasive worldwide. Inflammation, including inflammation resulting from free fatty acid (FFA) activation of toll-like receptor (TLR) signaling, has been suggested to be an essential component of the pathophysiology of both insulin resistance and NAFLD. High fat (HF) diets promote an increased uptake and storage of FFAs and triglycerides in hepatocytes, which initiates inflammation and steatosis that induces lipotoxicity and an exacerbation of inflammation. In previous studies, we have established the efficacy of phenylmethimazole, a TLR3/4 inhibitor, to prevent and reverse HF diet-induced NAFLD, inflammation, and insulin resistance. A new library of small molecule compounds, including COB-214, was generated to identify even more potent inhibitors of inflammation. The objectives of this study were to evaluate the efficacy of COB-214 to delay and/or prevent hepatic steatosis, inflammation, and insulin resistance in a HF diet-induced model of NAFLD. C57BL/6J male mice were fed a HF diet (60 % fat, 20% protein, 70% carbohydrate) and divided into 3 groups (N=8 for each group): sham injection (stress control), DMSO (vehicle control), COB-214. Each treatment was administered once daily at a dosage of 1mg/kg for 16 weeks. Histological examination of liver sections from these mice using hematoxylin and eosin (H&E) revealed less hepatic lipid accumulation in mice treated with COB-214 when compared to mice in the sham- and DMSO-treated groups. Transcription of pro-inflammatory cytokines was down-regulated in both liver and mesenteric adipose tissue isolated from COB-214-treated mice when compared to sham- and DMSO-treated mice. Treatment with COB-214 prevented HF diet-induced insulin resistance measured by a 3-hour intraperitoneal glucose tolerance test (IPGTT) and 1.5-hour intraperitoneal insulin tolerance test (IPITT). Future directions include determining the efficacy of COB-214 to reverse HF diet-induced NAFLD, inflammation, and insulin resistance. At the conclusion of this study, we hope to have established the role of a novel class of small molecule inhibitors of inflammation in the treatment and prevention of NAFLD.

Chitooligosaccharide supplementation prevents the development of high fat diet-induced non-alcoholic fatty liver disease (NAFLD) in mice via the inhibition of cluster of differentiation 36 (CD36)

Abstract The effects of (GlcN)2-3 on the development of high fat diet-induced non-alcoholic fatty liver disease in C57BL/6J mice and the potential structural-functional relationship between different singular degrees of polymerization (DPs) COSs and CD36 activity were investigated. (GlcN)2-3 was found to significantly inhibit the levels of triglyceride, low density lipid protein and total cholesterol in the serum and liver, thus reducing hepatic steatosis and, ultimately, altering lipid accumulation. This phenomenon was associated with a decrease in the mRNA and protein expressions of CD36, PXR, DGAT2, LXRα and PPARγ, which subsequently decreased the uptake of FFAs and triglyceride synthesis. Using structural analysis, (GlcN)2-3 blocked the core cavity and inhibited the translocation of FFAs in CD36. Furthermore, the molecular size and steric hindrance effect play crucial roles in the deactivation of CD36. These findings will provide a better understanding of the modulating actions of specific singular-DPs COS in high fat diet-induced hepatic steatosis.

Abstract WP534: Cyanidin 3-glucoside and its Metabolites Protect Against Nonalcoholic Fatty Liver Disease: Crosstalk Between Serum Lipids, Inflammatory Cytokines and MAPK/ERK Pathway

Background: Serum lipids and inflammatory cytokines are considered as potential therapeutic targets for nonalcoholic fatty liver disease, which has become the most common chronic liver disease in adolescents. Cyanidin 3-glucoside (C3G) is a natural anthocyanin occurs widely in plants, and has shown potential inhibitory effect on inflammatory cytokines in our previous studies. Methods: First, serum levels of inflammatory cytokines including TNF-α and MCP-1 were measured in 80 adolescents (9-15 years old) selected based on their body mass index and serum levels of lipids. Second, the protective effects of C3G and its metabolites including protocatechuic acid (PCA), phloroglucinaldehyde (PGA), ferulic acid, and vanillic acid on nonalcoholic fatty liver disease were measured in a mouse model in which C57BL/6N mice (n=4 for each group) were fed a normal diet, high fat diet only, or high fat diet containing 0.4% of C3G or the four metabolites for 3 months. Finally, the regulatory effects of C3G and its metabolites on inflammatory pathways were clarified in mouse macrophages. Results: Compared with serum levels of MCP-1 (273.13±16.89 pg/ml, n=16) and TNF-α (26.07±1.36 pg/ml) in normal adolescents, those who were obese with abnormal high serum LDL-c/HDL-c ratio (2.88±0.11) had higher MCP-1 (345.19±11.82 pg/ml, P &lt;0.05) and TNF-α (35.70±1.90 pg/ml, P &lt;0.05) levels. However, no significant change was observed in MCP-1 or TNF-α levels in adolescents who had a lower LDL-c/HDL-c ratio, even though their serum levels of total cholesterol and triacylglycerol were significantly higher ( P &lt;0.05) than normal level. Mice experiments revealed that supplement with C3G, PCA or PGA, but not ferulic acid or vanillic acid, prevented high fat diet-induced obesity and fatty liver with lower serum LDL-c/HDL-c ratio and levels of MCP-1 and TNF-α. Cell signaling analysis indicated that C3G, PCA and PGA suppressed the activation of MAPK pathway, especially, C3G and PGA could directly bind to ERK1/2. Conclusion: The serum LDL-c/HDL-c ratio is closely associated with the inflammatory status in nonalcoholic fatty liver disease, and C3G can suppress the inflammation via MAPK/ERK pathway potentially through its metabolites PCA and PGA.

Conophylline inhibits high fat diet-induced non-alcoholic fatty liver disease in mice.

Conophylline (CnP), a vinca alkaloid extracted from the leaves of the tropical plant Tabernaemontana divaricate, attenuates hepatic fibrosis in mice. We have previously shown that CnP inhibits non-alcoholic steatohepatitis (NASH) using a methionine-choline-deficient (MCD) diet-fed mouse model. However, little is known about the CnP mediated inhibition of hepatic steatosis in high-fat diet-induced non-alcoholic fatty liver disease (NAFLD) mouse models. CnP (0.5 and 1 μg/g/body weight) was co-administered along with a high-fat diet to male BALB/c mice. After nine weeks of administering the high-fat diet, hepatic steatosis, triglyceride, and hepatic fat metabolism-related markers were examined. Administration of a high-fat diet for 9 weeks was found to induce hepatic steatosis. CnP dose-dependently attenuated the high-fat diet-induced hepatic steatosis. The diet also attenuated hepatic peroxisome proliferator-activated receptor alpha (PPARA) mRNA levels. PPARA is known to be involved in β-oxidation. CnP upregulated the mRNA levels of hepatic PPARA and its target genes, such as carnitine palmitoyl transferase 1 (CPT1) and CPT2, in a dose-dependent manner in the liver. Furthermore, levels of hepatic β-hydroxybutyrate, which is a type of ketone body, were increased by CnP in a dose-dependent manner. Finally, CnP increased the expression of the autophagosomal marker LC3-II and decreased the expression of p62, which are known to be selectively degraded during autophagy. These results indicate that CnP inhibits hepatic steatosis through the stimulation of β-oxidation and autophagy in the liver. Therefore, CnP might prove to be a suitable therapeutic target for NAFLD.

A novel resveratrol-curcumin hybrid, a19, attenuates high fat diet-induced nonalcoholic fatty liver disease

Both inflammation and fibrosis are essential in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Taking inflammatory cytokines and signaling pathways as vital mediators, the inhibition of inflammation response may be an effective approach for treating NAFLD. a19, a resveratrol-curcumin hybrid, has been confirmed to exhibit a good anti-inflammatory activity by preventing LPS-induced inflammatory response in macrophages. The study aims to evaluate the protective effect of a19 on high fat diet (HFD)-induced NAFLD. In the present study, compound a19 significantly inhibited the HFD-induced lipid accumulation, liver injury, liver inflammation and fibrosis in mouse model. In vitro, a19 obviously suppressed the expression of PA-induced inflammatory cytokines and fibrosis markers mRNA. Meanwhile, the anti-inflammatory effect of a19 was found to be associated with the inhibition of ERK signal pathway. These results indicated that a19 can be potentially used as a protective agent for NAFLD.

Proteomics approach to investigate dynamic protein profile involved in high fat diet-induced fatty liver disease in rats.

Nonalcoholic fatty liver disease (NAFLD) is a disorder of the liver found worldwide. The molecular mechanisms underlying NAFLD initiation and progression, however, remain poorly understood. In this study, fluorescence difference gel electrophoresis (DIGE) combined with mass spectrometry was performed to profile the intracellular processes in the rat liver at the proteome level when rats were fed a high-fat diet for 8 weeks. Dynamic changes of 27 protein spots were observed. Among them, upregulation of 14 spots and downregulation of 13 spots were observed during the eight weeks of the high fat diet-induction period. These spots were analyzed by matrix-assisted laser desorption/ionization tandem time-of-flight mass spectrometry (MALDI-TOF/TOF), and ultimately 24 proteins were identified with more than 95% confidence. Gene ontology (GO) annotation indicated that these proteins were implicated in the metabolism of carbohydrates, lipids, and amino acids. Four proteins were validated by western blot. Further functional studies on these dynamically changing proteins may lead to a better understanding of the mechanisms of high fat diet-induced fatty liver disease.

Neuregulin in Health and Disease.

The neuregulins Neuregulins, a family of EGF-like signaling molecules, are involved in cell-cell crosstalk and play an important role in development, maintenance and repair of the nervous system, heart, breast and other organs. Independent studies described a ligand for the oncogene ErbB2 (neu, Her2) and factors that stimulated proliferation of Schwann cells, as well as synthesis of receptors for acetylcholine by muscle. These ligands and factors are essentially products of the same gene, referred to by Marchionni M. as neuregulin (NRG-1) [1]. Besides NRG-1 gene, there are other genes that encode related proteins, such as NRG-2 (Don-1, NTAK), NRG-3 and NRG-4. There are few studies that describe NRG-2, −3 and −4 and a complete analysis of their function remains a challenge. However, NRG-2 was recently reported as a component of stress granules (SG), microscopically visible aggregates of translationally stalled messenger ribonucleoprotein complexes that are formed in response to direct stress conditions [2]. Furthermore, it was shown that NRG-2, secreted from astrocytes, bound to ErbB3 on neurons and promoted neuronal survival [3]. NRG-3 was shown to be associated with schizophrenia (SZ) in a Chinese population [4], with bipolar disorder (BD) [5] and with the risk and age of onset of Alzheimer disease (AD) [6]. In addition, NRG-3 has a key function in promoting early mammary morphogenesis and is involved in breast cancer (BC) [7]. NRG-4 expression was decreased in human inflammatory bowel disease samples and mouse models of colitis, suggesting that activation of ErbB4 is altered [8]. An interesting study [9] showed that NRG-4 overexpression prevents high fat diet-induced weight gain and fatty liver and reduces obesity-induced chronic inflammation. Considering the increasing interest and research focused on NRG-1 in the past years, this review summarizes what is currently known about NRG-1 and its impact on health and disease as well as its current and potential use(s) as a CNS anti-inflammatory agent against inducers of brain inflammation and injury as well as in the treatment of various neurological disorders. Neuregulin-1: Structure, function and signaling pathways: NRG-1 gene encodes 21 exons located on human chromosome 8p22–21. Alternative splicing of more than 30 exons in different parts of the NRG-1 transcript generates more than 30 isoforms that can be grouped into six types (I-VI) [10–12] (Figure 1). They are synthesized as transmembrane precursors consisting of either an immunoglobulin-like (Ig) domain or cysteine-rich domain (CRD), an EGF-like domain, a transmembrane domain and a cytoplasmic tail [13]. NRG-1 types I and II are released from the cell surface after protease-mediated proteolytic cleavage and may function as paracrine signals [14]. NRG-1 type III remains tethered to the cell membrane after cleavage and acts as a juxtacrine signal [15]. Full-length type IV spans 1.8 kb and encodes a putative protein of 590 amino acids with a predicted molecular mass of approximately 66 kDa [15]. Further-more, there are two major classes of NRG-1 identified as α and β isoforms. NRG-1α and NRG-1β contain related, but structurally distinct EGF-like domains composed of a common amino terminal segment followed by α or β variant sequences [16]. NRG-1β isoforms predominate in the nervous system while α isoforms are common in mesenchymal cells and are critically important for breast development [14]. Type I NRGα and β isoforms are the predominant isoforms expressed in early embryogenesis, whereas type II and type III are undetectable until the mid-gestation stage [17]. Type I or Heregulin is an acetylcholine receptor activator, type II is a Glial Growth Factor, type III is a sensory and motor neuron-derived factor and type IV is involved in neuronal activity regulation. Functions of types V and VI are not well known and their investigation remains a challenge. Types I, II and III of NRG-1 express in human peripheral blood in addition to neurons, while types IV and V express specifically in the brain [18]. Open in a separate window Figure 1: Neuregulin (NRG) and ErbB receptor structures. NRG gene products share a structural characteristic for the extracellular epidermal growth factor (EGF) domain and it differentiates this subfamily from other members of the EGF family. All EGF family members are ligands of ErbB receptors, although with varying affinities, with ErbB3 and ErbB4 being specific NRG-binding receptors. NRG-1 isoforms have been classified in types I-VI on the basis of differences in the NH2-terminal distal region [19].

Proteoglycan 4 deficiency protects against glucose intolerance and fatty liver disease in diet-induced obese mice

ObjectiveProteoglycan 4 (Prg4) has emerged from human association studies as a possible factor contributing to weight gain, dyslipidemia and insulin resistance. In the current study, we investigated the causal role of Prg4 in controlling lipid and glucose metabolism in mice. MethodsPrg4 knockout (KO) mice and wild-type (WT) littermates were challenged with an obesogenic high-fat diet (45% of total calories as fat) for 16 weeks. To further stimulate the development of metabolic alterations, 10% fructose water was provided starting from week 13. ResultsPrg4 deficiency only tended to reduce diet-induced body weight gain, but significantly improved glucose handling (AUC: −29%; p < 0.05), which was also reflected by a tendency towards a reduced HOMA-IR score (−49%; p = 0.06 as compared to WT mice). This coincided with lower hepatic expression of glycolysis (Gck: −30%; p < 0.05) and lipogenesis (Acc: −21%; p < 0.05 and Scd1: −38%; p < 0.001) genes, which translated in significantly lower hepatic triglyceride levels (−56%; p < 0.001) in Prg4 KO mice as compared to WT mice. Prg4 KO mice likely had lower glucose utilization by skeletal muscle as compared to WT mice, judged by a significant reduction in the genes Glut4 (−29%; p < 0.01), Pfkm (−21%; p < 0.05) and Hk2 (−39%; p < 0.001). Moreover, Prg4 KO mice showed a favorable white adipose tissue phenotype with lower uptake of triglyceride-derived fatty acids (−46%; p < 0.05) and lower gene expression of inflammatory markers Cd68, Mcp1 and Tnfα (−65%, −81% and −63%, respectively; p < 0.01) than WT mice. ConclusionPrg4 KO mice are protected from high-fat diet-induced glucose intolerance and fatty liver disease.

Hepatoprotective potential of aqueous extract of Allium eriophyllum Boiss in high-fat diet-induced fatty liver diseases

In recent years, Iranian traditional medicine has been used to control, prevent, and treat various diseases such as fatty liver. One of these plants is Allium eriophyllum Boiss. In this research, we assessed the potential of aqueous extract of A. eriophyllum in the treatment of fatty liver disease in Wistar male rats. At beginning of the study, a total of 10 rats were selected as the negative control, and 50 rats were treated with a high-fat diet for 4 months. Then, the animals were randomly divided into six subgroups, including negative healthy control, untreated negative control, and four groups receiving the aqueous extract of A. eriophyllum at 25, 50, 100, and 200 mg/kg concentrations. After 2 months, the rats were sacrificed, and blood and liver samples were collected. The data were analyzed by SPSS 21 software. All groups of A. eriophyllum (especially A200) could significantly (p ≤ 0.05) decrease the raised weights of body and liver and the concentrations of ALP, AST, ALT, GGT, cholesterol, LDL, triglyceride, total and conjugated bilirubin, glucose, and GR and increase the concentrations of HDL, total protein, albumin, SOD, CAT, and GPx as compared to the untreated group. Also, A. eriophyllum (especially A200) decreased the degree of hepatic steatosis as compared to the untreated group. In finally, it appears that the aqueous extract of A. eriophyllum can treat the fatty liver disease in rats.

Sleeve gastrectomy attenuates high fat diet-induced non-alcoholic fatty liver disease

BackgroundA high-fat diet (HFD) is known to lead to obesity, and contributes to the progression of non-alcoholic fatty liver disease. The objective of this study was to evaluate the effects of sleeve gastrectomy (SG) on the progression of HFD-induced hepatic steatosis.MethodsFifteen 4-week-old, male Wistar rats were randomly assigned into three groups: NC, HFD + SHAM and HFD + SG. Their body weight, glucose-lipid metabolism, inflammation indices, hepatic steatosis and fibroblast growth factor 21 (FGF21) levels were measured.ResultsPostoperatively, body weights in the HFD + SHAM and HFD + SG group rats decreased during the first week. Thereafter, HFD + SG rats regained their body weight. Differences in insulin, homeostasis model assessment of insulin resistance, triglyceride, free fatty acid, tumor necrosis factor-α and monocyte chemotactic protein-1 levels were statistically significant across the three groups (all P < 0.05). Interestingly, FGF21 levels in the HFD + SG group were markedly lower than in the HFD + SHAM group (P = 0.015), however, there were no differences in the NC group. Hematoxylin and eosin staining demonstrated that more vacuoles were present in the HFD + SHAM liver when compared to the HFD + SG liver. Oil-red O staining showed less red dots in the HFD + SG liver.ConclusionsDespite eating, surgical re-routing of the gut may prevent weight accumulation, regulate glucose-lipid metabolism and insulin sensitivity, control a chronic inflammatory state, change the secretion pattern of FGF21 and alleviate the severity of fatty liver.

Histopathological and biochemical effects of aqueous extract of Tragopogon graminifolius on the liver tissues of Wistar rats fed with high-fat diet

The fatty liver disease is one of the most usual metabolic diseases among people around the world. Appropriate strategies for treating this disease are prioritized by each country. The purpose of the new research was to survey the therapeutical property of aqueous extract of Tragopogon graminifolius on the high-fat diet-induced fatty liver disease in Wistar male rats. In this study, 60 rats were used. A total of ten rats were chosen as the negative control, and the rest of them were treated with a high-fat diet for 4 months. Then, the animals were randomly divided into six subgroups, including negative healthy control, untreated negative control, and four groups receiving the aqueous extract of T. graminifolius at 20, 40, 80, and 160 mg/kg concentrations. After 2 months, the rats were sacrificed, and the blood and liver samples of them were collected for biochemical and histopathological parameter analysis. All doses of T. graminifolius could significantly (p ≤ 0.05) decrease the raised levels of ALP, AST, ALT, GGT, cholesterol, LDL, triglyceride, total and conjugated bilirubin, and glucose and increased HDL, total protein, albumin, SOD, and CAT as compared to the untreated group. Also, aqueous extract of T. graminifolius decreased the degree of hepatic steatosis as compared to the untreated group. In conclusion, the obtained results demonstrated the hepatoprotective effect of T. graminifolius aqueous extract.