Relationship between serum osteocalcin levels and non‐alcoholic fatty liver disease in Chinese men

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Role of mitochondria and mitochondria‐targeted agents in non‐alcoholic fatty liver disease

Mitochondria play a pivotal role in the fatty acid oxidation and have been found to be affected early during the macrovesicular fat accumulation in the hepatocytes. The fatty infiltration is the primary cause of oxidative stress and inflammation in the non‐alcoholic fatty liver disease (NAFLD), which can lead to the peroxidation of phospholipids, such as cardiolipin. Oxidative stress‐induced damage to mitochondrial DNA can result in the impairment of oxidative phosphorylation and further increases the generation of reactive oxygen species. The mitochondrial damage may eventually lead to apoptotic death of hepatocytes. The apoptosis along with the generated cytokines from the stellate and Kupffer cells further augment the fibrotic changes to advance the disease. Hence, alleviation of the mitochondrial impairment, particularly in the early stages of NAFLD, may prevent the progression of the disease. Among the various experimentally studied mitochondrial‐targeted agents, triphenylphosphonium cation ligated ubiquinone Q10 and vitamin E, Szeto‐Scheller peptides, and superoxide dismutase mimetic‐salen manganese complexes (EUK‐8 and EUK‐134) have been found to be most promising. In addition to these mitochondrial‐targeted agents, a novel area of therapy called mitotherapy have also emerged. However, clinical studies conducted so far are still fragmentary to validate their efficacy. This review article discusses the mitochondria‐targeted molecules and their potential role in the treatment of NAFLD.     

A high‐fat diet and multiple administration of carbon tetrachloride induces liver injury and pathological features associated with non‐alcoholic steatohepatitis in mice

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Non‐alcoholic fatty liver disease (NAFLD) fibrosis score predicts 6.6‐year overall mortality of Chinese patients with NAFLD

The non‐alcoholic fatty liver disease (NAFLD) fibrosis score (NFS) has emerged as a useful predictor of long‐term outcome in NAFLD patients. We evaluated the predictive performance of the NFS for overall mortality in a Chinese population with NAFLD. All NAFLD patients diagnosed ultrasonographically at Xixi Hospital of Hangzhou between 1996 and 2011 were retrospectively recruited to the study. Outcome was determined by interview and causes of death were confirmed by medical records. The area under the receiver operating characteristic curve (AUC_ROC) was used to determine the predictive accuracy of the NFS, BARD (body mass index, aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio, diabetes) score, FIB‐4 index and the AST/platelet ratio index (APRI) for mortality. Data from a total of 180 eligible patients (median age 39 years; 96 men) were analysed, with 12 deaths over a median follow‐up period of 6.6 years (range 0.5–14.8 years). Using Cox model analysis, the NFS as a continuous variable was identified as the only predictor for all‐cause mortality (hazard ratio 2.743, 95% confidence interval (CI) 1.670–4.504). The NFS yielded the highest AUC_ROC of 0.828 (95% CI 0.728–0.928, P < 0.05), followed by the FIB‐4 index, APRI and BARD score (AUC_ROC 0.806 (P < 0.05), 0.732 (P < 0.05) and 0.632, respectively). The data indicated that the NFS is a useful predictor of 6.6‐year all‐cause mortality for Chinese patients with NAFLD.     

Serum vitamin D levels are inversely related with non‐alcoholic fatty liver disease independent of visceral obesity in Chinese postmenopausal women

The aim of the present study was to investigate the association between serum vitamin D levels and both visceral adipose and with non‐alcoholic fatty liver disease (NAFLD) in Chinese postmenopausal women. Four hundred and fifty‐one postmenopausal women between 45 and 74 years of age (mean (± SD) age 57.3 ± 4.6 years) were enrolled in the study. All subjects participated in the Shanghai Obesity Study between June and August 2011 and underwent abdominal magnetic resonance imaging and an abdominal ultrasonography. Patients with a visceral fat area (VFA) ≥ 80 cm² were classified as abdominally obese. Serum 25‐hydroxyvitamin D₃ (25(OH)D₃) levels were measured with an electrochemiluminescence immunoassay. The prevalence of NAFLD in the study population was 34.8% (n = 157). Women with abdominal obesity had significantly lower serum 25(OH)D₃ levels than those without abdominal obesity (median (interquartile range) 11.23 (8.64–14.12) vs 12.56 (9.41–15.98) ng/mL, respectively; P < 0.01). Regardless of abdominal obesity status, serum 25(OH)D₃ levels in patients with NAFLD were lower than those without non‐NAFLD (11.14 (8.63–13.81) vs 12.92 (9.48–16.37) ng/mL (P < 0.05) for those without abdominal obesity; 10.86 (8.61–13.56) vs 11.55 (8.82–16.38) ng/mL (P < 0.05) for those with abdominal obesity). Partial correlation analyses demonstrated a negative correlation between serum 25(OH)D₃ levels and VFA (P < 0.05). Logistic regression analysis revealed that high serum 25(OH)D₃ levels were a protective factor against NAFLD after adjusting for risk factors such as VFA. In conclusion, independent of visceral obesity, vitamin D is inversely correlated with NAFLD in Chinese postmenopausal women.     

Down‐regulation of microRNA‐375 regulates adipokines and inhibits inflammatory cytokines by targeting AdipoR2 in non‐alcoholic fatty liver disease

Non‐alcoholic fatty liver disease (NAFLD) has been considered as a multi‐factorial metabolic syndrome. MicroRNA‐375 (MiR‐375) was significantly up‐regulated in serum of NAFLD patients and the role of miR‐375 was addressed as a putative biomarker of NAFLD progression. However, the specific function of miR‐375 in the progression of NAFLD is still unclear and the molecular mechanisms underlying NAFLD have yet to be elucidated. Our study aimed at investigating the regulatory role of miR‐375 in the molecular mechanisms of the pathogenic progression of NAFLD and to find out whether miR‐375 regulates the expression level of adipokines and inflammatory cytokines in NAFLD. We found that miR‐375 expression was increased in the serum of high fat diet (HFD)‐feeding mice comparing to that in healthy controls, whereas the expression of Adiponectin receptor 2 (AdipoR2) was decreased in mice fed with HFD. Moreover, inhibiton of miR‐375 up‐regulated the expression of Adiponectin, inhibited the lipid accumulation and down‐regulated both the level of Leptin and inflammatory cytokines including tumour necrosis factor (TNF)‐α and interleukin (IL)‐6 in palmiticacid (PA)‐induced human hepatocellular carcinoma HepG2 cells. In addition, we also found that AdipoR2 was a target of miR‐375 by binding directly to the 3′UTR of it. Of note, the reduced level of TNF‐α, IL‐6 as well as Leptin and the production of Adiponectin by miR‐375 inhibitors was significantly reversed by silencing of AdipoR2 in PA‐induced HepG2 cells. Our findings bring new insight into understanding the complex mechanisms underlying the pathogenesis of NAFLD and provide evidence that miR‐375 might represent a novel therapeutic target for NAFLD.     

(‐)‐Epigallocatechin‐3‐gallate and atorvastatin treatment down‐regulates liver fibrosis‐related genes in non‐alcoholic fatty liver disease

Non‐alcoholic fatty liver disease (NAFLD) and associated advanced liver diseases have become prevalent conditions in many countries and are associated with increased mortality. Gene expression profiles in NAFLD have been examined recently but changes in expression elicited by chemical compound treatments have not been investigated. Since (‐)‐Epigallocatechin‐3‐gallate (EGCG) and atorvastatin (ATST) exhibit similar efficacy in NAFLD models, we reasoned that some common key genes might alter after treatment of EGCG and ATST. Accordingly, we applied integrated bioinformatics analyses of RNA microarray data from EGCG and ATST treatment groups compared to controls in a NAFLD phenotypic mouse model. Using differential expression (DE) analysis, Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analysis, Gene Set Enrichment Analysis (GSEA) and ClueGO enrichment, shared EGCG and ATST down‐regulated pathways were identified which included extracellular matrix (ECM)‐receptor interaction and protein processing in endoplasmic reticulum (ER). To refine key genes associated with liver fibrosis, a human NAFLD signature derived from patients of different fibrosis stages was analyzed. The results showed that fibrosis‐related genes Col1a1, Col1a2, Col3a1 and Col6a3 were significantly down‐regulated. These four genes were further validated as down‐regulated in an independent mouse NAFLD dataset. We conclude that EGCG and ATST treatment results in the significant down‐regulation of genes related to liver fibrosis.     

The association of serum FGF23 and non‐alcoholic fatty liver disease is independent of vitamin D in type 2 diabetes patients

Recent studies have shown that circulating fibroblast growth factor (FGF) 23 and vitamin D levels are closely correlated with insulin resistance. The aim of this study was to investigate the relationship among serum FGF 23 levels, serum 25‐hydroxyvitamin D [25(OH)D] levels, and non‐alcoholic fatty liver disease (NAFLD) in Chinese patients with type 2 diabetes mellitus (T2DM). This study enrolled 331 hospitalized T2DM patients (209 patients with NAFLD and 122 patients without NAFLD). Serum FGF23 levels were measured using a sandwich enzyme‐linked immunosorbent assay. Serum 25(OH)D levels were determined by an electrochemiluminescence immunoassay. NAFLD was diagnosed by hepatic ultrasound, and the fatty liver index (FLI) was calculated to quantify hepatic steatosis. Results showed that T2DM patients with NAFLD had significantly higher serum FGF23 levels (44.17 [37.92‐51.30] pg/mL vs 40.21 [34.07‐48.33] pg/mL, P = .002), but lower serum 25(OH)D levels (16.43 [12.70‐21.37] ng/mL vs 19.59 [13.78‐26.26] ng/mL, P = .002) than those without NAFLD. Moreover, the incidence rate of NAFLD increased with increasing serum FGF23 levels and decreased with increasing 25(OH)D levels (both P < .05). Logistic regression analysis showed that both serum FGF23 and 25(OH)D levels were independent factors for NAFLD (both P < .05). Furthermore, a multiple stepwise regression analysis also revealed that both serum FGF23 and 25(OH)D levels were independently correlated with FLI (both P < .01). In conclusion, both high FGF23 and low vitamin D levels showed an independent relationship with NAFLD in Chinese T2DM patients, indicating that FGF23 and vitamin D function via different regulatory pathways in the liver.     

Circulating microRNA 122 in the methionine and choline‐deficient mouse model of non‐alcoholic steatohepatitis

Non‐alcoholic steatohepatitis (NASH) is a progressive form of non‐alcoholic fatty liver disease (NAFLD) and is a major cause of liver cirrhosis and hepatic failure. The methionine choline‐deficient diet (MCD) is a frequently used hepatotoxicity animal model of NASH that induces hepatic transaminase (ALT, AST) elevations and hepatobiliary histological changes similar to those observed in human NASH. Liver‐specific microRNA‐122 (miR‐122) has been shown as a key regulator of cholesterol and fatty acid metabolism in adult liver, and has recently been proposed as a sensitive and specific circulating biomarker of hepatic injury. The purpose of this study was to assess miR‐122 serum levels in mice receiving an MCD diet for 0, 3, 7, 14, 28 and 56 days and compare the performance vs. routine clinical chemistry when benchmarked against the histopathological liver findings. MiR‐122 levels were quantified in serum using RT‐qPCR. Both miR‐122 and ALT/AST levels were significantly elevated in serum at all timepoints. MiR‐122 levels increased on average by 40‐fold after 3 days of initiating the MCD diet, whereas ALT and AST changes were 4.8‐ and 3.3‐fold, respectively. In general, miR‐122 levels remained elevated across all time points, whereas the ALT/AST increases were less robust but correlated with the progressive severity of NASH as assessed by histopathology. In conclusion, serum levels of miR‐122 can potentially be used as a sensitive biomarker for the early detection of hepatotoxicity and can aid in monitoring the extent of NAFLD‐associated liver injury in mouse efficacy models. Copyright © 2013 John Wiley & Sons, Ltd.     

The natural flavonoid galangin ameliorates dextran sulphate sodium–induced ulcerative colitis in mice: Effect on Toll‐like receptor 4, inflammation and oxidative stress

This study was carried out to investigate the potential therapeutic effect of galangin, a promising active principle of honeybee propolis, in dextran sulphate sodium (DSS)–induced colitis in mice. We explored the possible underlying mechanisms for galangin action and the therapeutic benefit of adding galangin to the standard therapy sulphasalazine. A galangin dose of 40 mg/kg was selected based on a preliminary dose‐selection study for investigation in a 4‐week cyclical model of DSS‐induced colitis. Mice received 3% DSS in their drinking water during the first and third weeks and were administered the treatments (40 mg/kg galangin, 100 mg/kg sulphasalazine and a combination of 20 mg/kg galangin and 50 mg/kg sulphasalazine) daily starting from the second week. Galangin significantly ameliorated DSS‐induced histopathological alterations and tissue injury, down‐regulated Toll‐like receptor 4 expression, suppressed NF‐κB p65 activation, lowered inflammatory cytokine levels and demonstrated antioxidant effects. The combination of galangin and sulphasalazine at half doses yielded comparable results to either drug alone at full dose. This study highlights galangin as a promising therapy for colitis management.     

Resveratrol protects against hepatic insulin resistance in a rat's model of non‐alcoholic fatty liver disease by down‐regulation of GPAT‐1 and DGAT2 expression and inhibition of PKC membranous translocation

Non‐alcoholic fatty liver disease (NAFLD) is associated with hepatic insulin resistance (IR). Resveratrol (RES) a potent hypolipidemic dietary polyphenol has been identified for its ability to prevent hepatic steatosis and hepatic IR in high‐fat diet (HFD)‐fed murine models of NAFLD. In the present study, we have carried an in vivo animal experiment to identify a novel mechanism for RES protective action. Sub‐chronic (45 days) RES pretreatment in 3 days HFD‐fed adult Wistar rats prevented early hepatic IR through inhibiting PKC/JNK activation; decreasing p‐IRS (Ser³⁰⁷) and increasing p‐IRS(Tyr⁶¹²), p‐Akt(Ser⁴⁷³) and p‐GSK3(Ser⁹). These effects of RES were associated with reduced expression of acyl‐CoA:glycerol‐sn‐3‐phosphate acyltransferase (GPAT‐1) and diacylglycerol:acyl‐CoA acyltransferase (DGAT2), two critical enzymes in the glycerol‐3‐phosphate pathway for de novo triglycerides synthesis. These data indicate that RES protects against NAFLD, initially, by inhibiting the early development of hepatic IR.     

Inhibition of microglial activity alters spinal wide dynamic range neuron discharge and reduces microglial Toll‐like receptor 4 expression in neuropathic rats

It is believed that neuropathic pain results from aberrant neuronal discharges although some evidence suggests that the activation of glia cells contributes to pain after an injury to the nervous system. This study aimed to evaluate the role of microglial activation on the hyper‐responsiveness of wide dynamic range neurons (WDR) and Toll‐like receptor 4 (TLR4) expressions in a chronic constriction injury (CCI) model of neuropathic pain in rats. Adult male Wistar rats (230 ± 30 g) underwent surgery for induction of CCI neuropathy. Six days after surgery, administration of minocycline (10, 20, and 40 mg/kg, i.p.) was initiated and continued until day 14. After administration of the last dose of minocycline or saline, a behavioral test was conducted, then animals were sacrificed and lumbar segments of the spinal cord were collected for Western blot analysis of TLR4 expression. The electrophysiological properties of WDR neurons were investigated by single unit recordings in separate groups. The findings showed that after CCI, in parallel with thermal hyperalgesia, the expression of TLR4 in the spinal cord and the evoked response of the WDR neurons to electrical, mechanical, and thermal stimulation significantly increased. Post‐injury administration of minocycline effectively decreased thermal hyperalgesia, TLR4 expression, and hyper‐responsiveness of WDR neurons in CCI rats. The results of this study indicate that post‐injury, repeated administration of minocycline attenuated neuropathic pain by suppressing microglia activation and reducing WDR neuron hyper‐responsiveness. This study confirms that post‐injury modulation of microglial activity is a new strategy for treating neuropathic pain.     

The role of Toll‐like receptor 4 (TLR4) in cardiac ischaemic‐reperfusion injury,cardioprotection and preconditioning

Cardiac ischaemic‐reperfusion injury (IRI) remains the primary cause of mortality throughout the developed world. Molecular mechanisms underlying IRI are complex and are often interlinked with each other driving a synergistic response. Toll‐like receptor 4 (TLR4), an immunosurveillance receptor, is known to enhance tissue injury during IRI by enhancing the inflammatory response. The release of endogenous components during IRI bind onto TLR4 leading to the activation of multiple signalling kinases. Once this event occurs these proteins are defined as danger associated molecular patterns molecules (DAMPs) or alarmins. Examples include heat shock proteins, high mobility group box one (HMGB1) and extracellular matrix proteins, all of which are involved in IRI. However, literature in the last two decades suggests that transient stimulation of TLR4 may suppress IRI and thus improve cardiac recovery. Furthermore, it remains to be seen what role TLR4 plays during ischaemic‐preconditioning where acute bouts of ischaemia, preceding a harmful bout of ischaemic‐reperfusion, is cardioprotective. The other question which also needs to be considered is that if transient TLR4 signalling drives a preconditioning response then what are the ligands which drive this? Hence the second part of this review explores the possible TLR4 ligands which may promote cardioprotection against IRI.     

Increased incidence of non‐alcoholic fatty liver disease in male rat offspring exposed to fluoxetine during fetal and neonatal life involves the NLRP3 inflammasome and augmented de novo hepatic lipogenesis

Up to 10% of women take selective serotonin reuptake inhibitors (SSRI) during pregnancy. Children exposed to SSRIs in utero have an increased risk of being overweight suggesting that fetal exposure to SSRIs can cause permanent metabolic changes. We have previously shown in rats that fetal and neonatal exposure to the SSRI antidepressant fluoxetine results in metabolic perturbations including increased hepatic triglyceride content; a hallmark of non‐alcoholic fatty liver disease (NAFLD). Therefore, the aim of this study was to identify the mechanism(s) underlying the fluoxetine‐induced increase in intrahepatic triglyceride content. Female nulliparous Wistar rats were given vehicle or fluoxetine (10 mg/kg/day) orally for 2 weeks prior to mating until weaning. At 6 months of age, we assessed whether SSRI exposure altered components of the hepatic triglyceride biosynthesis pathway in the offspring and examined the molecular mechanisms underlying these changes. Male SSRI‐exposed offspring had a significant increase in the steady‐state mRNA levels of Elovl6 and Dgat1 and core components of the NLRP3 inflammasome (apoptosis‐associated speck‐like protein containing a caspase activation recruitment domain [ASC] and caspase‐1). Augmented expression of Asc in the SSRI‐exposed offspring coincided with increased histone acetylation in the proximal promoter region. Given that we have previously demonstrated that antenatal exposure to SSRIs can lead to fatty liver in the offspring, this raises concerns regarding the long‐term metabolic sequelae of fetal SSRI exposure. Moreover, this study suggests that elevated hepatic triglyceride levels observed in the SSRI‐exposed offspring may be due, in part, to activation of the NLRP3 inflammasome and augmentation of de novo lipogenesis.     

Baicalin and its nanoliposomes ameliorates nonalcoholic fatty liver disease via suppression of TLR4 signaling cascade in mice

As a natural flavonoid compound, baicalin(BA)has been reported to exhibit hepatoprotective and anti-inflammatory properties. However, the characteristic of poor solubility and low bioavailability greatly limits its application. In addition, the effects and underlying mechanisms of BA in nonalcoholic fatty liver disease (NAFLD) remain elusive. In this study, Methionine and choline deficient diet (MCD)-induced NAFLD mice were treated with baicalin or baicalin-loaded nanoliposomes (BA-NL), then hepatic histopathological changes, biochemical parameters and inflammatory molecules were observed. We found that mice in MCD group showed significant increases in plasma transaminase, hepatocyte apoptosis, hepatic lipid accumulation, liver fibrosis, and infiltration of neutrophils and macrophages compared with control group, however, BA and BA-NL markedly attenuated MCD-induced the above changes. Besides, further analysis indicated that BA and BA-NL also inhibited the up-regulation of toll-like receptor 4 (TLR4) signal and the production of inflammatory mediators in MCD mice. Importantly, BA-NL was found to be more effective than baicalin on MCD-induced NAFLD in mice. These data suggested that BA and its nanoliposomes BA-NL could effectively protect mice against MCD-induced NAFLD, which might be mediated through inhibiting TLR4 signaling cascade.