Xinxia Chang

Circulating Fibroblast Growth Factor 21 Levels Are Closely Associated with Hepatic Fat Content: A Cross-Sectional Study

Background and Aims Fibroblasts growth factor 21 (FGF21), a liver-secreted endocrine factor involved in regulating glucose and lipid metabolism, has been shown to be elevated in patients with non-alcoholic fatty liver disease (NAFLD). This study aimed to evaluate the quantitative correlation between serum FGF21 level and hepatic fat content. Methods A total of 138 subjects (72 male and 66 female) aged from 18 to 65 years with abnormal glucose metabolism and B-ultrasonography diagnosed fatty liver were enrolled in the study. Serum FGF21 levels were determined by an in-house chemiluminescence immunoassay and hepatic fat contents were measured by proton magnetic resonance spectroscopy. Results Serum FGF21 increased progressively with the increase of hepatic fat content, but when hepatic fat content increased to the fourth quartile, FGF21 tended to decline. Serum FGF21 concentrations were positively correlated with hepatic fat content especially in subjects with mild/moderate hepatic steatosis (r = 0.276, p = 0.009). Within the range of hepatic steatosis from the first to third quartile, FGF21 was superior to any other traditional clinical markers including ALT to reflect hepatic fat content. When the patients with severe hepatic steatosis (the fourth quartile) were included, the quantitative correlation between FGF21 and hepatic fat content was weakened. Conclusions Serum FGF21 was a potential biomarker to reflect the hepatic fat content in patients with mild or moderate NAFLD. In severe NAFLD patients, FGF21 concentration might decrease due to liver inflammation or injury.

Efficacy of Berberine in Patients with Non-Alcoholic Fatty Liver Disease

Objectives A randomized, parallel controlled, open-label clinical trial was conducted to evaluate the effect of a botanic compound berberine (BBR) on NAFLD. Methods A randomized, parallel controlled, open-label clinical trial was conducted in three medical centers (NIH Registration number: NCT00633282). A total of 184 eligible patients with NAFLD were enrolled and randomly received (i) lifestyle intervention (LSI), (ii) LSI plus pioglitazone (PGZ) 15mg qd, and (iii) LSI plus BBR 0.5g tid, respectively, for 16 weeks. Hepatic fat content (HFC), serum glucose and lipid profiles, liver enzymes and serum and urine BBR concentrations were assessed before and after treatment. We also analyzed hepatic BBR content and expression of genes related to glucose and lipid metabolism in an animal model of NAFLD treated with BBR. Results As compared with LSI, BBR treatment plus LSI resulted in a significant reduction of HFC (52.7% vs 36.4%, p = 0.008), paralleled with better improvement in body weight, HOMA-IR, and serum lipid profiles (all p<0.05). BBR was more effective than PGZ 15mg qd in reducing body weight and improving lipid profile. BBR-related adverse events were mild and mainly occurred in digestive system. Serum and urine BBR concentrations were 6.99ng/ml and 79.2ng/ml, respectively, in the BBR-treated subjects. Animal experiments showed that BBR located favorably in the liver and altered hepatic metabolism-related gene expression. Conclusion BBR ameliorates NAFLD and related metabolic disorders. The therapeutic effect of BBR on NAFLD may involve a direct regulation of hepatic lipid metabolism. Trial Registration ClinicalTrials.gov NCT00633282

The effects of berberine on hyperhomocysteinemia and hyperlipidemia in rats fed with a long-term high-fat diet

BackgroundThe study was undertaken to examine the effects of berberine (BBR) on serum homocysteine, lipids and the aortic lesion in Sprague–Dawley (SD) rats fed with a long-term high-fat diet (HFD).MethodsHealthy male SD rats weighing 190-210 g received randomly standard diet or a high-fat diet for 24 weeks. After 8 weeks of feeding, rats fed with HFD were randomized to receive berberine (200 mg · kg-1· day-1) or vehicle by gavage for 16 weeks. After overnight fasting, all rats were sacrificed and total blood samples were also collected for determinant of fasting serum homocysteine (Hcy), total cholesterol (TC) and low density lipoprotein cholesterol (LDL-c) levels. The aorta was stained with hematoxylin and eosin (HE) and Sudan Ш to evaluate aortic lesion. The livers were dissected out and snap-frozen in liquid nitrogen for hepatic TC content and molecular analysis. 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGR), Lipoprotein receptors and apolipoproteins gene expression in the liver were determined by real-time PCR.ResultsIntragastrical administration with berberine for 16 weeks lowered serum Hcy in rats fed with a high-fat diet. In parallel, it also decreased body weight and improved serum TC and LDL-c. Berberine also tended to decrease hepatic cholesterol. Consistently, berberine also upregulated LDL receptor (LDLR) mRNA level and suppressed HMGR gene expression. Meanwhile, upon berberine-treated rats, there was a significant increase in apolipoprotein E (apoE) mRNA, but no change in apoAI and scavenger receptor (SR) mRNA in the liver. Further, no atherosclerotic lesions were developed in berberine-treated rats for 16 weeks.ConclusionBerberine can counteract HFD-elicited hyperhomocysteinemia and hyperlipidemia partially via upregulating LDLR and apoE mRNA levels and suppressing HMGR gene expression.

I148M variant of PNPLA3 increases the susceptibility to non-alcoholic fatty liver disease caused by obesity and metabolic disorders.

The patatin‐like phospholipase 3 (PNPLA3) rs738409 gene polymorphism is an important genetic determinant of non‐alcoholic fatty liver disease (NAFLD). However, the associations between liver fat and metabolic traits in rs738409 G allele carriers and the allelic influence on this association have not been fully studied.

Renal function‐dependent association of serum uric acid with metabolic syndrome and hepatic fat content in a middle‐aged and elderly Chinese population

The effect of uric acid (UA) on the pathogenesis of metabolic disorders is highly dependent on its physicochemical properties, and hyperuricaemia associated with different conditions may have different clinical meanings. The aim of the present study was to investigate the association of serum UA levels with metabolic syndrome and non‐alcoholic fatty liver disease (NAFLD) in a middle‐aged and elderly population with normal and impaired renal function. The cross‐sectional study was performed on 1141 participants (426 men, 715 women; mean age 62 years) enrolled from the Shanghai Changfeng community. Each participant underwent a standard interview, with anthropometric and laboratory measurements. Hepatic fat content (HFC) was determined by a newly established quantitative ultrasound method. Univariate correlation analysis showed that serum UA was associated with all components of metabolic syndrome and HFC (r = 0.193, P < 0.001), especially in participants with a normal estimated glomerular filtration rate (eGFR; r = 0.255, P < 0.001). Logistic regression analysis demonstrated an independent association of serum UA with metabolic syndrome and NAFLD in participants with normal renal function, but not in those with eGFR < 90 mL/min per 1.73 m2. Furthermore, multivariate linear analysis showed that UA levels were independently associated with HFC (P = 0.003), but only in participants with normal eGFR. Elevated serum UA is independently associated with metabolic syndrome and NAFLD in patients with normal renal excretory function. However, in those with renal insufficiency, hyperuricaemia has no association with metabolic disorders.

Assessment of liver fat content using quantitative ultrasonography to evaluate risks for metabolic diseases.

The ultrasound quantitative method for liver fat content (LFC) is a recent established method for non‐invasive assessment of liver steatosis. Its use in clinical practice is further explored by investigating the quantitative relationships between LFC measured by quantitative ultrasonography and metabolic diseases in a middle‐aged and elderly Chinese population.

Serum retinol binding protein 4 is negatively related to beta cell function in Chinese women with non-alcoholic fatty liver disease: a cross-sectional study

BackgroundTo observe the relationship between serum retinol binding protein 4(RBP4) and β cell function in Chinese subjects with non-alcoholic fatty liver disease (NAFLD) and without known diabetes.Methods106 patients diagnosed as fatty liver by ultrasonography (M/F: 61/45; aged 47.44 ± 14.16 years) were enrolled in our current cross-sectional study. Subjects with known diabetes, chronic virus hepatitis and excessive alcohol consumption were excluded. Serum RBP4 was detected by ELISA and validated by quantitative Western blotting. β cell function were assessed by HOMA in all subjects and by hyperglycemic clamp in 17 normal glucose tolerance subjects (M = 6, F = 11).ResultsThe levels of serum RBP4 in men were higher than that in women (55.96 ± 11.14 vs 45.87 ± 10.31 μg/ml, p < 0.001). Pearson’s correlation analysis demonstrated that in women, serum RBP4 levels were significantly associated with fasting blood glucose (FBG), HOMA-β, and increment of first phase insulin secretion (1PH), but not associated with age, BMI, waist circumference, WHR, systolic (SBP) and diastolic blood pressure (DBP), TC, TG, HDL-c, LDL-c, 2 h blood glucose, HOMA-IR, ALT, AST, γ-GT, hepatic fat content (HFC), and insulin sensitivity index (ISI). However, in men, serum RBP4 levels were significantly associated with HDL-c, ALT, AST, but not associated with any other parameters as mentioned above. A stepwise multiple linear regression analysis demonstrated that in women, HOMA-IR and RBP4 were significantly associated with HOMA-β, while in men, HOMA-IR and BMI were significantly variables associated with HOMA-β.ConclusionsSerum RBP4, secreted mainly by liver and adipose tissue, may involve in the pathogenesis of β cell dysfunction in Chinese women patients with NAFLD.

Influence of ethnicity on the accuracy of non-invasive scores predicting non-alcoholic fatty liver disease

Objectives Presence of non-alcoholic fatty liver disease (NAFLD) can predict risks for diabetes, cardiovascular disease and advanced liver disease in the general population. We aimed to establish a non-invasive score for prediction of NAFLD in Han Chinese, the largest ethnic group in the world, and detect whether ethnicity influences the accuracy of such a score. Methods Liver fat content (LFAT) was measured by quantitative ultrasound in 3548 subjects in the Shanghai Changfeng Community and a Chinese score was created using multivariate logistic regression analyses. This new score was internally validated in Chinese and externally in Finns. Its diagnostic performance was compared to the NAFLD liver fat score, fatty liver index (FLI) and hepatic steatosis index (HSI) developed in Finns, Italians and Koreans. We also analyzed how obesity related to LFAT measured by 1H-MRS in 79 Finns and 118 Chinese with type 2 diabetes (T2D). Results The metabolic syndrome and T2D, fasting serum insulin, body mass index (BMI) and AST/ALT ratio were independent predictors of NAFLD in Chinese. The AUROC in the Chinese validation cohort was 0.76 (0.73–0.78) and in Finns 0.73 (0.68–0.78) (p<0.0001). 43%, 27%, 32% and 42% of Chinese had NAFLD when determined by the Chinese score, NAFLD liver fat score (p<0.001 vs. Chinese score), FLI (p<0.001) and HSI (NS). For any given BMI and waist circumference, the Chinese had a markedly higher LFAT than the Finns. Conclusion The predictors of NAFLD in Han Chinese are as in Europids but the Chinese have more LFAT for any given degree of obesity than Europids. Ethnicity needs to be considered when NAFLD is predicted using risk scores.

Metformin attenuates triglyceride accumulation in HepG2 cells through decreasing stearyl-coenzyme A desaturase 1 expression

BackgroundThe prevalence of nonalcoholic fatty liver disease (NAFLD) has increased worldwide. Metformin decreases triglyceride (TG) accumulation in hepatocytes in vivo and in vitro. Stearyl-coenzyme A desaturase 1 (SCD1) knockout mice also show decreased liver TG accumulation; however, whether SCD1 plays a role in the effect of metformin on TG accumulation is unknown. Therefore, the aim of this study was to investigate whether SCD1 mediated the effect of metformin on TG accumulation.MethodsHepG2 and AML12 cells were exposed to high glucose and high insulin with or without metformin. An adenovirus was used for the SCD1 knockdown and overexpression. The triglyceride level in cells was detected. The expression of related genes was detected by Western blot and quantitative real-time PCR. A dual-luciferase reporter assay was used to determine the effect of metformin on the transcriptional activity of the SCD1 promoter.ResultsMetformin decreased TG accumulation to normal level in HepG2 cells exposed to high glucose and high insulin. The expression of SCD1 and fatty acid synthetase (FAS) was also decreased to normal level by metformin. Knockdown of SCD1 mimicked the effect of metformin on decreasing TG levels in AML12 cells, and the overexpression of SCD1 attenuated the effect of metformin on decreasing TG accumulation in HepG2 cells. The dual-luciferase reporter assay showed that the transcriptional activity of the SCD1 promoter (− 550/+ 199) after metformin treatment was 2-fold lower compared to control group in HepG2 cells. Additionally, the phosphorylation of AMPK after metformin treatment was 2-fold higher, and the expression of sterol regulatory element-binding protein-1c (SREBP-1c) after metformin treatment was about 2-fold lower compared to high glucose and high insulin group in HepG2 cells.ConclusionsTogether, these results reveal that metformin reduces TG accumulation in HepG2 cells via inhibiting the expression of SCD1.

Serum retinol binding protein 4 is negatively related to estrogen in Chinese women with obesity: a cross-sectional study

BackgroundThe association between serum Retinol Binding Protein 4 (RBP4) and obesity is still controversial. Serum RBP4 levels varies by gender, and estradiol may play a role in the difference. To investigate the participation of sex hormones in the association of RBP4 and obesity in humans, we measured serum RBP4, BMI, and sex hormones in 87 women from the outpatient.MethodsEighty-seven subjects of Chinese women origin from the outpatient (aged 40.22 ± 15.54 years) were enrolled. Subjects with diseases affecting the metabolic state or not suitable to participate in this study were excluded. Anthropometrics and laboratory tests, including lipid profile, luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin (PRL), estradiol (E2),progesterone (PROG), testosterone (TESTO), and dehydroepiandrosterone (DHEA) were conducted. Serum RBP4 was detected by an enzyme immunoassay kit and validated by quantitative Western blotting.ResultsCirculating RBP4 levels were positively associated with BMI, waist circumference, waist-to-hip ratio (WHR), systolic and diastolic (SBP), diastolic blood pressure (DBP), triglycerides (TG), low high-density lipoprotein cholesterol(LDL-c), and testosterone (TESTO) in the total group. While only in obese individuals, serum RBP4 levels were negatively associated with E2. The highest value was in the subjects with both obesity and the low estrogen level. Multiple linear regression analysis revealed that RBP4 correlated independently with TG, TC and insulin in all subjects, TC in non- obese individuals. However, E2 were significantly associated with serum RBP4 only in obese individuals.ConclusionsRBP4 could be a marker of obesity-related factors; estrogen was negatively related to RBP4 and might be one of the influential factors.