Bile acid receptors in non-alcoholic fatty liver disease

Accumulating data have shown that bile acids are important cell signaling molecules, which may activate several signaling pathways to regulate biological processes. Bile acids are endogenous ligands for the farnesoid X receptor (FXR) and TGR5, a G-protein coupled receptor. Gain- and loss-of-function studies have demonstrated that both FXR and TGR5 play important roles in regulating lipid and carbohydrate metabolism and inflammatory responses. Importantly, activation of FXR or TGR5 lowers hepatic triglyceride levels and inhibits inflammation. Such properties of FXR or TGR5 have indicated that these two bile acid receptors are ideal targets for treatment of non-alcoholic fatty liver disease, one of the major health concerns worldwide. In this article, we will focus on recent advances on the role of both FXR and TGR5 in regulating hepatic triglyceride metabolism and inflammatory responses under normal and disease conditions.     

Green tea polyphenol epigallocatechin-3-gallate ameliorates insulin resistance in non-alcoholic fatty liver disease mice

Aim:

Epigallocatechin-3-gallate (EGCG) is a major polyphenol in green tea. In this study, we investigated the effects of EGCG on insulin resistance and insulin clearance in non-alcoholic fatty liver disease (NAFLD) mice.

Methods:

Mice were fed on a high-fat diet for 24 weeks. During the last 4 weeks, the mice were injected with EGCG (10, 20 and 40 mg·kg⁻¹·d⁻¹, ip). Glucose tolerance, insulin tolerance and insulin clearance were assessed. After the mice were euthanized, blood samples and tissue specimens were collected. Glucose-stimulated insulin secretion was examined in isolated pancreatic islets. The progression of NAFLD was evaluated histologically and by measuring lipid contents. Insulin-degrading enzyme (IDE) protein expression and enzyme activity were detected using Western blot and immunocapture activity assays, respectively.

Results:

The high-fat diet significantly increased the body weight and induced grade 2 or 3 liver fatty degeneration (steatosis, lobular inflammation and ballooning) accompanied by severe hyperlipidemia, hyperglycemia, hyperinsulinemia and insulin resistance in the model mice. Administration of EGCG dose-dependently ameliorated the hepatic morphology and function, reduced the body weight, and alleviated hyperlipidemia, hyperglycemia, hyperinsulinemia and insulin resistance in NAFLD mice. Furthermore, EGCG dose-dependently enhanced insulin clearance and upregulated IDE protein expression and enzyme activity in the liver of NAFLD mice.

Conclusion:

EGCG dose-dependently improves insulin resistance in NAFLD mice not only by reducing body weight but also through enhancing the insulin clearance by hepatic IDE. The results suggest that IDE be a potential drug target for the treatment of NAFLD.     

A pilot study of atorvastatin treatment in dyslipemid, non-alcoholic fatty liver patients

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of liver injury. Currently, there are no proven effective therapies available. Atorvastatin is a new 3-hydroxy-3-metylglutaryl coenzyme A reductase inhibitor that reduces lipid serum levels. AIM: To evaluate the effectiveness and safety of atorvastatin in dyslipemid, non-alcoholic fatty liver patients. PATIENTS AND METHODS: We prospectively enrolled 25 patients with NAFLD; 22 of them completed the study. Body mass index, serum lipids, liver function tests and liver density assessed by echography were measured at baseline and after 1, 3, 6, 9 and 12 months of treatment. Normalization of transaminases and/or improvement in liver density were treatment end points. Patients received atorvastatin (10-80 mg/daily) according to basal serum choleresterol levels; additionally, they were given standard weight-loss counselling and encouraged to follow a low fat diet. RESULTS: All 22 patients (14 men, mean age 47 +/- 10 years) had high cholesterol levels at baseline and 11 (44%) also presented high trygliceride levels. After 6 months of treatment, eight patients (36.3%) presented normal transaminase levels. The remaining patients continued treatment for 12 months when 20% of patients presented with normal transaminase levels, while the other patients showed a 10% reduction in basal levels. Mean cholesterol levels were 268.5 +/- 44.2 and 186.8 +/- 14.4 mg/dL before and after treatment, respectively (P < 0.05). The mean body mass index was 27.4 +/- 3.1 at baseline and 26.3 +/- 2.8 kg/cm2 at the end of treatment (P > 0.05). No side effects were reported. CONCLUSIONS: Serum aminotransferase and lipid levels were reduced significantly in all patients with atorvastatin treatment. Therapy with atorvastatin in NAFLD patients with hyperlipidemia was found to be both effective and safe.     

Impairment of reproductive function in a male rat model of non-alcoholic fatty liver disease and beneficial effect of N-3 fatty acid supplementation

Non-alcoholic fatty liver disease (NAFLD) is closely associated with reduced levels of testosterone, which may affect fertility. Herein, we investigated whether NAFLD impairs the reproductive function of male rats. Male Sprague-Dawley rats were fed a high fat diet (HFD) until they developed NAFLD. N-3 polyunsaturated fatty acid (PUFA) was then given for 4 weeks to prevent hepatic steatosis. Testes weight and serum and testicular testosterone were significantly lower in rats with NAFLD compared with healthy controls. Testicular pathological changes in NAFLD rats included markedly reduced sperm number and motility, and the number of apoptotic spermatogenic cells was higher, which was consistent with a reduction in the number of tetraploid cells. Breeding experiments indicated that paternal NAFLD affected neither the sperm morphology nor the development of fetuses and offspring, but did prolong the days required for insemination. However, administration of N-3 PUFA alleviated the impairment of reproductive function. These results suggest that NAFLD impairs reproductive function in male rats by decreasing testicular testosterone synthesis, and N-3 PUFA treatment may have a beneficial therapeutic effect.     

n-3多不饱和脂肪酸在慢性肾脏疾病中的应用

数十年来的动物研究支持鱼油中的主要成分n-3多不饱和脂肪酸(n-3PUFA)在肾脏疾病治疗中的有效性,在一些人类肾小球疾病如IgA肾病中n-3PUFA也被证实有益,但临床试验结果并不一致。n-3PUFA应用能否成为肾脏疾病的一种新的治疗手段,仍需进一步的大规模临床研究。     

Caffeine is protective in patients with non-alcoholic fatty liver disease

Aliment Pharmacol Ther 2012; 35: 76–82

Summary

Background Non‐alcoholic fatty liver disease (NAFLD), the hepatic manifestation of metabolic syndrome, is the most common cause of primary liver disease. Although recent studies have found that coffee drinking is protective against end stage chronic liver disease, there are scarce caffeine intake data in NAFLD specifically. Aim To investigate the effects of dietary behaviour in NAFLD patients, using four continuous cycles of the National Health and Nutrition Examination Surveys (NHANES 2001–2008). Methods Using data from four continuous cycles of NHANES, dietary intake questionnaires that list 62 nutrition components. Logistic regression was used to identify independent predictors of NAFLD among nutrition components after adjustment for potential clinical confounders. All analyses were run using sas 9.1 and sudaan 10.0 (SAS Institute Inc., Cary, NC, USA). Results Of the 62 nutrient components used for the univariate analysis, 38% were significant (P‐value <0.05) in NAFLD with caffeine consumption being higher in the control group (P‐value <0.001). The multivariate analysis using demographics, clinical parameters and nutritional components found five factors independently associated with NAFLD [African American Race P‐value <0.001); Male gender P‐value <0.001); Obesity (BMI ≥ 30) P‐value <0.001); Caffeine intake (mg) P‐value <0.001) and total plain water consumption (g) P‐value ≤0.02)]. Conclusions Our analysis shows that caffeine intake is independently associated with a lower risk for NAFLD suggesting a potential protective effect. These data necessitate further research to elucidate the mechanism by which caffeine can protect against NAFLD.     

Health-related quality of life in patients with non-alcoholic fatty liver disease

BACKGROUND: The relative impact of non-alcoholic fatty liver disease (NAFLD) on health-related quality of life (HRQL) compared to other chronic liver diseases has not been fully explored. AIM: To compare the domain scores of the 29-item Chronic Liver Disease Questionnaire (CLDQ) for patients with NAFLD to those with chronic hepatitis B and chronic hepatitis C. METHODS: A HRQL questionnaire, CLDQ, was routinely administered to patients attending a liver clinic. Additional clinical and laboratory data were obtained on patients with NAFLD, chronic hepatitis B, and chronic hepatitis C from our quality of life database. Scores for each of the six CLDQ domains were compared using one-way anova and multiple regression. RESULTS: Complete data were available for 237 patients. NAFLD patients scored lowest on multiple CLDQ domains. Based on the bivariate data, NAFLD patients have the poorest HRQL, followed by chronic hepatitis C and chronic hepatitis B patients. Multivariate analysis showed that some specific domain score correlations remained significant for NAFLD diagnosis, cirrhosis, gender, and body mass index. CONCLUSION: NAFLD patients had significantly lower quality of life scores compared with patients with hepatitis B or hepatitis C on multiple CLDQ domains, suggesting that HRQL was severely impaired in patients with NAFLD.     

Hyperuricemia is associated with histological liver damage in patients with non-alcoholic fatty liver disease

Aliment Pharmacol Ther 2011; 34: 757–766

Summary

Background Hyperuricemia has been associated with metabolic disorders. In this line recent studies observed an independent link between higher uric acid serum levels and clinical diagnosis of non‐alcoholic fatty liver disease (NAFLD). Aims We aimed to assess the potential association between uric acid serum levels and histological liver damage in a homogeneous cohort of biopsy‐proven NAFLD patients. Methods Consecutive NAFLD patients (n = 166), assessed by liver biopsy (Kleiner score), anthropometric, biochemical and metabolic features, were included. Enzymatic colorimetric test was used for serum uric acid assays (Roche Diagnostics GmbH, Mannheim, Germany). Hyperuricemia was diagnosed when uric acid serum levels were >7 mg/dL in men, and >6 mg/dL in women. Results Mean uric acid serum level was 5.75 mg/dL, and about 20% of patients had hyperuricemia, that was independently associated with younger age (OR 0.951, 95% CI 0.918–0.984, P = 0.004), lobular inflammation (OR 2.144, 95% CI 1.055–4.357, P = 0.03) and steatosis grade (OR 1.859, 95% CI 1.078–3.205, P = 0.02), by multivariate logistic regression analysis. Female gender (OR 2.656, 95% CI 1.190–5.928, P = 0.01), higher HOMA index (OR 1.219, 95% CI 1.043–1.426, P = 0.01), and hyperuricemia (OR 4.906, 95% CI 1.683–14.296, P = 0.004) were linked to NAFLD activity score (NAS) ≥ 5 by multiple logistic regression analysis. Conversely, higher HOMA index (OR 1.140, 95% CI 1.001–1.229, P = 0.04), and NAS (OR1.954, 95% CI 1.442–2.649, P < 0.001) were independently associated with significant fibrosis by logistic regression analysis. Conclusions In NAFLD patients, hyperuricemia is independently associated with the severity of liver damage, representing, in this setting of patients, together with insulin resistance, a potential new therapeutic target in future intervention trials.     

Effects of lipoic acid and n-3 long-chain polyunsaturated fatty acid on the liver ovariectomized rat model of menopause

Background

Bilateral ovariectomy is an experimental model used to analyse the effects of menopause and develop strategies to mitigate the deleterious effects of this condition. Supplementation of the diet with antioxidants has been used to reduce potential oxidative stress caused by menopause. The purpose of the study was to analyse the effects of α-lipoic acid (LA), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), dietary supplementation on oxidative stress in the livers of ovariectomized rats.

Dietary supplementation with n-3 polyunsaturated fatty acids attenuates the depression of food-motivated behavior during zymosan-induced peritonitis

Peripheral inflammation is accompanied by neurobehavioral alterations such as depression of feeding, exploratory and sexual behaviors. Our previous investigation reported that dietary enrichment with n-3 polyunsaturated fatty acids (PUFA) attenuated the depression of food-motivated behavior and social exploration, but not endocrinological and metabolic disturbances in the mice with systemic inflammation induced by lipopolysaccharide (LPS). We here demonstrate that dietary n-3 PUFA also attenuate the reduction of food-motivated behavior during zymosan-induced peritonitis in mice without influencing plasma leakage into peritoneum and writhing response. Our results suggest that the common mechanism is involved in the attenuation of behavioral depression during systemic and local inflammation by dietary n-3 PUFA.     

水林佳治疗非酒精性脂肪性肝病疗效观察

目的观察水林佳（水飞蓟宾-磷脂复合物）治疗非酒精性脂肪性肝病的临床疗效。方法将56例患者随机分为2组,治疗组予水林佳口服,对照组予硫普罗宁口服,均3个月为1个疗程,疗程结束后,观察临床症状、ALT、AST、TC、TG和超声影像的变化。同时观察2组患者用药期间的不良反应。结果治疗组和对照组总有效率分别为89.3%及71.4%,治疗组明显高于对照组,2组比较差异有显著性（P〈0.05）。治疗组在改善患者临床症状、肝功能、血脂及超声影像方面疗效确切,无明显不良反应。结论水林佳治疗非酒精性脂肪性肝病有较好临床疗效。     

水林佳治疗非酒精性脂肪肝的疗效观察

目的:探讨水林佳治疗非酒精性脂肪肝的疗效。方法:随机选择非酒精性脂肪肝患者90例,试验组46例,服用水林佳105mg,3次/日;对照组44例,口服硫普罗宁100 mg,3次/日,观察期为3个月。治疗前后检测肝转氨酶、血胆固醇、甘油三酯、肝纤维谱及超声影像变化。同时观察两组患者用药期间的不良反应。结果:治疗结束时,试验组ALT、AST、TC、TG及HA、LN、PC-Ⅲ均明显下降,肝脏影像学也有明显改善。对照组虽ALT、AST有所下降,但HA、LN、PC-Ⅲ和肝脏影像学无明显改善。观察期间两组均未出现明显不良反应。结论:水林佳具有保肝、降血脂、改善肝纤维化的作用,对非酒精性脂肪肝有治疗作用。     

非酒精性脂肪肝患者血清鸢尾素水平变化的研究

目的：探讨不同病变程度非酒精性脂肪肝（non-alcoholic fatty liver disease，NAFLD）患者血清鸢尾素（Irisin）水平的变化情况及Irisin与其他生化指标的相关性。方法选取135例NAFLD患者（轻度脂肪病变患者73例，中、重及极重度脂肪病变患者共62例）作为观察组，健康体检者150例为对照组，全自动生化分析仪测定其各项血脂指标水平及各项生化指标；酶联免疫吸附法测定血清Irisin水平；依据稳态模型评估法计算胰岛素抵抗指数，并同时测量身高、体质量等多项基线指标。结果血清Irisin水平与对照组相比，轻度NAFLD患者，中、重及极重度NAFLD患者均增高（P＜0．05）；其它各项指标与对照组相比，NAFLD组患者的BMI、TC、TG、AST、ALT、收缩压、舒张压、腰围、臀围、血糖、FINS及HOMA-IR均呈现不同程度升高，差异多有统计学意义（P＜0．05）；而年龄、性别、HDL-C、LDL-C水平差异多无统计学意义（P＞0．05）。Spearman相关分析结果显示，研究对象血清Irisin水平与BMI（rs ＝0．168，P＜0．05），FINS（rs ＝0．204，P＜0．01），HOMA-IR（rs ＝0．205，P＜0．05），AST（rs＝0．149，P＜0．05），腰围（rs ＝0．147，P＜0．05）呈现正相关，而与TC（rs ＝－0．205，P＜0．05），HDL-C（rs ＝－0．165，P＜0．05）呈现负相关；FINS、HOMA-IR、AST是影响血浆Irisin水平的独立相关因素。结论血清Irisin水平在NAFLD组患者中较正常人群增高，且在轻度NAFLD患者中水平最高。     

Cardiovascular protective effects of n-3 polyunsaturated fatty acids with special emphasis on docosahexaenoic acid

It is widely accepted that n-3 polyunsaturated fatty acids (PUFAs) rich in fish oils protect against several types of cardiovascular diseases such as myocardial infarction, arrhythmia, atherosclerosis, or hypertension. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may be the active biological components of these effects. Although the precise cellular and molecular mechanisms underlying the beneficial effects are still uncertain, the protective effects of n-3 PUFAs are attributable to their direct effects on vascular smooth muscle cell (VSMC) functions. These n-3 PUFAs activate K(+)(ATP) channels and inhibit certain types of Ca(2+) channels, probably via at least 2 distinct mechanisms. N-3 PUFAs favorably alter the eicosanoid profile and regulate cytokine-induced expression of inducible nitric oxide synthase and cyclooxygenase-2 via mechanisms involving modulation of signaling transduction events. N-3 PUFAs also modulate VSMC proliferation, migration, and apoptosis. These recent data suggest that modulation of these VSMC functions contribute to the beneficial effects of n-3 PUFAs on various cardiovascular disorders. Furthermore, recent studies strongly suggest that DHA has more potent and beneficial effects than EPA. However, many questions about the cellular and molecular mechanisms still remain to be answered.     

Histological progression of non-alcoholic fatty liver disease in Chinese patients

BACKGROUND: Non-alcoholic fatty liver disease is an important cause of chronic hepatitis and cryptogenic cirrhosis. The natural history of non-alcoholic fatty liver disease is not well understood especially in Asian populations. AIM: To investigate the histological progression in Chinese patients with biopsy-proven non-alcoholic fatty liver disease. METHODS: Chinese patients who had liver biopsy at least 3 years ago and confirmed to have non-alcoholic fatty liver disease were invited for a second liver biopsy. Clinical and laboratory parameters related to their liver function and metabolic syndrome were recorded and analysed. Liver biopsies were scored for the degree of steatosis, necroinflammation and fibrosis. Correlation coefficients were calculated to assess the association between changes in histological scores and metabolic parameters. RESULTS: Seventeen patients who had been followed up for a median period of 6.1 (range: 3.8-8.0) years underwent a second liver biopsy. Nine (53%) patients had progressive disease with worsening of fibrosis score. No statistically significant correlation was found between the changes in histological scores and metabolic parameters. Seven patients developed hypertension or diabetes mellitus during the period of follow-up. CONCLUSIONS: Non-alcoholic fatty liver disease is a progressive disease in Chinese patients as in their Caucasian counterparts. Diagnosis of non-alcoholic fatty liver disease may predate development of new components of metabolic syndrome.     

Models for non-alcoholic fatty liver disease: a link with vascular risk

Non alcoholic fatty liver disease (NAFLD) is often part of the metabolic syndrome which includes central obesity, dyslipidaemia, insulin resistance/type 2 diabetes mellitus and hypertension. In turn, NAFLD may be associated with an increased vascular risk. Several experimental models which express histological steatosis or steatohepatitis with fibrosis have been described. This review identifies those models of NAFLD with features of vascular risk.