胰岛素抵抗和非酒精性脂肪性肝病研究进展

非酒精性脂肪性肝病(NAFLD)是现在临床上最为常见的肝病之一,其病因及发病机制均相当复杂,至今尚未完全阐明.目前认为,胰岛素抵抗(IR)不仅是NAFLD的触发因素,而且还可能间接促进单纯性脂肪肝向脂肪性肝炎(NASH)乃至肝纤维化转变的过程.至于IR是否直接参与NASH的发生、发展尚存在争议.此外,NAFLD本身也可能诱发及加重IR,比如肝细胞内蓄积的脂肪、TNF-α、瘦素抵抗等都参与这一过程.随着二者关系及相关因素的发展,NAFLD在诊疗方面也取得了较大的进展.近年来,有关这方面的研究很多,本文对此作阐述.

Comprehensive Understanding of Immune Cells in The Pathogenesis of Non-alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease(NAFLD)is the most common chronic liver disease,defined by several phases,ranging from benign fat accumulation to non-alcoholic steatohepatitis(NASH),which can lead to liver cancer and cirrhosis.Although NAFLD is a disease of disordered metabolism,it also involves several immune cell-mediated inflammatory processes,either promoting and/or suppressing hepatocyte inflammation through the secretion of pro-inflammatory and/or anti-inflammatory factors to influence the NAFLD process.However,the underlying disease mechanism and the role of immune cells in NAFLD are still under investigation,leaving many open-ended questions.In this review,we presented the recent concepts about the interplay of immune cells in the onset and pathogenesis of NAFLD.We also highlighted the specific non-immune cells exhibiting immunological properties of therapeutic significance in NAFLD.We hope that this review will help guide the development of future NAFLD therapeutics.

Liver histology according to the presence of metabolic syndrome in nonalcoholic fatty liver disease cases

AIM:To investigate the histologic features of the liver in nonalcoholic fatty liver disease (NAFLD) cases according to the presence of metabolic syndrome or its individual components. METHODS:We enrolled 81 patients (40 male,41 fe-male) who were diagnosed with fatty liver by ultraso-nographic scan and fulfi lled the inclusion criteria. First anamnesis,anthropometric,clinical,laboratory and imaging features of all participants were recorded and then liver biopsy was performed after gaining consent from patients. Diagnosis of metabolic syndrome was dependent on patients having 3 or more out of 5 risk criteria defined by the WHO. Biopsy specimens were assessed according to Brunt et al's classification. RESULTS:Sixty-nine of the 81 patients had nonalco-holic steatohepatitis (NASH),11 had simple fatty liver and 1 had cirrhosis according to histologic evaluation. Comparisons were made between two groups of NASH patients,those with and without metabolic syndrome. We did not detect statistically significant differences in liver histology between NASH patients with and wit-hout metabolic syndrome. CONCLUSION:NASH can progress without metabolic risk factors or the presence of metabolic syndrome.

Olive oil consumption and non-alcoholic fatty liver disease

The clinical implications of non-alcoholic fatty liver diseases(NAFLD)derive from their potential to progress to fibrosis and cirrhosis.Inappropriate dietary fat intake,excessive intake of soft drinks,insulin resistance and increased oxidative stress results in increased free fatty acid delivery to the liver and increased hepatic triglyceride(TG)accumulation.An olive oil-rich diet decreases accumulation of TGs in the liver,improves postprandial TGs,glucose and glucagonlike peptide-1 responses in insulin-resistant subjects, and upregulates glucose transporter-2 expression in the liver.The principal mechanisms include:decreased nuclear factor-kappaB activation,decreased lowdensity lipoprotein oxidation,and improved insulin resistance by reduced production of inflammatory cytokines(tumor necrosis factor,interleukin-6)and improvement of jun N-terminal kinase-mediated phosphorylation of insulin receptor substrate-1.The beneficial effect of the Mediterranean diet is derived from monounsaturated fatty acids,mainly from olive oil.In this review,we describe the dietary sources of the monounsaturated fatty acids,the composition of olive oil,dietary fats and their relationship to insulin resistance and postprandial lipid and glucose responses in non-alcoholic steatohepatitis,clinical and experimental studies that assess the relationship between olive oil and NAFLD,and the mechanism by which olive oil ameliorates fatty liver,and we discuss future perspectives.

Signal transduction mechanism of TRB3 in rats with non-alcoholic fatty liver disease

AIM： To evaluate the possible role of Tribble 3 （TRB3） in a rat model of non-alcoholic fatty liver disease （NAFLD） and its signal transduction mechanism.METHODS： Thirty Sprague-Dawley rats were randomized into three groups： normal control group, non-alcoholic fatty liver group A （fed on a high-fat diet for 8 wk） and group B （fed on a high-fat diet for 16 wk）. To determine the degree of hepatic steatosis in rats of each group, livers were stained with hematoxylin and eosin, and evaluated; real-time fluorescent quantitative reverse transcriptase-polymerase chain reaction was performed to measure the expression levels of TRI33 mRNA, and Western blotting analysis was done to determine the expression levels of protein kinase B （Akt） and phosphorylated protein kinase B （p-Akt-Thr308, p-Akt-Ser473）.RESULTS： Hepatic steatosis was evident in both NAFLD groups： mild to moderate hepatic steatosis occurred in group A, mainly as mild steatosis.Moderate to severe hepatic steatosis occurred in group B, mainly as severe steatosis. The expression level of TRB3 mRNA in group B was significantly higher than in the control group （122.28 ± 95.37 vs 3.06 ± 2.33,P = 0.002） and group A （122.28 ± 95.37 vs 5.77 ± 4.20,P = 0.001）. There was no significant difference in the expression levels of Akt （1.03 ± 0.53 vs 1.12 ± 0.77,P = 0.729） and p-Akt-Thr308 （0.82 ± 0.45 vs 0.92 ± 0.38, P = 0.592） between group A and the control group. The expression level of Akt and p-Akt-Thr308 in group B was significantly lower than in group A （Akt 0.41 ± 0.16 vs 1.12 ± 0.77, P = 0.008; p-Akt-Thr308 0.47 ± 0.19 vs 0.82 ± 0.45, P = 0.036） and the control group （Akt 0.41 ± 0.16 vs 1.03 ± 0.53, P = 0.018;p-Akt-Thr308 0.47 ± 0.19 vs 0.92 ± 0.38, P = 0.010）.The expression level of p-Akt-Ser473 in group A was significantly higher than in group B （1.48 ± 0.50 vs 0.81± 0.39, P = 0.041） as well as the control group （1.48 ± 0.50 vs 0.45 ± 0.26, P = 0.003）.CONCLUSION： TRB3 blocks insulin signaling by inhibiting Akt activation, which contributes to insulin resistance. It may be an important factor in the occurrence and development of NAFLD.

Non-alcoholic steatohepatitis with normal aminotransferase values

AIM： To investigate the aspects of liver histology in patients with non-alcoholic steatohepatitis （NASH） who had normal aminotransferase levels. METHODS： Thirty-four patients diagnosed with liver steatosis by ultrasonographic examination participated in the study. We compared all non- alcoholic fatty liver disease and NASH cases, according to aminotransferase level, aspartate aminotransferase （AST）/alanine aminotransferase （ALT） ratio and presence of metabolic syndrome. RESULTS： Sixteen of 25 patients with high aminotransferase levels were diagnosed with NASH and nine with simple fatty liver according to liver histology. Among the nine patients with normal aminotransferase levels, seven had NASH and two had simple fatty liver. The patients with normal and high liver enzyme levels had almost the same prevalence of NASH and metabolic syndrome. Liver histology did not reveal any difference according to aminotransferase levels and AST/ALT ratio. CONCLUSION： Aminotransferase levels and AST/AIT ratio do not seem to be reliable predictors for NASH. Despite numerous non-invasive biomarkers, all patients with fatty liver should undergo liver biopsy.

Is adiponectin level a predictor of nonalcoholic fatty liver disease in nondiabetic male patients?

AIM: To study the levels of adiponectin in nondiabetic patients with nonalcoholic fatty liver disease (NAFLD) in comparison with control group.METHODS: Thirty-five patients who had elevated serum aminotransferase levels with bright liver and 34 healthy volunteers without liver disease were evaluated. Age,gender and body mass index (BMI) were recorded. Fasting plasma glucose, insulin, adiponectin, proinsulin and lipid profile were measured. A standard oral glucose tolerance test (OGTT) with insulin response was performed and the index of insulin resistance was calculated according to the homeostasis model assessment (HOMA) method.RESULTS: According to the OGTT results, none of the participants had diabetes. Serum adiponectin levels were statistically significantly lower in patients with NAFLD than in control group (8.14±3.4 μg/mL vs12.4±9.4 μg/mL,respectively, P＜0.01). A statistically significant correlation was found between adiponectin and BMI (r: -0.33, P＜0.01),HOMA (r: -0.26, P＜0.05), proinsulin (r: -0.32, P＜0.01),AST (r: -0.25, P＜0.05), ALT (r: -0.26, P＜0.05) or GGT (r: -0.22, P＜0.05). In multiple regression analysis models,adiponectin levels were the only predictor of NAFLD in males, whereas in female group it was the BMI.CONCLUSION: Low adiponectin level might be a predictor of NAFLD especially in male nondiabetics.

The Gut Microbiota, Tumorigenesis, and Liver Diseases

In recent decades, diseases concerning the gut microbiota have presented some of the most serious public health problems worldwide. The human host＇s physiological status is influenced by the intestinal microbiome, thus integrating external factors, such as diet, with genetic and immune signals. The notion that chronic inflammation drives carcinogenesis has been widely established for various tissues. It is surprising that the role of the microbiota in tumorigenesis has only recently been recognized, given that the presence of bacteria at tumor sites was first described more than a century ago. Extensive epidemiological studies have revealed that there is a strong link between the gut microbiota and some common cancers. However, the exact molecular mechanisms linking the gut microbiota and cancer are not yet fully understood. Changes to the gut microbiota are instrumental in determining the occurrence and progression of hepatocarcinoma, chronic liver diseases related to alcohol, nonalcoholic fatty liver disease （NAFLD）, and cirrhosis. To be specific, the gut milieu may play an important role in systemic inflammation, endotoxemia, and vasodilation, which leads to complications such as spontaneous bacterial peritonitis and hepatic encephalopathy. Relevant animal studies involving gut microbiota manipulations, combined with observational studies on patients with NAFLD, have provided ample evidence pointing to the contribution of dysbiosis to the pathogenesis of NAFLD. Given the poor prognosis of these clinical events, their prevention and early management are essential. Studies of the composition and function of the gut microbiota could shed some light on understanding the prognosis because the microbiota serves as an essential component of the gut milieu that can impact the aforementioned clinical events. As far as disease management is concerned, probiotics may provide a novel direction for therapeutics for hepatocellular carcinoma （HCC） and NAFLD, given that probiotics function as a type of medicine that can improve human health by regulating the immune system. Here, we provide an overview of the relationships among the gut microbiota, tumors, and liver diseases. In addition, considering the significance of bacterial homeostasis, we discuss probiotics in this article in order to guide treatments for related diseases.

Hyperferritinemia is a risk factor for steatosis in chronic liver disease

AIM: To investigate the relationship between ferritin and steatosis in patients with chronically abnormal liver function tests (LFTs) and high ferritin level. METHODS: One hundred and twenty-four consecutive patients with hyperferritinemia (male > 300 ng/mL, female > 200 ng/mL) were evaluated; clinical, biochemical and serological data, iron status parameters, HFE gene mutations and homeostasis model assessment score were obtained. Steatosis was graded by ultrasound as absent or present. Histology was available in 53 patients only. RESULTS: Mean level of ferritin was 881 ± 77 ng/mL in men and 549 ± 82 ng/mL in women. The diagnosis was chronic hepatitis C in 53 (42.7%), non-alcoholic fatty liver disease/non-alcoholic steatohepatitis in 57 (45.9%), and cryptogenic liver damage in 14 (11.3%). None was diagnosed as hereditary hemochromatosis (HH). Hepatic siderosis on liver biopsy was present in 17 of 54 (32%) patients; grade 1 in eight and grade 2 in nine. Overall, 92 patients (74.2%) had steatosis. By logistic regression, ferritin and γ-glutamyltransferase were independent predictors of steatosis. Ferritin levels were signifi cantly related to low platelet count, steatosis and hepatitis C virus infection. CONCLUSION: In a non-obese cohort of non-alcoholic patients with chronically abnormal LFTs without HH, high serum ferritin level is a risk factor for steatosis.

Observation on clinical effects of acupoint thread-embedding method for non-alcoholic fatty liver disease

Objective： To observe the clinical effects of acupoint thread-embedding method for non-alcoholic fatty liver disease （NAFLD） in pattern of liver qi stagnation and spleen deficiency. Methods： A total of 180 cases in conformity with the diagnostic criteria of NAFLD in pattern of liver qi stagnation and spleen deficiency were randomly divided into a treatment group and a control group, 90 cases in each group, and finally 88 cases in the treatment group and 90 cases in the control group were recruited for statistics. The treatment group was managed by acupoint thread-embedding method, and the control group was treated by oral administration of Polyene Phosphatidylcholine capsules. Both groups were treated for 6 months. Before and after the treatment, liver enzymology, blood fat test, abdominal B ultrasonic examination, and assessment of clinical effects were respectively processed. Results： After treatment, alanine transaminase （ALT）, aspartate transaminase （AST）, total cholesterol （TC）, and triglyceride （TG） decreased in the treatment group, and were significantly different from those in the control group after treatment （all P〈0.05）. There was no statistically significant inter-group difference in the degree of fatty liver （by B ultrasound examination） before treatment （P〉0.05）. After treatment, the improvement degree of fatty liver in the treatment group was more significant than that in the control group （P〈0.05）. The total effective rates were 89.8% in the treatment group and 76.7% in the control group, with a statistically significant difference between the two groups （P〈0.05）. Conclusion： The acupoint thread-embedding method can reduce the levels of ALT, AST, TC and TG in NAFLD patients, and can improve the pathologic degree of fatty liver and its clinical effects are remarkably better than that of oral medications.

Association between non-alcoholic fatty liver disease and arterial stiffness in the non-obese, non-hypertensive, and non-diabetic young and middle-aged Chinese population

Background and objective： Non-alcoholic fatty liver disease（NAFLD） is associated with arterial stiffness in the general population. Age, obesity, hypertension, and diabetics are risk factors for arterial stiffness. In this study, we aimed to investigate the association between NAFLD and arterial stiffness as measured by brachial-ankle pulse wave velocity（baPWV） in the non-obese, non-hypertensive, and non-diabetic young and middle-aged Chinese population. Methods： A cross-sectional study with 1296 non-obese, non-hypertensive, and non-diabetic young and middle-aged（20–65 years） subjects undergoing routine medical check-ups in the International Health Care Center of the Second Affiliated Hospital of School of Medicine of Zhejiang University was carried out. Fatty liver was diagnosed by ultrasonography, and baPWV was measured using an automatic waveform analyzer. The subjects were classified into two groups according to the presence of NAFLD, and divided into a further two groups according to their baPWV. Results： The overall incidence of NAFLD was 19.0%, and NAFLD patients had a significantly higher level of baPWV than the controls（（1321±158） cm/s vs.（1244±154） cm/s; P〈0.001）. The incidence of NAFLD was clearly higher in the increased baPWV group than in the normal baPWV group（29.3% vs. 16.9%; P〈0.001）, and the incidence increased in line with the increase of baPWV quartiles in the normal range as well as with the severity of arterial stiffness（both P for trend 〈0.001）. Multiple linear logistic regression analysis showed that the presence of NAFLD was positively and independently associated with baPWV. Conclusions： Our results suggest that the presence of NAFLD is associated with arterial stiffness as measured by baPWV in the non-obese, non-hypertensive, and non-diabetic young and middle-aged Chinese population.