INTRODUCTION

Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease[1,2]. It represents a wide range in liver damage that may lead to severe liver disease such as cirrhosis and hepatocellular carcinoma[3]. Adults as well as children with fatty liver display abnormal glucose and lipid metabolism.Therefore, NAFLD is now considered an important component of the metabolic syndrome (MetS)[4]. The mechanism of liver injury in NAFLD is considered to be a “multiple-hit process”. The first “hit” leads to an increase in liver fat, while the next multiple factors lead to inflammation[5]. Indeed, the early manifestation of NAFLD is triglyceride accumulation in the liver associated with insulin resistance, which is considerably affected by factors such as hyperenergetic diets, sedentary lifestyle, and genetic susceptibility. Fat accumulation in the liver is associated with lipotoxic hepatocellular injury due to elevated free fatty acids, free cholesterol and other lipid metabolites. Thus, mitochondrial dysfunction with oxidative stress and endoplasmic reticulum stressassociated mechanisms are activated[6].

Obesity is considered a key player in the development of NAFLD, and the majority of patients with NAFLD are either obese or overweight. However,NAFLD has been reported also in lean subjects.“Lean” NAFLD represents subpopulation of patients with fatty liver and normal BMI. These patients are usually insulin resistant and have low HDL-C and higher triglyceride concentrations when compared to lean healthy controls[7]. Visceral obesity (as opposed to general obesity), insulin resistance, high fructose and high cholesterol intake are the most prevalent risk factors for lean NAFLD, although genetic factors(e.g., Palatin-like phospholipase domain -containing 3 and Transmembrane 6 superfamily member 2 gene variants) may have an important role.

NAFLD diagnosis requires proof of steatosis, which relies on imaging techniques in clinical practice. Liver biopsy remains the gold standard to address such diagnosis and is the only valid method for differentiating NASH from simple steatosis, however it is neither feasible nor ethical to perform liver biopsy as a tool in all putative patients. Noninvasive imaging techniques,such as ultrasound (US), computed tomography(CT), magnetic resonance imaging (MRI), and proton magnetic resonance spectroscopy (MRS), can also identify fatty in filtration of the liver[8-10]. US is perhaps the most practical way to assess hepatic steatosis, due to its relatively low cost, availability, and safety. A major limitation of this operator-dependent technique is its limited sensitivitiy and specificity for diagnosing and quantifying hepatic steatosis. MRS is considered the non-invasive reference standard in the assessment of liver steatosis, because it is able to measure the real concentration of triglycerides within the hepatocytes.However, MRS is too time consuming for routine clinical practice, and requires a skilled operator to correctly perform the examination, process the data,and interpret the results. MRI has shown greater promise for the quantitative assessment of hepatic steatosis in adults and children. Until recently, the most widely used method was based on the modified Dixon technique[8]. This imaging method is reliable in the absence of magnetic field non-homogeneity and iron deposition. Recent improvement in MRI have provided measurement of the proton density fat-fraction [(PDFF):The fraction of the liver proton density attributable to liver fat],which is a inherent property of tissue and a direct measure of liver fat content. MRI-PDFF is accurate, precise, and reliable for quantifying liver steatosis having been validated against liver biopsy in both adults and children[9,10].

随着全民医保覆盖面的扩大、异地就医结算等许多便民医疗措施的全面落实以及医疗诊治水平的提高和社会事业各个层面的飞速发展，临床用血的需求出现刚性增长[3]，我院的情况与之近似。就专业而言，外科和肿瘤科是我院的重点学科；就所处地域而言，位于城区东部，城市东扩所需的各种基础设施的施工建设是导致我院外科用血量大幅增加的主要原因，另外还与城市化步伐加快导致的人口车辆猛增、老年意外摔伤等因素有关；再加上就医我院的肿瘤患者人数的增多，使临床供血短缺的现状更加凸显。

Currently, there is no agreement with respect to the pharmacological treatment of NAFLD. However, lifestyle interventions based on exercise and a balanced diet for quality and quantity, are considered the cornerstone of NAFLD management[11]. Mediterranean diet (MD),which is characterized by a significant amount of fibers, polyunsaturated fats and antioxidants, has been suggested to decrease the risk of cardiovascular diseases (CVD). In adults, MD has also been demonstrated to be efficacious in reducing the risk of MetS[12-15]. However, few studies are available on the effects of MD in both adults and children with NAFLD.Thus, the present narrative review aims to present an analysis of the available literature on the effects of the MD in patients with NAFLD, and to summarize the main mechanisms of action of MD components on this condition. To identify relevant studies, a systematic literature search on MEDLINE and EMBASE databases was conducted using the following keywords: “Mediterranean diet”, “nonalcoholic fatty liver disease”, “hepatic steatosis”, “steatohepatitis”. All searches were limited to studies published in English language

DIET IN NAFLD TREATMENT

Results of studies regarding pharmacological options for treatment of NAFLD are inconclusive[11]. At the moment the best treatment to manage NAFLD is lifestyle intervention to achieve weight loss[11]. A 7% to 10%body weight reduction after energy restriction and/or regular physical activity is associated with histological improvement, resolution of liver fat, necroinflammation and fibrosis[16,17]. Though weight loss is considered the most effective treatment in NAFLD, some diets that involve excessive and/or rapid weight loss (e.g, very low carbohydrate, high fat diets) may actually cause or exacerbate the disease, inducing insulin resistance[18,19].As weight reduction is a consequence of physical activity and a ‘healthy diet’, dietary habits rather than weight loss per se may improve NAFLD[18]. Dietary treatment to achieve weight loss must have not only quantitative but also qualitative characteristics. Most studies conclude that energy restriction alone is not enough to treat NAFLD[20], and that the composition of the diet,with modulation of both macro and micronutrients,is crucial[21]. Therefore, a balanced nutrition and a moderate weight loss can now be considered as the best therapeutic approach in NAFLD. According to international guidelines, the first step for treating NAFLD is to limit the intake of calories, of fats (saturated fatty acids, trans fatty acids), and of fructose and, conversely,to increase the intake of lean protein, fibers, and n-3 polyunsaturated fatty acid (PUFA)[15]. Indeed, MD appears as a useful dietary option to produce weight loss followed by concomitant metabolic benefit for NAFLD.

MEDITERRANEAN DIET

MD is a nutritional model which has its origins in the States surrounding the Mediterranean Sea. It was therefore traditionally used by the populations living in these regions. Although MD pattern may vary among countries and regions owing to cultural, ethnic,religious and agricultural differences, the common MD pattern consists of eating primarily unrefined cereals,vegetables and fresh fruit, olive oil, and nuts; eating fish, white meat and legumes in moderation; limiting red meat, processed meats and sweets; and drinking red wine in moderation (Table 1). Therefore, the main characteristics of MD are beneficial fatty acid profile consisting of a low consumption of saturated fat and cholesterol, and, conversely, of a high consumption of monounsaturated fatty acid (MUFA) with a balanced PUFA omega-6 to omega-3 ratio, along with a high content of complex carbohydrates and fibers. Ancel Keys, who conducted large multinational studies in the 1950s-1980s[22-24], first reported a lower mortality rate from CVD and cancer among people living in Greece - as well as in certain parts of Italy and the former Yugoslavia - in comparison to other populations.Afterwards, other studies have con firmed these findings,recognizing MD as a healthy and useful diet for reducing the risk of CVD and cancer[25-28] as well as of obesity and type 2 diabetes[29]. Yet, MD has been proposed as a longevity determinant in these populations[30].Many studies suggest that the protective effects of MD may be due mostly to the anti-inflammatory and antioxidant properties of its components. In particular,the capacity of MD to reduce the risk of development and progression of NAFLD has been attributed to the nutraceutical effect of bioactive compounds and phytochemicals with antioxidant and anti-inflammatory capacity such as fibers, monounsaturated and omega-3 fatty acids and phytosterols[31,32]. NAFLD is associated with visceral obesity, insulin resistance, dyslipidemia,and chronic inflammation all of which are features of Mets. MD may improve NAFLD by modulating the presence of these conditions. In particular, the antioxidant and anti-inflammatory effects as well as the lipid-lowering effects and gut-microbiota-mediated production of metabolites are the principal mechanisms by which MD can influence metabolic health as well as NAFLD.

社会策略主要就是懂得合作式学习。学校和教师都应为大学生提供良好的合作学习平台。学校应举办丰富多彩的英语活动，例如，英语角、英语咖啡屋、英语话剧比赛、英语配音比赛、英语听写大赛、英语辩论赛和英语演讲比赛等活动，为学生提供更多与他人学习和交流英语的机会，展现英语水平。学生在与他人交流的过程中也能增强自信。同时，教师在课堂上要摈弃填鸭式的传统教学方法，坚持以学生为中心，在教学内容和教学任务的安排上为学生提供更多的锻炼机会，鼓励学生尝试。学生也应该积极配合教师的安排，主动争取锻炼英语的交流机会。教师要多表扬学生的参与行为，使学生获得成就感，激发社交热情，促进合作式学习的开展，提高英语水平。

CLINICAL STUDIES ON MEDITERRANEAN DIET IN NAFLD PATIENTS

Cross sectional studies

47 Pacifico L, Celestre M, Anania C, Paolantonio P, Chiesa C, Laghi A. MRI and ultrasound for hepatic fat quantification:relationships to clinical and metabolic characteristics of pediatric nonalcoholic fatty liver disease. Acta Paediatr 2007; 96: 542-547 [PMID:17306008 DOI: 10.1111/j.1651-2227.2007.00186.x]

In children (Table 2), there are only two studies on the association between NAFLD and MD[39,40]. Cakir et al[39]first analyzed in obese youths the association between MD adherence [as assessed by the Mediterranean Diet Quality Index (KIDMED)] and NAFLD (as diagnosed by ultrasound and/or elevated ALT levels, as well as by exclusion of other causes of fatty liver disease). The authors evaluated overweight/obese children with (n =106) and without (n = 21) NAFLD, as well as children(n = 54) with normal BMI and without known chronic disease. Subjects with a low MD adherence were more likely to present with a higher BMI, though no correlation was found with other parameters including steatosis severity. Limitations of the study are the cross-sectional design; the small sample size; assessment of fatty liver severity by ultrasound; and failure to include physical activity level[39]. Very recently, Della Corte et al[40] analyzed the adherence to MD (as assessed by the KIDMED score)in 243 overweight/obese youths with and without NAFLD.Of these, 100 underwent liver biopsy. Poor adherence to MD was related to severity of liver damage as well as to higher levels of C-reactive protein (CRP), insulin and HOMA-IR values, homeostatic model assessment of β cell function and blood pressure levels, thus suggesting increased inflammatory potential of unhealthy diets[40].Lack of a normal weight control group as well as failure to adjust for confounding variables are major limitations of this study.

CLINICAL STUDIES ON MEDITERRANEAN DIET IN NAFLD PATIENTS

Longitudinal studies

Longitudinal studies are available, to our knowledge,only in adult patients (Table 3)[33,41-46]. Fraser et al[41] in a quasi-randomized trial evaluated the effect of three different dietary interventions [the 2003 recommended American Diabetes Association diet; a low glycemic index(LGI) diet; and a modified MD] on ALT concentrations in 259 individuals with obesity and type 2 diabetes. Foodenergy intake was similar across all three diets,but diet profiles differed in fat and carbohydrate components.The lowest ALT level at 6 and 12 mo of follow-up was achieved after MD intervention, independently of weight loss, HOMA-IR or triacylglycerol values[41]. In a very small, randomized, cross-over intervention trial involving 12 non-diabetic patients with biopsy-diagnosed NAFLD,Rayan et al[42] compared MD to an isoenergetic standard low fat-high carbohydrate diet. After 6 wk of treatment,patients experienced after MD intervention a 38% reduction in liver steatosis (as assessed by 1H-MRS) and improvement of insulin sensitivity compared to patients on low-fat, high-carbohydrate diet, independently of weight loss or waist circumference changes[42]. In a randomized,controlled study involving adult subjects wth type 2 diabetes, Bozzetto et al[43] evaluated the effects of an isoenergetic MUFA diet versus a diet higher in carbohydrate and fiber. They found that the hepatic fat content (as measured by 1H-MRS before and after 8 wk of intervention) significantly decreased with MUFA diet, independently of exercise. Subsequently, in a single arm trial including 90 overweight NAFLD patients,Trovato et al[44] evaluated the Bright Liver Score at baseline and 1, 3, and 6 mo after MD intervention.Over the 6-mo period, adherence to MD resulted in a significant reduction of liver fat content, independently of other lifestyle changes[44]. In a 6-mo randomized controlled study, Abenavoli et al[45] compared three groups of overweight patients with ultrasound-diagnosed NAFLD who received either MD alone (n = 10), or MD supplemented with the Reasil complex including silybin(an extract of Silybum marianum commonly known as milk thistle), phosphatidylcholine and vitamin E (n =10), or no pharmacological and nutritional treatment(n = 30) . After 6 mo of follow-up, MD either alone or in association with the Realsil complex resulted in significant improvement in fat accumulation as well as in BMI, waist circumference, total cholesterol,triglyceride and insulin resistance values[45]. In a randomized controlled study, Misciagna et al[46] compared two groups of non-diabetic overweight-obese patients with moderate/severe ultrasound-diagnosed NAFLD who followed, respectively, a control diet (based on the Italian National Research Institute guidelines)and a low glycemic Index Mediterranean Diet (LGIMD).Compared to the control diet, LGIMD resulted in a major reduction of liver fat at both 3th and 6th month[46]. Finally,very recently, in a single arm, observational study, Gelli et al[33] treated with MD 46 normal weight (n = 11) or overweight/obese (n = 35) patients with NAFLD. They determined liver enzymes, metabolic parameters, CVD risk indexes, and ultrasound-based NAFLD severity. At the end of treatment, the proportion of patients with liver steatosis grade ≥ 2 was reduced from 93% to 48%. Also, metabolic parameters and liver enzymes decreased significantly[33].

Redesign of a Ship Measurement Module……………WANG Jiehuan, QIU Yicen(2·45)

Several points need be considered when interpreting the results of the aforementioned studies. First, they were based on high-risk populations, therefore not representative of the general population. Second, most of them were based on a small sample size. Notably,none of the studies provided information on how sample size was calculated and how participants were randomly assigned to the intervention groups. As matter of fact,there may be synergistic and antagonistic interactions among food components of MD that may be dif ficult to detect unless very large samples are used. Third, MD includes a variety of eating patterns and, therefore, a wide range in assessment score items. As such, using a score for assessment of adherence to a dietary pattern is limited by subjectivity, leading therefore to a great variability in interpretation of study results. Fourth,the majority of studies utilized ultrasonography that is known to be highly operator-dependent, and to have limited repeatability and reproducibility. In addition,ultrasonography has shown low accuracy in assessing severity of liver disease including presence and extent of fibrosis[47]. Fifth, most studies failed to take into account total energy intake. Finally, most studies failed to adjust for potential confounders including physical activity, and socioeconomic and cultural levels, which might have influenced lifestyle habits of the population studied.

BIOLOGICAL MACHANISMS OF MEDITERRANEAN DIET

Anti-inflammatory and antioxidant effects of MD components

MD is based on compounds, such as polyphenols,vitamins and other biomolecules that have antiinflammatory and antioxidant effects. This seems to be relevant, since inflammation and oxidative stress play a central role in the pathogenesis of NAFLD/NASH.

Polyphenols are present in whole-grain cereals,vegetables and fresh fruits, olive oil, nuts and red wine. They are a heterogenic group of bioactive compounds, including several hydro-soluble antioxidants,characterized by a phenolic structure[48]. Based on their chemical structure, there are two categories of polyphenols: flavonoid polyphenols, and the nonflavonoid polyphenols[49].

Flavonoids are polyphenolic compounds that are ubiquitously found[50] and provide much of the flavor and color to fruits and vegetables. They have hepatoprotective effects in view of their antioxidant and antiinflammatory potential[49,51-53]. Among non-flavonoids,resveratrol, a stilbene polyphenol content in red wine,has been shown to exert hepato-protective activity by affecting the three interacting components of homeostasis such as the vessel, the blood platelets and the clotting and the fibrinolytic system of plasma[54,55].Vitamins, which are significant components of MD,can also be considered dietary antioxidants. They reduce cellular stress and, in this way, they have a pivotal role in preventing NAFLD progression. Vitamin E has been shown to improve histological features of NASH[56-59]. Vitamin D has immunomodulatory, antiinflammatory and anti- fibrotic properties while vitamin D supplementation has been demonstrated to ameliorate NAFLD histopathology[60,61]. When incubated with isolated rat liver, vitamin C has been shown to decrease levels of mitochondrial reactive oxygen species generation, and to increase the levels of antioxidant enzymes and the activity of the electron transport chain[62].

Carotenoids are also part of MD; they comprise a class of natural fat-soluble pigments acting as antioxidants,which are found in several fruits and vegetables[63]. Among them, lycopene has been investigated as a potential protective agent in NAFLD in view of its potent antioxidant effects[64]. Studies in lycopene-fed rats have shown that lycopene has a preventive effect on experimental NASH by reducing steatosis and inflammation as well as oxidative stress[65].

Lipid-lowering effect of MD components

The beneficial effects of MD on the hepatic lipid metabolism and, consequently, on NAFLD prevention,is influenced primarily by its fatty acid composition which is characterized by high MUFA content with a balanced PUFA omega-6 to omega-3 ratio due to the abundance of vegetables, legumes, nuts, olive oil and fish (instead of red meats)[66]. It has been proved that MUFA intake may prevent the development of NAFLD by improving plasma lipid levels, reducing body fat accumulation and decreasing postprandial adiponectin expression[67,68]. PUFA regulate three major transcriptional factors controlling multiple pathways involved in hepatic carbohydrate and lipid metabolism. PUFA activation of hepatic peroxisome proliferator-activated alpha (PPARα)enhances fatty acid oxidation, while PUFA suppression of sterol regulatory element binding protein-1 (SREBP-1)and of carbohydrate regulatory element binding protein(ChREBP)/Max-like factor X (MLX) results in the inhibition of glycolysis and of de-novo lipogenesis. As such, PUFA promote a shift in metabolism toward fatty acid oxidation and away from fatty acid synthesis and storage, and may positively affect NAFLD[69,70]. In addition to improvement in steatosis, PUFA may induce an independent, antiinflammatory effect via suppression of tumor necrosis factor and interleukin-6, responsible for the inflammation occurring in NASH[71]. Opposite health effects have been found regarding the role of n-6 PUFA on NAFLD. N-6 PUFA, such as linoleic acid may have a pro-inflammatory role due to their direct relation with the production of arachidonic acid (AA). AA is metabolized to give rise to the eicosanoid family of inflammatory mediators (e.g.prostaglandins, leukotrienes and related metabolites),and through these to regulate the production of inflammatory cytokines[72]. Excessive amounts of omega-6 PUFA and a very high omega-6 to omega-3 ratio have been involved in the pathogenesis of many diseases, including CVD, cancer, and inflammatory and autoimmune diseases[73]. A proportionally high intake of n-6 PUFA is considered pro-inflammatory and possibly associated with an increased risk of MetS. Therefore, not only PUFA intake but also the n-6 PUFA to n-3 PUFA ratio is relevant.

Several studies have shown that a reduced intake of saturated fat is associated with a reduction of plasma concentrations of total cholesterol, very low density lipoprotein (LDL)-cholesterol and triglycerides[74].

MD can also contribute to lowering plasma cholesterol by high consumption of water-soluble fibers which are found in large concentration in some MD components, mainly beans, vegetables and fruits and whole-grain cereals. Water-soluble fibers have been shown to increase the rate of bile excretion therefore reducing serum total and LDL cholesterol[75].

GUT MICROBIOTA AND MD COMPONENTS

The liver is closely connected to the gut as it receives about 70% of its blood supply directly from the intestine via the portal vein. Therefore, it is one of the organs mostly exposed to gut-derived toxic products,such as bacteria and bacterial derivates. This crosstalking between the intestine and the liver is known as the “gut-liver axis” and has been linked to liver pathologies, including NAFLD. The relationship between NAFLD and altered microbiota is mainly supported by studies on animal models[76,77].There are limited data in humans[78,79]. Gut microbiota plays a crucial role in the complex pathogenesis of NAFLD through a variety of mechanisms such as predisposition to obesity, induction of insulin resistance as well as of liver inflammation, and alteration of choline metabolism[80].Other mechanisms include increased microbiomemodulated metabolites such as bile acids, short chain fatty acids, lipopolysaccharides as well as dysbiosisinduced intestinal barrier dysfunction[81]. Many different factors may influence microbiota composition, including age, comorbid conditions, host genotype and exposure to antibiotics, and dietary habits[82]. Diet largely influences gut microbiota and its products[83]. Specific dietary factors, such as macronutrient composition (e.g.increased protein intake), food type (e.g. glycemic index or load) or the presence of specific bioactive compounds(omega-3 fatty acids, fibers or polyphenols) have been shown to influence the diversity and functionality of the gut microbiota[84]. Also protein, insoluble fibers and fat content have important effects on gut microbiota structure, function, and its secretion of metabolites that modulate immune function and multiple metabolic and inflammatory pathways[85-87]. Therefore, MD may have a significant impact on the composition and diversity of the microbiota. As MD is characterized by a high dietary fiber intake, it promotes bene ficial modification of the gut microbiota with decreased Firmicutes and increased Bacteroides, which have been shown to ameliorate obesity, inflammation and related metabolic alterations.Polyphenols contained in MD induce an increase in Bifidobacteria, associated with various metabolic benefits such as plasma cholesterol reduction and a decrease of C-reactive protein (CRP)[88]. Gut microbial production of trimethylamine N-oxide from dietary choline and l-carnitine enhances the risk of developing CVD in both animals and humans, independently of CVD risk factors[89]. MD bene fits on the gut microbiota could also be the consequence of a low content of choline and l-carnitine in MD diet.

CONCLUSION

MD, low in saturated fats and animal protein, high in antioxidants, fiber and MUFA, and with an adequate omega-3 to omega-6 fatty balance, represents an healthy dietary pattern, which has been shown to decrease CVD, MetS, and type 2 diabetes. Although MD seems particularly attractive for its potential to improve liver status, literature concerning the efficacy of this dietary pattern in patients with NAFLD is still limited to few cross-sectional as well as to few longitudinal studies with certain limitations. In particular, longitudinal studies have included small sample size, short-term follow-up, different designs, different time points of data collection, and above all poor methodology for reporting the trial or diagnosing the liver outcome and its associated comorbidities, anyone of which or any combination of which may limit the generalizability of study results. There is room for adequate randomized dietary intervention trials comparing MD with a control diet in a large sample of the general population,along with a validation of the MD indexes in the heterogeneous patient population with NAFLD.

REFERENCES

1 Lazo M, Hernaez R, Eberhardt MS, Bonekamp S, Kamel I, Guallar E, Koteish A, Brancati FL, Clark JM. Prevalence of nonalcoholic fatty liver disease in the United States: the Third National Health and Nutrition Examination Survey, 1988-1994. Am J Epidemiol 2013; 178: 38-45 [PMID: 23703888 DOI: 10.1093/aje/kws448]

2 Pacifico L, Poggiogalle E, Cantisani V, Menichini G, Ricci P,Ferraro F, Chiesa C. Pediatric nonalcoholic fatty liver disease:A clinical and laboratory challenge. World J Hepatol 2010; 2:275-288 [PMID: 21161009 DOI: 10.4254/wjh.v2.i7.275]

3 Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002;346: 1221-1231 [PMID: 11961152 DOI: 10.1056/NEJMra011775]

4 Kotronen A, Yki-Järvinen H. Fatty liver: a novel component of the metabolic syndrome. Arterioscler Thromb Vasc Biol 2008; 28:27-38 [PMID: 17690317 DOI: 10.1161/ATVBAHA.107.147538]

5 Clemente MG, Mandato C, Poeta M, Vajro P. Pediatric nonalcoholic fatty liver disease: Recent solutions, unresolved issues,and future research directions. World J Gastroenterol 2016; 22:8078-8093 [PMID: 27688650 DOI: 10.3748/wjg.v22.i36.8078]

6 Buzzetti E, Pinzani M, Tsochatzis EA. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD).Metabolism 2016; 65: 1038-1048 [PMID: 26823198 DOI: 10.1016/j.metabol.2015.12.012]

7 Kumar R, Mohan S. Non-alcoholic Fatty Liver Disease in Lean Subjects: Characteristics and Implications. J Clin Transl Hepatol 2017; 5: 216-223 [PMID: 28936403 DOI: 10.14218/JCTH.2016.00068]

8 Pacifico L, Martino MD, Catalano C, Panebianco V, Bezzi M, Anania C, Chiesa C. T1-weighted dual-echo MRI for fat quantification in pediatric nonalcoholic fatty liver disease. World J Gastroenterol 2011; 17: 3012-3019 [PMID: 21799647 DOI:10.3748/wjg.v17.i25.3012]

9 Reeder SB, Cruite I, Hamilton G, Sirlin CB. Quantitative assessment of liver fat with magnetic resonance imaging and spectroscopy. J Magn Reson Imaging 2011; 34: 729-749 [PMID:21928307 DOI: 10.1002/jmri.22580]

10 Di Martino M, Pacifico L, Bezzi M, Di Miscio R, Sacconi B, Chiesa C, Catalano C. Comparison of magnetic resonance spectroscopy, proton density fat fraction and histological analysis in the quantification of liver steatosis in children and adolescents.World J Gastroenterol 2016; 22: 8812-8819 [PMID: 27818597 DOI: 10.3748/wjg.v22.i39.8812]

11 European Association for the Study of the Liver (EASL).European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASDEASO Clinical Practice Guidelines for the management of nonalcoholic fatty liver disease. J Hepatol 2016; 64: 1388-1402 [PMID:27062661 DOI: 10.1016/j.jhep.2015.11.004]

式中：i为减速箱总传动比；M为单侧最大驱动力矩，M=52300 N·m；T为采用的液压驱动马达的额定转矩，T=15 333 N·m。

12 Estruch R, Ros E, Salas-Salvadó J, Covas MI, Corella D, Arós F,Gómez-Gracia E, Ruiz-Gutiérrez V, Fiol M, Lapetra J, Lamuela-Raventos RM, Serra-Majem L, Pintó X, Basora J, Muñoz MA,Sorlí JV, Martínez JA, Martínez-González MA; PREDIMED Study Investigators. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2013; 368: 1279-1290 [PMID:23432189 DOI: 10.1056/NEJMoa1200303]

13 SofiF, Abbate R, Gensini GF, Casini A. Accruing evidence on benefits of adherence to the Mediterranean diet on health: an updated systematic review and meta-analysis. Am J Clin Nutr 2010;92: 1189-1196 [PMID: 20810976 DOI: 10.3945/ajcn.2010.29673]

14 Kastorini CM, Milionis HJ, Esposito K, Giugliano D,Goudevenos JA, Panagiotakos DB. The effect of Mediterranean diet on metabolic syndrome and its components: a meta-analysis of 50 studies and 534,906 individuals. J Am Coll Cardiol 2011; 57:1299-1313 [PMID: 21392646 DOI: 10.1016/j.jacc.2010.09.073]

25 Trichopoulou A, Costacou T, Bamia C, Trichopoulos D.Adherence to a Mediterranean diet and survival in a Greek population. N Engl J Med 2003; 348: 2599-2608 [PMID: 12826634 DOI: 10.1056/NEJMoa025039]

27 Fung TT, Rexrode KM, Mantzoros CS, Manson JE, Willett WC,Hu FB. Mediterranean diet and incidence of and mortality from coronary heart disease and stroke in women. Circulation 2009;119: 1093-1100 [PMID: 19221219]

17 Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzalez A, Gra-Oramas B, Gonzalez-Fabian L, Friedman SL,Diago M, Romero-Gomez M. Weight Loss Through Lifestyle Modification Significantly Reduces Features of Nonalcoholic Steatohepatitis. Gastroenterology 2015; 149: 367-378.e5; quiz e14-15 [PMID: 25865049 DOI: 10.1053/j.gastro.2015.04.005]

18 Asrih M, Jornayvaz FR. Diets and nonalcoholic fatty liver disease:the good and the bad. Clin Nutr 2014; 33: 186-190 [PMID:24262589 DOI: 10.1016/j.clnu.2013.11.003]

3.时间方面。申请者在申请时必须承诺每年至少出庭26个半天[6]13，一个半天一般是3-4个小时。英格兰和威尔士的许多地区申请者要承诺每周出庭半天或每两周出庭一整天。宪法事务部秘书和大法官则希望治安法官每年参加审理35个半天。[6]4治安法官出庭时间一般会在年初有个时间表，以便各个治安法官尽早做好出庭安排，遇到紧急情况也可以申请调剂。除了必需的出庭时间外，治安法官还需接受培训和实践教育不断提升自我和跟上时代的需要。如果治安法官时间比较充裕，那么可以出庭更多的时间服务治安法官工作。

19 Andersen T, Gluud C, Franzmann MB, Christoffersen P. Hepatic effects of dietary weight loss in morbidly obese subjects. J Hepatol 1991; 12: 224-229 [PMID: 2051001 DOI: 10.1016/0168-8278(91)90942-5]

20 Thoma C, Day CP, Trenell MI. Lifestyle interventions for the treatment of non-alcoholic fatty liver disease in adults: a systematic review. J Hepatol 2012; 56: 255-266 [PMID: 21723839 DOI:10.1016/j.jhep.2011.06.010]

坡地土壤全样的采样点是选择在一块垄作坡耕地和一块开挖复垦的循坡耕地，坡度变化为5°～20°。垄作坡耕地具有横向的垄沟，纵向间隔30 cm，垄沟深15～20 cm。在坡地中上位、坡中、坡下位等不同位置，循坡面按照顺坡采样点间的距离为3 m、带间距离为2 m的平行双条带剖面进行定点采样，每个样带各采集3个土壤样。采用直径15 cm，厚度3 cm的环刀采样器，采样深度为3 cm。采样时间分别是在玉米幼苗期(5月)、玉米结穗生长盛期(8月)。

21 Mouzaki M, Allard JP. The role of nutrients in the development,progression, and treatment of nonalcoholic fatty liver disease. J Clin Gastroenterol 2012; 46: 457-467 [PMID: 22469640 DOI:10.1097/MCG.0b013e31824cf51e]

22 Keys A, Aravanis C, Blackburn H, Buzina R, Djordjević BS,Dontas AS, Fidanza F, Karvonen MJ, Kimura N, Menotti A,Mohacek I, Nedeljković S, Puddu V, Punsar S, Taylor HL, Van Buchem FSP. Seven Countries. A multivariate analysis of death and coronary heart disease. Cambridge, MA: Harvard University Press, 1980: 381

23 Keys A, Menotti A, Karvonen MJ, Aravanis C, Blackburn H,Buzina R, Djordjevic BS, Dontas AS, Fidanza F, Keys MH. The diet and 15-year death rate in the seven countries study. Am J Epidemiol 1986; 124: 903-915 [PMID: 3776973 DOI: 10.1093/oxfordjournals.aje.a114480]

24 Keys A. Mediterranean diet and public health: personal reflections.Am J Clin Nutr 1995; 61: 1321S-1323S [PMID: 7754982 DOI:10.1093/ajcn/61.6.1321S]

15 Kesse-Guyot E, Ahluwalia N, Lassale C, Hercberg S, Fezeu L, Lairon D. Adherence to Mediterranean diet reduces the risk of metabolic syndrome: a 6-year prospective study. Nutr Metab Cardiovasc Dis 2013; 23: 677-683 [PMID: 22633793 DOI:10.1016/j.numecd.2012.02.005]

26 Mitrou PN, Kipnis V, Thiébaut AC, Reedy J, Subar AF, Wirfält E,Flood A, Mouw T, Hollenbeck AR, Leitzmann MF, Schatzkin A.Mediterranean dietary pattern and prediction of all-cause mortality in a US population: results from the NIH-AARP Diet and Health Study. Arch Intern Med 2007; 167: 2461-2468 [PMID: 18071168 DOI: 10.1001/archinte.167.22.2461]

16 Promrat K, Kleiner DE, Niemeier HM, Jackvony E, Kearns M, Wands JR, Fava JL, Wing RR. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis.Hepatology 2010; 51: 121-129 [PMID: 19827166 DOI: 10.1002/hep.23276]

推荐理由:《世界海洋法译丛》旨在通过向中国国内介绍国际海洋法律、条约及世界主要沿海国家的海洋立法和相关的国家法律实践案例，是结合我国海洋法研究的最新研究和翻译成果，为维护我国领土主权、海洋安全和海洋权益，更好地参与国际海洋合作，建设21世纪“海上丝绸”之路，正确处理国际海洋事务、解决国际海洋争端提供政策支持和法律借鉴。

28 SofiF, Cesari F, Abbate R, Gensini GF, Casini A. Adherence to Mediterranean diet and health status: meta-analysis. BMJ 2008;337: a1344 [PMID: 18786971 DOI: 10.1136/bmj.a1344]

29 Schröder H. Protective mechanisms of the Mediterranean diet in obesity and type 2 diabetes. J Nutr Biochem 2007; 18: 149-160[PMID: 16963247 DOI: 10.1016/j.jnutbio.2006.05.006]

30 Trichopoulou A, Kouris-Blazos A, Wahlqvist ML, Gnardellis C, Lagiou P, Polychronopoulos E, Vassilakou T, Lipworth L,Trichopoulos D. Diet and overall survival in elderly people. BMJ 1995; 311: 1457-1460 [PMID: 8520331]

31 Tosti V, Bertozzi B, Fontana L. Health Benefits of the Mediterranean Diet: Metabolic and Molecular Mechanisms. J Gerontol A Biol Sci Med Sci 2018; 73: 318-326 [PMID: 29244059 DOI: 10.1093/gerona/glx227]

32 Di Daniele N, Noce A, Vidiri MF, Moriconi E, Marrone G,Annicchiarico-Petruzzelli M, D’Urso G, Tesauro M, Rovella V, De Lorenzo A. Impact of Mediterranean diet on metabolic syndrome,cancer and longevity. Oncotarget 2017; 8: 8947-8979 [PMID:27894098 DOI: 10.18632/oncotarget.13553]

33 Gelli C, Tarocchi M, Abenavoli L, Di Renzo L, Galli A, De Lorenzo A. Effect of a counseling-supported treatment with the Mediterranean diet and physical activity on the severity of the non-alcoholic fatty liver disease. World J Gastroenterol 2017; 23:3150-3162 [PMID: 28533672 DOI: 10.3748/wjg.v23.i17.3150]

34 Kontogianni MD, Tileli N, Margariti A, Georgoulis M, Deutsch M, Tiniakos D, Fragopoulou E, Zafiropoulou R, Manios Y,Papatheodoridis G. Adherence to the Mediterranean diet is associated with the severity of non-alcoholic fatty liver disease.Clin Nutr 2014; 33: 678-683 [PMID: 24064253 DOI: 10.1016/j.clnu.2013.08.014]

35 Aller R, Izaola O, de la Fuente B, De Luis Román DA.Mediterranean diet is associated with liver histology in patients with non alcoholic fatty liver disease. Nutr Hosp 2015; 32:2518-2524 [PMID: 26667698 DOI: 10.3305/nh.2015.32.6.10074]

36 Chan R, Wong VW, Chu WC, Wong GL, Li LS, Leung J, Chim AM, Yeung DK, Sea MM, Woo J, Chan FK, Chan HL. Diet-Quality Scores and Prevalence of Nonalcoholic Fatty Liver Disease: A Population Study Using Proton-Magnetic Resonance Spectroscopy. PLoS One 2015; 10: e0139310 [PMID: 26418083 DOI: 10.1371/journal.pone.0139310]

37 Trovato FM, Martines GF, Brischetto D, Trovato G, Catalano D.Neglected features of lifestyle: Their relevance in non-alcoholic fatty liver disease. World J Hepatol 2016; 8: 1459-1465 [PMID:27957244 DOI: 10.4254/wjh.v8.i33.1459]

51 Salamone F, Galvano F, Cappello F, Mangiameli A, Barbagallo I, Li Volti G. Silibinin modulates lipid homeostasis and inhibits nuclear factor kappa B activation in experimental nonalcoholic steatohepatitis. Transl Res 2012; 159: 477-486 [PMID: 22633099 DOI: 10.1016/j.trsl.2011.12.003]

39 Cakir M, Akbulut UE, Okten A. Association between Adherence to the Mediterranean Diet and Presence of Nonalcoholic Fatty Liver Disease in Children. Child Obes 2016; 12: 279-285 [PMID:26871614 DOI: 10.1089/chi.2015.0197]

40 Della Corte C, Mosca A, Vania A, Alterio A, Iasevoli S, Nobili V. Good adherence to the Mediterranean diet reduces the risk for NASH and diabetes in pediatric patients with obesity: The results of an Italian Study. Nutrition 2017; 39-40: 8-14 [PMID: 28606575 DOI: 10.1016/j.nut.2017.02.008]

46 Misciagna G, Del Pilar Díaz M, Caramia DV, Bon figlio C, Franco I, Noviello MR, Chiloiro M, Abbrescia DI, Mirizzi A, Tanzi M,Caruso MG, Correale M, Reddavide R, Inguaggiato R, Cisternino AM, Osella AR. Effect of a Low Glycemic Index Mediterranean Diet on Non-Alcoholic Fatty Liver Disease. A Randomized Controlled Clinici Trial. J Nutr Health Aging 2017; 21: 404-412[PMID: 28346567 DOI: 10.1007/s12603-016-0809-8]

42 Ryan MC, Itsiopoulos C, Thodis T, Ward G, Trost N, Hofferberth S, O’Dea K, Desmond PV, Johnson NA, Wilson AM. The Mediterranean diet improves hepatic steatosis and insulin sensitivity in individuals with non-alcoholic fatty liver disease.J Hepatol 2013; 59: 138-143 [PMID: 23485520 DOI: 10.1016/j.jhep.2013.02.012]

他恋慕她，反而不是有太过强烈的欲望。脑子里也想象过拥抱住她的身体，感觉会是怎样，却并不觉得有付诸行动的可能。她不是他往日经验中熟悉的活跃丰满的白人女孩。她如同是从遥远古老的异国书籍或者薄绢画册里走出来的人物，是被提炼和重塑的形象，并非为世间而准备。她迅疾直接的方式让他惊诧。他无法猜度了解她的质地，只能打开界限由她摆布。

43 Bozzetto L, Prinster A, Annuzzi G, Costagliola L, Mangione A,Vitelli A, Mazzarella R, Longobardo M, Mancini M, Vigorito C,Riccardi G, Rivellese AA. Liver fat is reduced by an isoenergetic MUFA diet in a controlled randomized study in type 2 diabetic patients. Diabetes Care 2012; 35: 1429-1435 [PMID: 22723581 DOI: 10.2337/dc12-0033]

44 Trovato FM, Catalano D, Martines GF, Pace P, Trovato GM.Mediterranean diet and non-alcoholic fatty liver disease: the need of extended and comprehensive interventions. Clin Nutr 2015; 34:86-88 [PMID: 24529325 DOI: 10.1016/j.clnu.2014.01.018]

45 Abenavoli L, Greco M, Nazionale I, Peta V, Milic N, Accattato F, Foti D, Gulletta E, Luzza F. Effects of Mediterranean diet supplemented with silybin-vitamin E-phospholipid complex in overweight patients with non-alcoholic fatty liver disease. Expert Rev Gastroenterol Hepatol 2015; 9: 519-527 [PMID: 25617046 DOI: 10.1586/17474124.2015.1004312]

41 Fraser A, Abel R, Lawlor DA, Fraser D, Elhayany A. A modified Mediterranean diet is associated with the greatest reduction in alanine aminotransferase levels in obese type 2 diabetes patients:results of a quasi-randomised controlled trial. Diabetologia 2008; 51: 1616-1622 [PMID: 18597068 DOI: 10.1007/s00125-008-1049-1]

Recently, researchers have focused on the possible association between MD and NAFLD. Data from cross sectional studies suggest that MD components have a beneficial effect on NAFLD[33]. As such, the EASLEASD-EASO clinical Practice Guidelines have recently encouraged MD as a lifestyle choice for treating the disease[16]. The available studies are presented in Table 1[34-40]. Kontogianni et al[34] were the first to explore the potential impact of MD on NAFLD and its severity in 73 overweight/obese adult patients, of whom 34 had liver biopsies. They found that the MD score was inversely associated to serum alanine aminotransferase (ALT)and insulin concentrations as well as to histological characteristics of severe steatosis. A higher adherence to MD (as determined by MedDietScore) was not followed by a lower likelihood of having NAFLD, even after adjustment for abdominal fat level. However, it was associated with a less severe liver disease[34]. Indeed,patients with nonalcoholic steatohepatitis (NASH) were less likely to adhere to MD (P = 0.004) versus patients without NASH. Limitations of the study are the crosssectional design which enables to establish a casual relation; the small sample size; and patients’ selection criteria (elevated ALT, and ultrasound diagnosis of fatty liver and its severity). Similarly, in a study including 82 adult subjects with biopsy-proven NAFLD, Aller et al[35]demonstrated that patients with greater adherence to MD (as determined by the 14-item MD assessment tool) were less likely to present histological features of severe steatosis and NASH, as well as to have severe insulin resistance. In a population-based study involving 797 apparently healthy Chinese adults, Chan et al[36]evaluated the relationship between two diet-quality scores [Diet Quality Index-International (DQI-I) and MD score] in subjects with (n = 220) and without (n = 577)NAFLD [as established by proton-magnetic resonance spectroscopy (1H-MRS)]. DQI-I, but not the MD score,was significantly related to the NAFLD prevalence,and this association was stronger in overweight/obese versus normal weight subjects. Lack of an association between MD and NAFLD prevalence can be explained by the fact that the intake of certain foods such as milk and milk products, olive oil, wine and nuts was lower in this study cohort than in the traditional MD[36]. Although the study by Chan et al[36] included a relatively large sample size and the diagnosis of NAFLD was achieved by 1H-MRS, its major limitation is represented by lack of adjustment in the analysis of lifestyle factors such as physical activity. Recently, Trovato et al[37] in a study involving 1199 overweight/obese adult patients [with(n = 532) and without (n = 667) ultrasound-diagnosed hepatic steatosis] found that NAFLD patients were less likely to be adherent to MD. Notably, poor MD adherence strongly predicted the occurrence of NAFLD,independently of body mass index (BMI), homeostatic model assessment of insulin resistance (HOMA-IR), and physical activity score. Very recently, Baratta et al[38]showed that MD adherence was inversely related to NAFLD prevalence (as assessed by ultrasound) in a large cohort of overweight/obese adults with cardio-metabolic risk. Subjects with intermediate to high adherence to MD were less likely to have NAFLD and more likely to improve cardio-metabolic features[38]. Again, limitations of the last two studies include their cross-sectional study design; lack of a normal weight control group; and use of ultrasound for diagnosing NAFLD.

同时，通用型压电驱动器已经开始实现产业化，例如德国的Physik Instrumente (PI)公司，已经将压电驱动器商业化，并开发出系列产品。可见，压电驱动器也在向着通用化方向发展，这有利于压电驱动技术的广泛应用，并降低技术成本。

48 Scalbert A, Williamson G. Dietary intake and bioavailability of polyphenols. J Nutr 2000; 130: 2073S-2085S [PMID: 10917926 DOI: 10.1093/jn/130.8.2073S]

49 Rodriguez-Ramiro I, Vauzour D, Minihane AM. Polyphenols and non-alcoholic fatty liver disease: impact and mechanisms.Proc Nutr Soc 2016; 75: 47-60 [PMID: 26592314 DOI: 10.1017/S0029665115004218]

50 Van De Wier B, Koek GH, Bast A, Haenen GR. The potential of flavonoids in the treatment of non-alcoholic fatty liver disease.Crit Rev Food Sci Nutr 2017; 57: 834-855 [PMID: 25897647 DOI:10.1080/10408398.2014.952399]

38 Baratta F, Pastori D, Polimeni L, Bucci T, Ceci F, Calabrese C,Ernesti I, Pannitteri G, Violi F, Angelico F, Del Ben M. Adherence to Mediterranean Diet and Non-Alcoholic Fatty Liver Disease:Effect on Insulin Resistance. Am J Gastroenterol 2017; 112:1832-1839 [PMID: 29063908 DOI: 10.1038/ajg.2017.371]

21日上午，中国铁路太原局集团有限公司与山西省旅游发展委员会联合主办了“山西全域旅游铁路行”推介会，启动“山西全域旅游铁路行”，加快铁路客运供给侧结构性改革，推动山西全域旅游融合发展。

52 Salomone F, Godos J, Zelber-Sagi S. Natural antioxidants for non-alcoholic fatty liver disease: molecular targets and clinical perspectives. Liver Int 2016; 36: 5-20 [PMID: 26436447 DOI:10.1111/liv.12975]

53 Liu Y, Li D, Zhang Y, Sun R, Xia M. Anthocyanin increases adiponectin secretion and protects against diabetes-related endothelial dysfunction. Am J Physiol Endocrinol Metab 2014; 306:E975-E988 [PMID: 24595303 DOI: 10.1152/ajpendo.00699.2013]

制作一个收集气液用的收集筒，为便携式检测仪提供了一个半密闭的检测空间，该收集筒能有效防止被检测气体受周围环境气候影响，保持原有的浓度。检测时能隔离有害气体与操作员工的接触，检测过程中排放的气液不会散落在地面造成环境污染。这种检测方法能连续监测，同时提高检测的准确度，降低操作时的风险，减小环境污染。

54 Faghihzadeh F, Adibi P, Rafiei R, Hekmatdoost A. Resveratrol supplementation improves inflammatory biomarkers in patients with nonalcoholic fatty liver disease. Nutr Res 2014; 34: 837-843[PMID: 25311610 DOI: 10.1016/j.nutres.2014.09.005]

55 Chen S, Zhao X, Ran L, Wan J, Wang X, Qin Y, Shu F, Gao Y,Yuan L, Zhang Q, Mi M. Resveratrol improves insulin resistance,glucose and lipid metabolism in patients with non-alcoholic fatty liver disease: a randomized controlled trial. Dig Liver Dis 2015;47: 226-232 [PMID: 25577300 DOI: 10.1016/j.dld.2014.11.015]

通过对咏叹调《一抹夕阳》的剧情背景,曲式,演唱与情感表现做了简要的分析,我们对于这首歌的剧情背景、曲式和演唱和情感表现有了初步的认识及了解,根据剧情的背景情况,我们就可以对整个歌曲感情的变化有深入的了解,这将对以后的音乐演唱提供良好的借鉴作用。

56 Hasegawa T, Yoneda M, Nakamura K, Makino I, Terano A.Plasma transforming growth factor-beta1 level and efficacy of alpha-tocopherol in patients with non-alcoholic steatohepatitis: a pilot study. Aliment Pharmacol Ther 2001; 15: 1667-1672 [PMID:11564008 DOI: 10.1046/j.1365-2036.2001.01083.x]

笔者日前从有关部委及权威人士处获悉，包括农村土地征收、集体经营性建设用地入市、宅基地制度改革在内的“三块地”改革试点即将收官，近期还将重点完成承包地确权登记颁证工作。按照计划，土地确权登记及“三块地”改革试点均要在今年年底前完成。接下来将进入农村土地改革三项试点总结评估期，在此基础上加快土地管理法修改。

57 Harrison SA, Torgerson S, Hayashi P, Ward J, Schenker S. Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis. Am J Gastroenterol 2003; 98: 2485-2490 [PMID: 14638353 DOI: 10.1111/j.1572-0241.2003.08699.x]

58 Madan K, Batra Y, Gupta DS, Chander B, Anand Rajan KD, Singh R, Panda SK, Acharya SK. Vitamin E-based therapy is effective in ameliorating transaminasemia in nonalcoholic fatty liver disease.Indian J Gastroenterol 2005; 24: 251-255 [PMID: 16424622]

59 Lavine JE. Vitamin E treatment of nonalcoholic steatohepatitis in children: a pilot study. J Pediatr 2000; 136: 734-738 [PMID:10839868 DOI: 10.1016/S0022-3476(00)05040-X]

60 Potter JJ, Liu X, Koteish A, Mezey E. 1,25-dihydroxyvitamin D3 and its nuclear receptor repress human α1 (I) collagen expression and type I collagen formation. Liver Int 2013; 33: 677-686 [PMID:23413886 DOI: 10.1111/liv.12122]

61 Eliades M, Spyrou E. Vitamin D: a new player in non-alcoholic fatty liver disease? World J Gastroenterol 2015; 21: 1718-1727[PMID: 25684936 DOI: 10.3748/wjg.v21.i6.1718]

62 Valdecantos MP, Pérez-Matute P, Quintero P, Martínez JA.Vitamin C, resveratrol and lipoic acid actions on isolated rat liver mitochondria: all antioxidants but different. Redox Rep 2010; 15:207-216 [PMID: 21062536 DOI: 10.1179/135100010X128264469 21464]

63 Stahl W, Sies H. Antioxidant activity of carotenoids. Mol Aspects Med 2003; 24: 345-351 [PMID: 14585305 DOI: 10.1016/S0098-2997(03)00030-X]

64 Murillo AG, DiMarco DM, Fernandez ML. The Potential of Non-Provitamin A Carotenoids for the Prevention and Treatment of Non-Alcoholic Fatty Liver Disease. Biology (Basel) 2016; 5:[PMID: 27834813 DOI: 10.3390/biology5040042]

65 Bahcecioglu IH, Kuzu N, Metin K, Ozercan IH, Ustündag B, Sahin K, Kucuk O. Lycopene prevents development of steatohepatitis in experimental nonalcoholic steatohepatitis model induced by high-fat diet. Vet Med Int 2010; 2010: [PMID:20953409 DOI: 10.4061/2010/262179]

66 Godos J, Federico A, Dallio M, Scazzina F. Mediterranean diet and nonalcoholic fatty liver disease: molecular mechanisms of protection. Int J Food Sci Nutr 2017; 68: 18-27 [PMID: 27484357 DOI: 10.1080/09637486.2016.1214239]

67 Paniagua JA, de la Sacristana AG, Sánchez E, Romero I, Vidal-Puig A, Berral FJ, Escribano A, Moyano MJ, Peréz-Martinez P,López-Miranda J, Pérez-Jiménez F. A MUFA-rich diet improves posprandial glucose, lipid and GLP-1 responses in insulin-resistant subjects. J Am Coll Nutr 2007; 26: 434-444 [PMID: 17914131 DOI: 10.1080/07315724.2007.10719633]

68 Eccel Prates R, Beretta MV, Nascimento FV, Bernaud FR, de Almeira JC, Rodrigues TC. Saturated fatty acid intake decreases serum adiponectin levels in subjects with type 1 diabetes. Diabetes Res Clin Pract 2016; 116: 205-211 [PMID: 27321337 DOI:10.1016/j.diabres.2016.03.019]

69 Jump DB, Ren B, Clarke S, Thelen A. Effects of fatty acids on hepatic gene expression. Prostaglandins Leukot Essent Fatty Acids 1995; 52: 107-111 [PMID: 7784444]

70 Arendt BM, Comelli EM, Ma DW, Lou W, Teterina A, Kim T,Fung SK, Wong DK, McGilvray I, Fischer SE, Allard JP. Altered hepatic gene expression in nonalcoholic fatty liver disease is associated with lower hepatic n-3 and n-6 polyunsaturated fatty acids. Hepatology 2015; 61: 1565-1578 [PMID: 25581263 DOI:10.1002/hep.27695]

71 Kahn SE, Hull RL, Utzschneider KM. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 2006; 444:840-846 [PMID: 17167471 DOI: 10.1038/nature05482]

72 Monteiro J, Leslie M, Moghadasian MH, Arendt BM, Allard JP,Ma DW. The role of n - 6 and n - 3 polyunsaturated fatty acids in the manifestation of the metabolic syndrome in cardiovascular disease and non-alcoholic fatty liver disease. Food Funct 2014; 5:426-435 [PMID: 24496399 DOI: 10.1039/c3fo60551e]

73 Simopoulos AP. The importance of the omega-6/omega-3 fatty acid ratio in cardiovascular disease and other chronic diseases. Exp Biol Med (Maywood) 2008; 233: 674-688 [PMID: 18408140 DOI:10.3181/0711-MR-311]

74 Garg A. High-monounsaturated-fat diets for patients with diabetes mellitus: a meta-analysis. Am J Clin Nutr 1998; 67: 577S-582S[PMID: 9497173]

75 Theuwissen E, Mensink RP. Water-soluble dietary fibers and cardiovascular disease. Physiol Behav 2008; 94: 285-292 [PMID:18302966 DOI: 10.1016/j.physbeh.2008.01.001]

76 Dumas ME, Barton RH, Toye A, Cloarec O, Blancher C, Rothwell A, Fearnside J, Tatoud R, Blanc V, Lindon JC, Mitchell SC,Holmes E, McCarthy MI, Scott J, Gauguier D, Nicholson JK.Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice. Proc Natl Acad Sci U S A 2006; 103: 12511-12516 [PMID: 16895997 DOI: 10.1073/pnas.0601056103]

77 Le Roy T, Llopis M, Lepage P, Bruneau A, Rabot S, Bevilacqua C, Martin P, Philippe C, Walker F, Bado A, Perlemuter G,Cassard-Doulcier AM, Gérard P. Intestinal microbiota determines development of non-alcoholic fatty liver disease in mice.Gut 2013; 62: 1787-1794 [PMID: 23197411 DOI: 10.1136/gutjnl-2012-303816]

78 Wong VW, Tse CH, Lam TT, Wong GL, Chim AM, Chu WC, Yeung DK, Law PT, Kwan HS, Yu J, Sung JJ, Chan HL.Molecular characterization of the fecal microbiota in patients with nonalcoholic steatohepatitis--a longitudinal study. PLoS One 2013;8: e62885 [PMID: 23638162 DOI: 10.1371/journal.pone.0062885]

79 Mouzaki M, Comelli EM, Arendt BM, Bonengel J, Fung SK,Fischer SE, McGilvray ID, Allard JP. Intestinal microbiota in patients with nonalcoholic fatty liver disease. Hepatology 2013;58: 120-127 [PMID: 23401313 DOI: 10.1002/hep.26319]

80 Abu-Shanab A, Quigley EM. The role of the gut microbiota in nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol 2010; 7: 691-701 [PMID: 21045794 DOI: 10.1038/nrgastro.2010.172]

81 Bashiardes S, Shapiro H, Rozin S, Shibolet O, Elinav E. Nonalcoholic fatty liver and the gut microbiota. Mol Metab 2016; 5:782-794 [PMID: 27617201 DOI: 10.1016/j.molmet.2016.06.003]

82 Gómez-Hurtado I, Santacruz A, Peiró G, Zapater P, Gutiérrez A,Pérez-Mateo M, Sanz Y, Francés R. Gut microbiota dysbiosis is associated with inflammation and bacterial translocation in mice with CCl4-induced fibrosis. PLoS One 2011; 6: e23037 [PMID:21829583 DOI: 10.1371/journal.pone.0023037]

83 David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE, Ling AV, Devlin AS, Varma Y, Fischbach MA,Biddinger SB, Dutton RJ, Turnbaugh PJ. Diet rapidly and reproducibly alters the human gut microbiome. Nature 2014; 505:559-563 [PMID: 24336217 DOI: 10.1038/nature12820]

84 Nadal I, Santacruz A, Marcos A, Warnberg J, Garagorri JM,Moreno LA, Martin-Matillas M, Campoy C, Martí A, Moleres A,Delgado M, Veiga OL, García-Fuentes M, Redondo CG, Sanz Y.Shifts in clostridia, bacteroides and immunoglobulin-coating fecal bacteria associated with weight loss in obese adolescents. Int J Obes (Lond) 2009; 33: 758-767 [PMID: 19050675 DOI: 10.1038/ijo.2008.260]

85 Clemente JC, Ursell LK, Parfrey LW, Knight R. The impact of the gut microbiota on human health: an integrative view.Cell 2012; 148: 1258-1270 [PMID: 22424233 DOI: 10.1016/j.cell.2012.01.035]

86 Muegge BD, Kuczynski J, Knights D, Clemente JC, González A, Fontana L, Henrissat B, Knight R, Gordon JI. Diet drives convergence in gut microbiome functions across mammalian phylogeny and within humans. Science 2011; 332: 970-974 [PMID:21596990 DOI: 10.1126/science.1198719]

87 Richards JL, Yap YA, McLeod KH, Mackay CR, Mariño E. Dietary metabolites and the gut microbiota: an alternative approach to control inflammatory and autoimmune diseases. Clin Transl Immunology 2016; 5: e82 [PMID: 27350881 DOI: 10.1038/cti.2016.29]

88 Queipo-Ortuño MI, Boto-Ordóñez M, Murri M, Gomez-Zumaquero JM, Clemente-Postigo M, Estruch R, Cardona Diaz F, Andrés-Lacueva C, Tinahones FJ. Influence of red wine polyphenols and ethanol on the gut microbiota ecology and biochemical biomarkers. Am J Clin Nutr 2012; 95: 1323-1334[PMID: 22552027 DOI: 10.3945/ajcn.111.027847]

89 Lopez-Garcia E, Rodriguez-Artalejo F, Li TY, Fung TT, Li S,Willett WC, Rimm EB, Hu FB. The Mediterranean-style dietary pattern and mortality among men and women with cardiovascular disease. Am J Clin Nutr 2014; 99: 172-180 [PMID: 24172306 DOI:10.3945/ajcn.113.068106]