Fatty liver and global cardiometabolic risk

Non-alcoholic fatty liver disease (NAFLD) can be found in approximately 30% of adults in industrialized societies. Non-alcoholic steatohepatitis (NASH) is its most severe histological form and progresses to cirrhosis in 20% of these patients. Once developed, 30% to 40% of patients with cirrhosis will suffer liver-related death. NAFLD is considered the hepatic manifestation of the metabolic syndrome. Recent findings linking the components of metabolic syndrome with NAFLD and the progression to nonalcoholic steatohepatitis will be reviewed; in particular, the role of visceral adipose tissue, insulin resistance, adipocytokines, oxidative stress and diminished antioxidants within the liver in the exacerbation of these conditions. It is now widely accepted that non-hepatic mechanisms are largely responsible for the development of insulin resistance, which causes hepatic steatosis. Insulin resistance, a key feature of metabolic syndrome, is crucial for NASH development. We have a classical chicken-egg problem: insulin resistance causes hepatic steatosis or vice-versa? A possible sequence of the pathogenetic events is the following: increased free fatty acid supply - increased de novo lipogenesis - triglyceride and VLDL overproduction - atherogenic dyslipidemia- oxidative stress (lipid oxidation and peroxidation) - exhaustion of antioxidant defense system- "Tsunami" of inflammatory cytokines- fibrosis- carcinogenesis. Given the strong association of NAFLD with metabolic syndrome, early recognition, assessment and management are essential. The management emphasizes weight reduction and attention to global cardiometabolic risk factors, similar to recommendations for management of the elements of metabolic syndrome.     

Nutritional Management of Insulin Resistance in Nonalcoholic Fatty Liver Disease (NAFLD)

Nonalcoholic fatty liver disease (NAFLD) is an emerging global health concern. It is the most common form of chronic liver disease in Western countries, affecting both adults and children. NAFLD encompasses a broad spectrum of fatty liver disease, ranging from simple steatosis (NAFL) to nonalcoholic steatohepatitis (NASH), and is strongly associated with obesity, insulin resistance, and dyslipidemia. First-line therapy for NAFLD includes weight loss achieved through diet and physical activity. However, there is a lack of evidenced-based dietary recommendations. The American Diabetes Association’s (ADA) recommendations that aim to reduce the risk of diabetes and cardiovascular disease may also be applicable to the NAFLD population. The objectives of this review are to: (1) provide an overview of NAFLD in the context of insulin resistance, and (2) provide a rationale for applying relevant aspects of the ADA recommendations to the nutritional management of NAFLD.     

Beneficial Activities of Alisma orientale Extract in a Western Diet-Induced Murine Non-Alcoholic Steatohepatitis and Related Fibrosis Model via Regulation of the Hepatic Adiponectin and Farnesoid X Receptor Pathways

The hepatic adiponectin and farnesoid X receptor (FXR) signaling pathways play multiple roles in modulating lipid and glucose metabolism, reducing hepatic inflammation and fibrosis, and altering various metabolic targets for the management of non-alcoholic fatty liver disease (NAFLD). Alisma orientale (AO, Ze xie in Chinese and Taeksa in Korean) is an herbal plant whose tubers are enriched with triterpenoids, which have been reported to exhibit various bioactive properties associated with NAFLD. Here, the present study provides a preclinical evaluation of the biological functions and related signaling pathways of AO extract for the treatment of NAFLD in a Western diet (WD)-induced mouse model. The findings showed that AO extract significantly reversed serum markers (liver function, lipid profile, and glucose) and improved histological features in the liver sections of mice fed WD for 52 weeks. In addition, it also reduced hepatic expression of fibrogenic markers in liver tissue and decreased the extent of collagen-positive areas, as well as inhibited F4/80 macrophage aggregation and inflammatory cytokine secretion. The activation of adiponectin and FXR expression in hepatic tissue may be a major mechanistic signaling cascade supporting the promising role of AO in NAFLD pharmacotherapy. Collectively, our results demonstrated that AO extract improves non-alcoholic steatohepatitis (NASH) resolution, particularly with respect to NASH-related fibrosis, along with the regulation of liver enzymes, postprandial hyperglycemia, hyperlipidemia, and weight loss, probably through the modulation of the hepatic adiponectin and FXR pathways.     

Inositol and Non-Alcoholic Fatty Liver Disease: A Systematic Review on Deficiencies and Supplementation

Liver lipid accumulation is a hallmark of non-alcoholic fatty liver disease (NAFLD), broadly associated with insulin resistance. Inositols (INS) are ubiquitous polyols implied in many physiological functions. They are produced endogenously, are present in many foods and in dietary supplements. Alterations in INS metabolism seems to play a role in diseases involving insulin resistance such as diabetes and polycystic ovary syndrome. Given its role in other metabolic syndromes, the hypothesis of an INS role as a supplement in NAFLD is intriguing. We performed a systematic review of the literature to find preclinical and clinical evidence of INS supplementation efficacy in NAFLD patients. We retrieved 10 studies on animal models assessing Myoinosiol or Pinitol deficiency or supplementation and one human randomized controlled trial (RCT). Overall, INS deficiency was associated with increased fatty liver in animals. Conversely, INS supplementation in animal models of fatty liver reduced hepatic triglycerides and cholesterol accumulation and maintained a normal ultrastructural liver histopathology. In the one included RCT, Pinitol supplementation obtained similar results. Pinitol significantly reduced liver fat, post-prandial triglycerides, AST levels, lipid peroxidation increasing glutathione peroxidase activity. These results, despite being limited, indicate the need for further evaluation of INS in NAFLD in larger clinical trials.     

Mediterranean diet and nonalcoholic fatty liver disease: molecular mechanisms of protection

Nutritional habits modifications have shown an important impact in preventing and ameliorating metabolic alterations, such as nonalcoholic fatty liver disease (NAFLD). Among several dietary approaches that exert positive effects in NAFLD patients, the Mediterranean dietary pattern has shown notable benefits. This review explores the molecular mechanisms through which the Mediterranean diet would improve risk factors associated with metabolic syndrome and NAFLD. The main features of the Mediterranean diet acting on metabolism are represented by its whole-grain and low glycemic index cereal-based items, its fatty acid profile, and its content in phytochemical compounds. Carbohydrate-rich foods high in dietary fiber inducing low glycemic response are able to interact with glucose and insulin metabolism. Unsaturated fatty acids are associated with better hepatic lipid metabolism. Finally, phytochemical compounds, such as dietary polyphenols, are thought to ameliorate inflammation, which is considered one of the mechanisms through which NALFD may evolve into nonalcoholic steatohepatitis (NASH).     

Differential Effects of Dietary Components on Glucose Intolerance and Non-Alcoholic Steatohepatitis

Pharmacological treatment modalities for non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) are scarce, and discoveries are challenged by lack of predictive animal models adequately reflecting severe human disease stages and co-morbidities such as obesity and type 2 diabetes. To mimic human NAFLD/NASH etiology, many preclinical models rely on specific dietary components, though metabolism may differ considerably between species, potentially affecting outcomes and limiting comparability between studies. Consequently, understanding the physiological effects of dietary components is critical for high translational validity. This study investigated the effects of high fat, cholesterol, and carbohydrate sources on NASH development and metabolic outcomes in guinea pigs. Diet groups (n = 8/group) included: low-fat low-starch (LF-LSt), low-fat high-starch (LF-HSt), high-fat (HF) or HF with 4.2%, or 8.4% sugar water supplementation. The results showed that caloric compensation in HF animals supplied with sugar water led to reduced feed intake and a milder NASH phenotype compared to HF. The HF group displayed advanced NASH, weight gain and glucose intolerance compared to LF-LSt animals, but not LF-HSt, indicating an undesirable effect of starch in the control diet. Our findings support the HF guinea pig as a model of advanced NASH and highlights the importance in considering carbohydrate sources in preclinical studies of NAFLD.     

The role of diet and nutrient composition in nonalcoholic Fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the developed world. NAFLD is tightly linked to insulin resistance and considered to be the hepatic manifestation of the metabolic syndrome. The cornerstone of any treatment regimen for patients with NAFLD is lifestyle modification focused on weight loss, exercise, and improving insulin sensitivity. Here we review the literature and discuss the role of diet and nutrient composition in the management of NAFLD. Because there are currently no specific dietary guidelines for NAFLD, this review proposes a dietary framework for patients with NAFLD based on the available evidence and extrapolates from dietary guidelines aimed at reducing insulin resistance and cardiovascular risk.     

Nutritional Modulation of Non-Alcoholic Fatty Liver Disease and Insulin Resistance

Non-alcoholic fatty liver disease (NAFLD) covers a spectrum of disorders ranging from simple steatosis (non-alcoholic fatty liver, NAFL) to non-alcoholic steatohepatitis (NASH) and cirrhosis. NAFL increases the risk of liver fibrosis. If the liver is fatty due to causes of insulin resistance such as obesity and physical inactivity, it overproduces glucose and triglycerides leading to hyperinsulinemia and a low high-density lipoprotein (HDL) cholesterol concentration. The latter features predispose to type 2 diabetes and cardiovascular disease (CVD). Understanding the impact of nutritional modulation of liver fat content and insulin resistance is therefore of interest for prevention and treatment of NAFLD. Hypocaloric, especially low carbohydrate ketogenic diets rapidly decrease liver fat content and associated metabolic abnormalities. However, any type of caloric restriction seems effective long-term. Isocaloric diets containing 16%–23% fat and 57%–65% carbohydrate lower liver fat compared to diets with 43%–55% fat and 27%–38% carbohydrate. Diets rich in saturated (SFA) as compared to monounsaturated (MUFA) or polyunsaturated (PUFA) fatty acids appear particularly harmful as they increase both liver fat and insulin resistance. Overfeeding either saturated fat or carbohydrate increases liver fat content. Vitamin E supplementation decreases liver fat content as well as fibrosis but has no effect on features of insulin resistance.     

Epigenetic Mechanisms Underlying the Link between Non-Alcoholic Fatty Liver Diseases and Nutrition

Non-alcoholic fatty liver disease (NAFLD) is defined as a pathologic accumulation of fat in the form of triglycerides (TG) in the liver (steatosis) that is not caused by alcohol. A subgroup of NAFLD patients shows liver cell injury and inflammation coupled with the excessive fat accumulation (steatohepatitis), which is referred to as non-alcoholic steatohepatitis (NASH). Patients with NASH may develop cirrhosis and hepatocellular carcinoma (HCC). NAFLD shares the key features of metabolic syndrome including obesity, hyperlipidemia, hypertension, and insulin resistance. The pathogenesis of NAFLD is multi-factorial, however the oxidative stress seems to plays a major role in the development and progression of the disease. The emerging field of epigenetics provides a new perspective on the pathogenesis of NAFLD. Epigenetics is an inheritable but reversible phenomenon that affects gene expression without altering the DNA sequence and refers to DNA methylation, histone modifications and microRNAs. Epigenetic manipulation through metabolic pathways such as one-carbon metabolism has been proposed as a promising approach to retard the progression of NAFLD. Investigating the epigenetic modifiers in NAFLD may also lead to the development of preventive or therapeutic strategies for NASH-associated complications.     

Nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is a spectrum of disorders that encompasses simple hepatic steatosis and the more serious nonalcoholic steatohepatitis (NASH) that can progress to cirrhosis. Although the prevalence of NAFLD in childhood is not clear, it is apparently more common than originally thought. The major association with NAFLD is obesity, and as the prevalence of obesity in childhood and adolescence increases, fatty liver is recognized with greater frequency. Although the factors associated with progression of liver disease have not been determined fully, the pathogenesis of NASH is a "two hit" process that includes disturbed lipid homeostasis, resistance to the effects of insulin and subsequent hyperinsulinemia, and local toxic effects of triglyceride on hepatocytes. Treatment options are currently limited.     

Dietary Omega-3 Fatty Acid Deficiency and High Fructose intake in the Development of Metabolic Syndrome Brain,Metabolic Abnormalities,and Non-Alcoholic Fatty Liver Disease

Western diets are characterized by both dietary omega-3 fatty acid deficiency and increased fructose intake. The latter found in high amounts in added sugars such as sucrose and high fructose corn syrup (HFCS). Both a low intake of omega-3 fatty acids or a high fructose intake contribute to metabolic syndrome, liver steatosis or non-alcoholic fatty liver disease (NAFLD), promote brain insulin resistance, and increase the vulnerability to cognitive dysfunction. Insulin resistance is the core perturbation of metabolic syndrome. Multiple cognitive domains are affected by metabolic syndrome in adults and in obese adolescents, with volume losses in the hippocampus and frontal lobe, affecting executive function. Fish oil supplementation maintains proper insulin signaling in the brain, ameliorates NAFLD and decreases the risk to metabolic syndrome suggesting that adequate levels of omega-3 fatty acids in the diet can cope with the metabolic challenges imposed by high fructose intake in Western diets which is of major public health importance. This review presents the current status of the mechanisms involved in the development of the metabolic syndrome, brain insulin resistance, and NAFLD a most promising area of research in Nutrition for the prevention of these conditions, chronic diseases, and improvement of Public Health.     

Nonalcoholic fatty liver disease: pathogenesis and the role of antioxidants

Nonalcoholic fatty liver disease (NAFLD) includes a wide spectrum of liver injury ranging from simple steatosis to steatohepatitis, fibrosis, and cirrhosis. Whereas simple steatosis has a benign clinical course, steatohepatitis is a recognized cause of progressive liver fibrosis and can develop into cirrhosis. NAFLD and nonalcoholic steatohepatitis (NASH) are the two most common chronic liver diseases in United States general population with a prevalence of 20% and 3%, respectively. Hepatic steatosis is frequently associated with obesity, type 2 diabetes, and hyperlipidemia with insulin resistance as a key pathogenic factor. A two-hit theory best describes the progression from simple steatosis to NASH, fibrosis, or cirrhosis. These two hits consist of the accumulation of excessive hepatic fat primarily owing to insulin resistance, and oxidative stress owing to reactive oxygen species (ROS). Mitochondria are the major cellular source of ROS in cases of NASH. Currently, treatment is focused on modifying risk factors such as obesity, diabetes mellitus, and hyperlipidemia. Antioxidants such as vitamin E, N-acetylcysteine, betaine, and others may be beneficial in the treatment of NASH.     

Resveratrol supplementation improves inflammatory biomarkers in patients with nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world. Resveratrol is a polyphenolic compound with antioxidant capacity that shows beneficial effects on down-regulation of inflammatory mediators and metabolic disorders. We hypothesized that supplementation with resveratrol can further improve the efficacy of lifestyle modifications in the management of NAFLD. In this randomized, double-blinded, controlled clinical trial, 50 NAFLD patients were supplemented with either a 500-mg resveratrol capsule or a placebo capsule for 12 weeks. Both groups were advised to follow an energy-balanced diet and received physical activity recommendations. Serum liver enzymes, inflammatory markers, hepatic steatosis and fibrosis, dietary intake, anthropometric measurements, and physical activity were assessed at both baseline and the end of the study. In both groups, anthropometric measurements (weight, body mass index, waist circumference), liver enzymes, and steatosis grade improved (P < 005). Resveratrol supplementation was associated with a significant reduction in liver enzyme alanine aminotransferase, inflammatory cytokines, nuclear factor κB activity, serum cytokeratin-18, and hepatic steatosis grade, as compared with placebo supplementation (P < .05). For the treatment of NAFLD, our results showed that 12 weeks of supplementation of 500 mg resveratrol, along with lifestyle modification, is superior to lifestyle modification alone. This is at least partially due to the attenuation of inflammatory markers and hepatocellular apoptosis. More studies are needed to confirm and increase the clinical application of the present results.     

Effect of vitamin E supplementation on aminotransferase levels in patients with NAFLD,NASH, and CHC: Results from a meta-analysis

ObjectiveThe antioxidant vitamin E has been extensively employed to treat chronic liver diseases. The aim of this study was to assess the effect of vitamin E supplementation in lowering alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in patients with nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), and chronic hepatitis C (CHC).MethodsWe searched all publications in PubMed, Web of Science, and Cochrane Library databases up to June 2013. In total, eight articles met the eligibility criteria, among which, two studies about NAFLD, four studies about NASH, and three studies about CHC, were identified and included in the meta-analysis.ResultsAccording to standardized mean difference and 95% confidence interval, 12.19 (−4.08 to 28.46) for ALT and 6.84 (−3.18 to 16.86) for AST in patients with NAFLD, 4.54 (1.62–7.46) for ALT and 3.55 (1.39–5.71) for AST in patients with NASH, and 0.61 (0.20–1.02) for ALT and 0.68 (0.07–1.29) for AST in patients with CHC, vitamin E supplementation could optimize ALT and AST levels in patients with NASH and CHC, although it was not statistically significantly associated with reduced ALT and AST levels in patients with NAFLD.ConclusionTo summarize, the evidence currently available supported the theory that vitamin E supplementation can optimize aminotransferase levels for patients with NAFLD, NASH, and CHC, and more well-designed, large-scale clinical trials are encouraged to examine the therapeutic effect of vitamin E for these disorders.     

Dietary Fructose Reduction Improves Markers of Cardiovascular Disease Risk in Hispanic-American Adolescents with NAFLD

Nonalcoholic fatty liver disease (NAFLD) is now thought to be the most common liver disease worldwide. Cardiovascular complications are a leading cause of mortality in NAFLD. Fructose, a common nutrient in the westernized diet, has been reported to be associated with increased cardiovascular risk, but its impact on adolescents with NAFLD is not well understood. We designed a 4-week randomized, controlled, double-blinded beverage intervention study. Twenty-four overweight Hispanic-American adolescents who had hepatic fat >8% on imaging and who were regular consumers of sweet beverages were enrolled and randomized to calorie-matched study-provided fructose only or glucose only beverages. After 4 weeks, there was no significant change in hepatic fat or body weight in either group. In the glucose beverage group there was significantly improved adipose insulin sensitivity, high sensitivity C-reactive protein (hs-CRP), and low-density lipoprotein (LDL) oxidation. These findings demonstrate that reduction of fructose improves several important factors related to cardiovascular disease despite a lack of measurable improvement in hepatic steatosis. Reducing dietary fructose may be an effective intervention to blunt atherosclerosis progression among NAFLD patients and should be evaluated in longer term clinical trials.     

Metabolic syndrome in childhood from impaired carbohydrate metabolism to nonalcoholic fatty liver disease

Compelling evidence supports the concept that nonalcoholic fatty liver disease (NAFLD) represents the hepatic component of metabolic syndrome (MetS). Intrahepatic fat seems to predict more strongly than does visceral adiposity an individual's cardiovascular risk and the likelihood that metabolic abnormalities are present in youth. Young individuals with fatty liver are more insulin resistant and present with a higher prevalence of metabolic abnormalities than do individuals without intrahepatic fat accumulation. They also present with a certain endothelial dysfunction and greater carotid intima-media thickness. Conversely, youth with MetS seem to have an increased risk of developing liver inflammation, a condition termed nonalcoholic steatohepatitis (NASH), and fibrosis. In the context of MetS, the liver is central in that it can drive both hepatic and systemic insulin resistance, trigger low-grade inflammation, and promote atherogenic processes. In the context of MetS, NAFLD and altered carbohydrate metabolism track from childhood to adulthood. Thus, prevention, recognition, and effective treatment of these two abnormalities may limit the burden of morbidity and mortality associated with obesity and may delay onset of cardiovascular disease in early adulthood. The present review aims at systematically presenting evidence of the critical interplay of fatty liver and altered glucose metabolism in youth. It attempts to provide pathogenetic explanations for such an association and the rationale for its treatment, with particular regard to nutritional interventions. Key teaching points: Overweight and obese youth should be screened for fatty liver disease once after puberty by liver function tests and ultrasonography. Screening for fatty liver should be accurately performed in young patients with features of metabolic syndrome. Obese patients with fatty liver are at increased risk for altered glucose metabolism, thus they should undergo an oral glucose tolerance test. A nutritional and behavioral intervention aimed at achieving a permanent change of the lifestyle in patients and their parents is recommended.     

Flaxseed supplementation in non-alcoholic fatty liver disease: a pilot randomized,open labeled,controlled study

A two-arm randomized open labeled controlled clinical trial was conducted on 50 patients with non-alcoholic fatty liver disease (NAFLD). Participants were assigned to take either a lifestyle modification (LM), or LM?+30?g/day brown milled flaxseed for 12 weeks. At the end of the study, body weight, liver enzymes, insulin resistance and hepatic fibrosis and steatosis decreased significantly in both groups (pp?Pp p?p?=?0.013] and steatosis score [?47 compared with ?15.45?dB/m; p =?0.022]. In conclusion, flaxseed supplementation plus lifestyle modification is more effective than lifestyle modification alone for NAFLD management.     

Non-Alcoholic Fatty Liver Disease (NAFLD) and Its Connection with Insulin Resistance,Dyslipidemia, Atherosclerosis and Coronary Heart Disease

Non-alcoholic fatty liver disease is marked by hepatic fat accumulation not due to alcohol abuse. Several studies have demonstrated that NAFLD is associated with insulin resistance leading to a resistance in the antilipolytic effect of insulin in the adipose tissue with an increase of free fatty acids (FFAs). The increase of FFAs induces mitochondrial dysfunction and development of lipotoxicity. Moreover, in subjects with NAFLD, ectopic fat also accumulates as cardiac and pancreatic fat. In this review we analyzed the mechanisms that relate NAFLD with metabolic syndrome and dyslipidemia and its association with the development and progression of cardiovascular disease.