Nonalcoholic fatty liver disease and the metabolic syndrome

PURPOSE OF REVIEW: Clinical, epidemiological and biochemical data strongly support the concept that nonalcoholic fatty liver disease is the hepatic manifestation of the metabolic syndrome. Insulin resistance is the common factor connecting obesity, diabetes, hypertension and dyslipidemia with fatty liver and the progression of hepatic disease to steatohepatitis, fibrosis, cirrhosis and hepatocellular carcinoma. RECENT FINDINGS: The association of nonalcoholic fatty liver disease with the features of the metabolic syndrome has been confirmed in several epidemiological studies. The diagnostic and clinical significance of raised liver enzymes has been questioned; advanced hepatic disease may also be present in individuals with ultrasonographically detected steatosis and normal aminotransferase levels. The role of adipokines (leptin, adiponectin) and cytokines (tumor necrosis factor-alpha, interleukin-6, transforming growth factor-beta) in disease progression is probably pivotal, mediated by oxidative stress. The importance of iron accumulation in this process has not been confirmed. Treatments aimed at weight loss remain a primary option; among pharmacological interventions, insulin sensitizers (glitazones and metformin) have confirmed beneficial effects on both biochemical and histological data, but new treatments are on the horizon. SUMMARY: Nonalcoholic fatty liver disease prevalence in Western countries is high and there is a trend towards a further increase, with millions of people at risk of advanced liver disease. The epidemiological evidence, the lifestyle origin of the disease and the cost of pharmacotherapy make prevention a primary goal, and will contribute to making behavior therapy the background treatment. We need specific programs and carefully controlled, randomized studies to tackle simultaneously all the components of the metabolic syndrome.     

Nonalcoholic fatty liver disease in severely obese adolescent and adult patients

Objectives:

Nonalcoholic fatty liver disease (NAFLD) is increasingly an indication for liver transplantation in adults. While severe obesity (SO, BMI ≥40 kg m^?2) in adults is long standing, it is recent in duration in adolescents. With adolescent obesity on the rise, NAFLD is becoming the most frequent liver disease in adolescents. The hypothesis that SO adolescents and adults have different severity of NAFLD because of longer duration of obesity in SO adults was tested.

Design and Methods:

Preoperative clinical data, NAFLD activity and NASH (Nonalcoholic steatohepatitis) scores from intraoperative liver biopsies were extracted from a prospective database of consecutively operated SO adolescents and adults (n = 24 each). Fasting preoperative serum inflammatory mediators were evaluated by ELISA.

Results:

Other than age, baseline BMI, ethnicity and gender distribution, the incidence and extent of dyslipidemia, hypertension, and metabolic syndrome were comparable between groups. Histologic scores for steatosis and inflammation were similar. Adolescents have significantly higher NASH incidence, hepatocyte injury scores and fibrosis. This was associated with higher serum C‐reactive protein and sCD14 levels.

Conclusion:

For comparable BMI and metabolic profile, SO adolescents have more advanced liver damage, more severe systemic inflammation, suggesting differences in NAFLD etiologies and more aggressive disease progression in the young obese population.

     

Nonalcoholic fatty liver disease: one entity,multiple impacts on liver health

Nonalcoholic fatty liver disease (NAFLD) is very prevalent and now considered the most common cause of chronic liver disease. Staging the severity of liver damage is very important because the prognosis of NAFLD is highly variable. The long-term prognosis of patients with NAFLD remains incompletely elucidated. Even though the annual fibrosis progression rate is significantly higher in patients with nonalcoholic hepatitis (NASH), both types of NAFLD (nonalcoholic fatty liver and nonalcoholic steatohepatitis) can lead to fibrosis. The risk for progressive liver damage and poor outcomes is assessed by staging the severity of liver injury and liver fibrosis. Algorithms (scores) that incorporate various standard clinical and laboratory parameters alongside imaging-based approaches that assess liver stiffness are helpful in predicting advanced fibrosis.     

Nonalcoholic fatty liver disease: predisposing factors and the role of nutrition

More than 20% of Americans have nonalcoholic fatty liver disease (NAFLD), and this is, by far, the leading cause of abnormal liver enzymes in the United States. Nonalcoholic steatohepatitis (NASH), a more serious form of NAFLD, can proceed to cirrhosis and even hepatocellular carcinoma. These liver diseases represent the hepatic component of the metabolic syndrome, and this spectrum of liver disease represents a major health problem both in the United States and worldwide. Hepatic steatosis is closely linked to nutrition, including obesity, possibly high-fructose corn syrup consumption and consumption of certain types of fats. There are a variety of second insults or "hits" that appear to transform simple steatosis into NASH, with some of these second hits including certain proinflammatory cytokines, oxidative stress and possibly industrial toxins. In certain underdeveloped countries, it appears likely that industrial toxins play a role in NASH, and there is increasing interest in the potential interaction of industrial toxins and nutrients. Moreover, optimal therapy for NAFLD appears to include lifestyle modification with exercise, diet and weight loss. Certain nutrients may also be of benefit. Important areas for future research are the effect(s) of nutritional supplements on NAFLD/NASH and the effects of industrial toxins.     

中医药治疗非酒精性脂肪性肝病的优势与展望

目前非酒精性脂肪性肝病的西医治疗手段与不断升高的发病率呈不相吻合的趋势。在临床治疗中,中医药占重要一席之地。作者认为,中医药治疗非酒精性脂肪性肝病的主要优势点在于：1）临床运用广泛且具疗效;2）中药多途径的治疗效应与疾病的复杂机理相对应;3）抑制炎症、保肝降酶效应显著。并在如何开展临床研究;从调节肠道菌群、抗肝纤维化、以及中药组分复方方面开展基础研究提出了设想和展望。     

Nonalcoholic fatty liver disease: Update on pathogenesis,diagnosis, treatment and the role of S-adenosylmethionine

Nonalcoholic fatty liver disease (NAFLD) is currently the most common liver disease worldwide affecting over one-third of the population in the U.S. It has been associated with obesity, type 2 diabetes, hyperlipidemia, and insulin resistance and is initiated by the accumulation of triglycerides in hepatocytes. Isolated hepatic steatosis (IHS) remains a benign process, while a subset develops superimposed inflammatory activity and progression to nonalcoholic steatohepatitis (NASH) with or without fibrosis. However, the molecular mechanisms underlying NAFLD progression are not completely understood. Liver biopsy is still required to differentiate IHS from NASH as easily accessible noninvasive biomarkers are lacking. In terms of treatments for NASH, pioglitazone, vitamin E, and obeticholic acid have shown some benefit. All of these agents have potential complications associated with long-term use. Nowadays, a complex hypothesis suggests that multiple parallel hits are involved in NASH development. However, the ‘key switch’ between IHS and NASH remains to be discovered. We have recently shown that knocking out enzymes involved in S-adenosylmethionine (SAMe) metabolism, the main biological methyl donor in humans that is abundant in the liver, will lead to NASH development in mice. This could be due to the fact that a normal SAMe level is required to establish the proper ratio of phosphatidylethanolamine to phosphatidylcholine that has been found to be important in NAFLD progression. New data from humans have also suggested that these enzymes play a role in the pathogenesis of NAFLD and that some of SAMe cycle metabolites may serve as noninvasive biomarkers of NASH. In this review, we discuss the evidence of the role of SAMe in animal models and humans with NAFLD and how studying this area may lead to the discovery of new noninvasive biomarkers and possibly personalized treatment for NASH.     

Nonalcoholic fatty liver disease: A main driver of insulin resistance or a dangerous liaison?

Insulin resistance is one of the key components of the metabolic syndrome and it eventually leads to the development of type 2 diabetes, making it one of the biggest medical problems of modern society. Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are tightly associated with insulin resistance. While it is fairly clear that insulin resistance causes hepatic steatosis, it is not known if NAFLD causes insulin resistance. Hepatic inflammation and lipid accumulation are believed to be the main drivers of hepatic insulin resistance in NAFLD. Here we give an overview of the evidence linking hepatic lipid accumulation to the development of insulin resistance, including the accumulation of triacylglycerol and lipid metabolites, such as diacylglycerol and ceramides. In particular, we discuss the role of obesity in this relation by reviewing the current evidence in terms of the reported changes in body weight and/or adipose tissue mass. We further discuss whether the activation or inhibition of inflammatory pathways, Kupffer cells and other immune cells influences the development of insulin resistance. We show that, in contrast to what is commonly believed, neither hepatic steatosis nor hepatic inflammation is sufficient to cause insulin resistance. Many studies show that obesity cannot be ignored as an underlying factor in this relationship and NAFLD is therefore less likely to be one of the main drivers of insulin resistance.     

Nonalcoholic fatty liver disease is associated with an altered hepatocyte microRNA profile in LDL receptor knockout mice

MicroRNAs modulate processes associated with cell cycle control and differentiation. Here we explored the potential of microRNAs in the modulation of hepatic lipid metabolism and the development of nonalcoholic fatty liver disease.MicroRNA profiles of hepatocytes from low-density lipoprotein (LDL) receptor knockout mice fed a chow diet or a hypertriglyceridemia/fatty liver-inducing Western-type diet (WTD) were determined using quantitative real-time polymerase chain reaction. Ninety-seven of 103 microRNAs measured were expressed by hepatocytes and low variability between hepatocyte pools was observed. Feeding WTD coincided with a marked fivefold decrease in the relative expression level of miR-216 (P<.05) and miR-302a (P<.01). Interestingly, an increased hepatic miR-216 expression was detected in response to fasting. MicroRNA/biological function linkage analysis suggested that the change in hepatocyte microRNA profiles in response to high dietary lipid levels is associated with changes in cell cycle control and proliferation. In accordance with a diminished miR-302a expression on the WTD, hepatocyte mRNA expression levels of miR-302a target genes ABCA1 and in particular ELOVL6 were increased in response to WTD (twofold to ninefold). This suggests a role for miR-302a in hepatic cholesterol, fatty acid and glucose metabolism.In conclusion, we have shown that fatty liver development in LDL receptor knockout mice is associated with a significant change in the hepatocyte microRNA profile, i.e., a fivefold decrease in miR-216 and miR-302a expression. Based upon our comparative gene and microRNA expression studies it is anticipated that miR-302a may prove to be a valuable therapeutic target in the regulation of hepatic fatty acid utilization and insulin resistance.     

Nonalcoholic fatty liver disease impairs the cytochrome P-450-dependent metabolism of α-tocopherol (vitamin E)

This study aims to investigate in in vivo and in vitro models of nonalcoholic fatty liver disease (NAFLD) the enzymatic metabolism of α-tocopherol (vitamin E) and its relationship to vitamin E-responsive genes with key role in the lipid metabolism and detoxification of the liver. The experimental models included mice fed a high-fat diet combined or not with fructose (HFD+F) and HepG2 human hepatocarcinoma cells treated with the lipogenic agents palmitate, oleate or fructose. CYP4F2 protein, a cytochrome P-450 isoform with proposed α-tocopherol ω-hydroxylase activity, decreased in HFD and even more in HFD+F mice liver; this finding was associated with increased hepatic levels of α-tocopherol and decreased formation of the corresponding long-chain metabolites α-13-hydroxy and α-13-carboxy chromanols. A decreased expression was also observed for PPAR-γ and SREBP-1 proteins, two vitamin E-responsive genes with key role in lipid metabolism and CYP4F2 gene regulation. A transient activation of CYP4F2 gene followed by a repression response was observed in HepG2 cells during the exposure to increasing levels of the lipogenic and cytotoxic agent palmitic acid; such gene repression effect was further exacerbated by the co-treatment with oleic acid and α-tocopherol and was also observed for PPAR-γ and the SREBP isoforms 1 and 2. Such gene response was associated with increased uptake and ω-hydroxylation of α-tocopherol, which suggests a minor role of CYP4F2 in the enzymatic metabolism of vitamin E in HepG2 cells. In conclusion, the liver metabolism and gene response of α-tocopherol are impaired in experimental NAFLD.     

Diet and nonalcoholic fatty liver disease

PURPOSE OF REVIEW: Nonalcoholic fatty liver disease is a common and serious form of chronic liver disease. It is characterized by lipid accumulation in the liver and is associated with all aspects - and may even be an initiating factor - of the metabolic syndrome. The purpose of this review is to summarize recent findings from human studies on dietary effects on hepatic lipid accumulation. RECENT FINDINGS: Epidemiological studies did not give consistent results. From intervention studies there is evidence to support a role for weight loss. Some studies have also suggested that decreasing total fat intake and increasing the intake of fish oils may be beneficial in the treatment of nonalcoholic steatohepatitis. SUMMARY: Only a few studies have focused on dietary effects on hepatic lipid accumulation. So far, there is only evidence to support a role for weight loss. Decreasing total fat intake and increasing the intake of fish oils may also be beneficial, but these conclusions are based on a limited number of studies, which sometimes lacked a proper control group. Also, other nutrients have not been studied in detail. Therefore, there is an urgent need for evidence-based dietary guidelines to prevent or even to treat nonalcoholic fatty liver disease.     

Dietary protein and fatty acid composition of liver lipids in the rat

In order to compare the effects of different sources of dietary protein on the fatty acid composition of phosphatidylcholines (PC), phosphatidylethanolamines (PE), phosphatidylinositols (PI), cholesteryl esters and triacylglycerols, male rats were fed for a 4-week period on cholesterol-free, or cholesterol-containing, diets based on casein, or soybean protein and olive oil. The most conspicuous difference observed was the occurrence of significantly higher levels of 5,8,11-eicosatrienoic acid, 20:3 (n - 9), in the different lipid classes of casein-fed, compared with soybean protein-fed, animals. In the PI fraction of livers from the groups of rats fed casein diet, this fatty acid amounted to between 9.9 and 13.3% by weight of the total fatty acids. Phospholipids from livers of casein-fed rats contained increased levels of oleic acid, 18:1 (n - 9) (in PC and PE) and reduced levels of stearic acid (18:0). Moreover, in this group of rats PI contained a reduced level of arachidonic acid, 20:4 (n - 6). A casein-related decrease in the linoleic acid, 18:2 (n - 6), content of PC and PE was observed only in the rats fed on cholesterol-free diet. Effects on the fatty acid composition were also observed in the triacyglycerol and cholesteryl ester fractions, in which the rats fed casein diet showed higher levels of palmitoleic acid, 16:1 (n - 7) (cholesterol-supplemented diet) and lower values for linoleic acid, than the soybean protein-fed rats.     

Hepatic triglyceride synthesis and nonalcoholic fatty liver disease

PURPOSE OF REVIEW: Nonalcoholic fatty liver disease is a spectrum of diseases ranging from simple steatosis to cirrhosis. The hallmark of nonalcoholic fatty liver disease is hepatocyte accumulation of triglycerides. We will review the role of triglyceride synthesis in nonalcoholic fatty liver disease progression and summarize recent findings about triglyceride synthesis inhibition and prevention of progressive disease. RECENT FINDINGS: Attempts to inhibit triglyceride synthesis in animal models have resulted in improvement in hepatic steatosis. Studies in animal models of nonalcoholic fatty liver disease demonstrate that inhibition of acyl-coenzyme A:diacylglycerol acyltransferase, the enzyme that catalyzes the final step in triglyceride synthesis, results in improvement in hepatic steatosis and insulin sensitivity. We recently confirmed that hepatic specific inhibition of acyl-coenzyme A:diacylglycerol acyltransferase with antisense oligonucleotides improves hepatic steatosis in obese, diabetic mice but, unexpectedly, exacerbated injury and fibrosis in that model of progressive nonalcoholic fatty liver disease. When hepatocyte triglyceride synthesis was inhibited, free fatty acids accumulated in the liver, leading to induction of fatty acid oxidizing systems that increased hepatic oxidative stress and liver damage. These findings suggest that the ability to synthesize triglycerides may, in fact, be protective in obesity. SUMMARY: Nonalcoholic fatty liver disease is strongly associated with obesity and peripheral insulin resistance. Peripheral insulin resistance increases lipolysis in adipose depots, promoting increased free fatty acid delivery to the liver. In states of energy excess, such as obesity, the latter normally triggers hepatic triglyceride synthesis. When hepatic triglyceride synthesis is unable to accommodate increased hepatocyte free fatty acid accumulation, however, lipotoxicity results. Thus, rather than being hepatotoxic, liver triglyceride accumulation is actually hepato-protective in obese, insulin-resistant individuals.     

In vivo grading of lipids in fatty liver by near-infrared autofluorescence and reflectance

The prevalence of nonalcoholic fatty liver (NAFLD) is rapidly increasing worldwide. When untreated, it may lead to complications such as liver cirrhosis or hepatocarcinoma. The diagnosis of NAFLD is usually obtained by ultrasonography, a technique that can underestimate its prevalence. For this reason, physicians aspire for an accurate, cost-effective, and noninvasive method to determine both the presence and the specific stage of the NAFLD. In this paper, we report an integrated approach for the quantitative estimation of the density of triglycerides in the liver based on the use of autofluorescence and reflectance signals generated by the abdomen of obese C57BL6/J mice. Singular value decomposition is applied to the generated spectra and its corresponding regression model provided a determination coefficient of 0.99 and a root mean square error of 240 mg/dl. This, in turn, enabled the quantitative imaging of triglycerides density in the livers of mice under in vivo conditions.